Is the presence and development of microvascular disease in type 1 diabetes related to changes in brain structure and cognitive function?

There is growing evidence that individuals with type 1 diabetes have mild
performance deficits in a range of neuropsychological tests compared to
non-diabetic controls, but the mechanisms underlying cognitive deterioration in
diabetes are poorly understood.
In the past decades, several studies have addressed the effects of recurrent
hypoglycemia on cognition. While retrospective studies in adult patients with
type 1 diabetes have demonstrated an association between a history of recurrent
severe hypoglycemia and a modest degree of cognitive impairment, two large
prospective studies did not find such an association. Reanalyses of the DCCT
findings confirmed this latter conclusion. Evidence for a damaging effect of
chronic hyperglycemia on brain function is now emerging. Hyperglycemia may lead
to accumulation of potentially toxic glucose metabolites, oxidative stress,
accelerated formation of advanced glycation end products and microvascular
changes in the brain, analogous to peripheral complications of diabetes.
The results of studies using Magnetic Resonance Imaging of the brain (MRI),
concerning the severity of cerebral atrophy and white matter lesions in
patients with type 1 diabetes, are inconsistent. Problems with study design,
including lack of appropriate controls, small sample sizes, and insensitive
rating methods, are likely to contribute to these apparent inconsistencies.
It is of great importance to determine whether the observed structural changes
in the brain are related to cognition and to assess whether these are
associated with disease variables such as chronic hyperglycemia, diabetes
duration and/or microvascular damage.

To answer the question if structural changes of the brain and impairments of
cognitive functioning in type 1 diabetes are related to the presence of
microvascular disease we will
· Compare brain structure (brain volume, white matter lesions) and study
cognition of type 1 diabetes patients and controls.
· Relate changes in structure and function in type 1 diabetes patients to the
progression of microvascular disease.
Besides standardised MRI techniques, we will apply additional, new techniques:
diffusion tensor imaging (DTI) and arterial spin labelling (ASL), to enhance
our understanding of the potential mechanisms underlying structural brain
damage in patients with type 1 diabetes.

The hypothesis will be tested cross-sectionally and longitudinally (after an
interval of four years) in healthy volunteers and type 1 diabetes patients with
and without sequelae of longstanding hyperglycemia (i.e. microvascular
complications: diabetic retinopathy as a marker of manifest microvascular
disease) and a diabetes duration of at least ten years. As indicators of
hyperglycemia: HbA1c in blood and Advanced Glycated End products in the
cerebrospinal fluid will be measured.

Risks for the participants are minimal: for the neuropsychological testing, we
will create the most ideal testing situation in which patients are able to
perform at their best. We will make sure that there are no distractions, that
there will be a non-threatening emotional climate, and we will protect all
participants from fatigue. For the ophthalmology examinations, we will use the
non-mydriatic Topcon camera. The pupils will require mydriatic eye drops.
Following the examination patients will use sunglasses and are not allowed to
drive their car.
Because of its non-invasiveness, the risks of the MRI are minimal. The insulin,
and in particular the glucose infusions needed for the hyperinsulinemic glucose
clamp may cause some local irritation and in rare cases thrombophlebitis.
Adequate rinse procedures with saline and careful insertion of the cannula can
prevent these adverse effects in most patients. Participants may suffer some
adverse effects of a single lumbar puncture.
Following the LP we will ask the patient to lie down for at least one hour, to
reduce the risk of headache.