Brain Changes Underlying Cognitive Dysfunction in Diabetes: What Can We Learn From MRI?


Diabetes is associated with cognitive dysfunction and an increased risk of dementia. This article addresses findings with brain MRI that may underlie cognitive dysfunction in diabetes. Studies in adults with type 1 diabetes show regional reductions in brain volume. In those with a diabetes onset in childhood, these volume reductions are likely to reflect the sum of changes that occur during brain development and changes that occur later in life due to exposure to diabetes-related factors. Type 2 diabetes is associated with global brain atrophy and an increased burden of small-vessel disease. These brain changes occur in the context of aging and often also in relation to an adverse vascular risk factor profile. Advanced imaging techniques detect microstructural lesions in the cerebral gray and white matter of patients with diabetes that affect structural and functional connectivity. Challenges are to further unravel the etiology of these cerebral complications by integrating findings from different imaging modalities and detailed clinical phenotyping and by linking structural MRI abnormalities to histology. A better understanding of the underlying mechanisms is necessary to establish interventions that will improve long-term cognitive outcomes for patients with type 1 and type 2 diabetes.


Alex’s Notes: Stemming off Tuesday’s article on the metabolic and inflammatory relationship between type-2 diabetes and Alzheimer’s disease, today I want to share with you an article that addresses another critically important part of our bodies: the brain. As discussed in Tuesday’s article, there is a clear association between cognitive decline and both type-1 (T1D) and type-2 diabetes (T2D). In order to prevent or counter-act this connection, we must develop an understanding of the causative mechanisms. Remember, correlation is important to suggest that there may be a link between two variables, but it doesn’t tell us definitively if there is or what the mechanisms behind it are. As such, the current article addresses brain changes that may underlie cognitive decline in diabetic adults, with a focus on brain volume and structural and functional connectivity through the use of MRI.

Studies comparing T1D and non-diabetic brains demonstrate modest reductions in brain volumes of the diabetic subjects, with one study showing an overall 7% reduction in grey matter. However, most studies only note regional differences, primarily in the frontal, posterior, and temporal cortex, and in subcortical gray matter. Importantly, smaller brain volumes are related not only to worse cognitive functioning, but also poor metabolic control reflected by chronic hyperglycemia and hyperglycemic events. Thus, it is no surprise that T2D has also consistently been associated with global brain atrophy comparable to about 3-5 years of normal aging. Some population-based studies have concluded that brain volume loss from T2D is up to three times the atrophy rate of normal aging. Given the importance of the hippocampus region of the brain in memory, and the associations between Alzheimer’s disease and diabetes, much interest has been in this area in particular. Indeed, hippocampal volumes are smaller in T2D subjects compared with non-diabetic subjects, but the degree of volume loss is comparable to the degree of total brain loss, meaning that the hippocampus is not more affected than other brain regions. On a final note about brain volume, smaller brains have also been associated with greater insulin resistance and longer diabetes duration, suggesting that long-term exposure to diabetes risk factors is especially harmful to the brain. Looking back at T1D, this is very problematic because T1D commonly has its onset in childhood when the brain is still developing, and studies in T1D children do show that alterations to brain volume are already detectable in adolescence. This may no longer even be unique to T1D with the increasing amount of fat and pre-diabetic youth in today’s age.

Another area of concern outside of volume changes is cerebral small vessel disease (SVD), which refers to pathological processes that affect the blood vessel feeding the brain. No surprise this would be detrimental to cognitive functioning; the brain needs blood! Fortunately, MRI markers of SVD don’t appear to be a key determinant of T1D associated cognitive decline. On the other hand, T2D is associated with an increased burden of SVD, and MRI markers of SVD are associated with cognitive dysfunction. However, the extent to which SVD contributes to this dysfunction is unknown.

Finally, we must consider the structural and functional impacts of diabetes on the brain. In T1D, more widespread tissue damage throughout the brain is prevalent, especially in the posterior regions, compared to non-diabetic controls, and the damage was associated with longer diabetes duration and reduced executive functioning. These findings are the same for those with T2D independent of age, sex, education, or SVD. These structural changes clearly impact connectivity of the brain regions as well. In fact, reduced functional connectivity has been observed between regions of the so-called default mode network, regions that are among the most highly connected in the brain. Indeed, impaired default mode network connectivity was related to reduced memory, executive functioning, and processing speed in older individuals free from Alzheimer’s disease.

Clearly diabetes is linked to abnormalities of the brain that likely play a role in diabetes-related cognitive decline. T1D abnormalities seem to manifest diffusely across the brain reflected by subtle changes to regional volume and connectivity, likely originating from the effects of childhood diabetes during brain development. T2D is surprisingly worse despite not occurring until the brain is fully developed. There is clean global atrophy and increased SVD. Unfortunately, children that are now being diagnosed with pre-diabetes or full blown T2D are probably getting the worst of both worlds.

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