Cognitive deficits associated with impaired awareness of hypoglycaemia in type 1 diabetes

Aims/hypothesis The aim of this study was to compare cognitive function in adults with type 1 diabetes who have impaired awareness of hypoglycaemia with those who have normal awareness of hypoglycaemia. A putative association was sought between cognitive test scores and a history of severe hypoglycaemia. Methods A total of 68 adults with type 1 diabetes were included: 33 had impaired and 35 had normal awareness of hypoglycaemia, as confirmed by formal testing. The groups were matched for age, sex and diabetes duration. Cognitive tests of verbal memory, object-location memory, pattern separation, executive function, working memory and processing speed were administered. Results Participants with impaired awareness of hypoglycaemia scored significantly lower on the verbal and object-location memory tests and on the pattern separation test (Cohen’s d −0.86 to −0.55 [95% CI −1.39, −0.05]). Participants with impaired awareness of hypoglycaemia had reduced planning ability task scores, although the difference was not statistically significant (Cohen’s d 0.57 [95% CI 0, 1.14]). Frequency of exposure to severe hypoglycaemia correlated with the number of cognitive tests that had not been performed according to instructions. Conclusions/interpretation Impaired awareness of hypoglycaemia was associated with diminished learning, memory and pattern separation. These cognitive tasks all depend on the hippocampus, which is vulnerable to neuroglycopenia. The findings suggest that hypoglycaemia contributes to the observed correlation between impaired awareness of hypoglycaemia and impaired cognition. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4233-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

locations of 18 coloured line drawings of various objects within a 6 x 6 grid in 90 seconds.
All objects are subsequently moved to the bottom of the screen. The participant is instructed to drag and drop the objects into their original places in the grid as a measure of immediate spatial recall. Performance is scored as the number of correctly placed objects.
Digit span backwards (working memory test): The participant is instructed to memorise a series of digits presented consecutively for 2 seconds each on the screen. After all digits in a trial have been presented, the participant is instructed to type the digits into a textbox in backward order using the keyboard, and when finished, click a button on the screen to continue to the next trial. The test consists of 18 trials, in which the number of digits to remember increases by one digit for every second trial starting with two digits in the first trial and ending with ten digits for the last trial. The test ends if a participant makes three consecutive erroneous responses. Performance is scored as the number of correct trials.
Tower test (assesses planning abilities, a part of executive functions): The participant is shown an image on the screen depicting the goal positions of three different coloured discs located on three pegs and instructed to move a set of discs around on three other pegs on the screen below this picture. The discs can only be moved by following certain rules. The first peg can only hold one disc, the second peg can hold two discs and the third peg can hold three discs at any time. Further, only the top disc of a peg can be moved. Failing to comply with these rules, results in an illegal move. The test consists of 15 trials in sets of three that requires a minimum of one, two, three, four or five moves in order to reach the goal position.
The test terminates automatically after 20 moves in one trial to prevent loss of motivation.
Performance is scored as total number of moves used to solve all trials and total number of illegal moves performed.
Coding (information processing speed test with an executive component): In this test the participant is presented with a stimuli key of numbers and geometrical symbols on the top of the screen. Below are rows containing a random presentation of the geometrical symbols and empty cells. The first empty cell is highlighted and the participant is instructed to type in the corresponding number and repeat this process as fast and accurately as possible in 90 seconds.
Performance is scored as the number of correct responses minus the number of erroneous responses.
Pattern separation (pattern separation abilities): In this test, the participant is presented with a series of images. For each image the participant is instructed to indicate whether the current image is identical to a previously presented image, similar to a previously presented image with a detail changed, or has never previously been presented in the image series. The test consists of 108 trials (images), with 32 first presentations, 16 same presentations (identical), 16 similar (lure) presentations, and 44 unrelated presentations (foils). The score is calculated as the difference between the rates of "Similar" responses given to the lure items minus the rate of "Similar" responses given to the foils, which corrects for response biases.
The test order was fixed in the following way: Verbal memory test (distraction and postdistraction recall), Digit span backwards, Tower test, Verbal memory test (delayed recall), Objects in grid, Pattern separation, and Coding.

Performance on the cognitive tests after excluding five participants with altered hypoglycaemia awareness status
The IAH group scored significantly lower than the NAH group on the Verbal memory delayed recall ( Grey bars, NAH.