Discussion
In this study of older adults with T1D, recurrent DKA was associated with poorer cognition. Recurrent DKA was associated with significantly lower scores on global cognitive function, in a range of models with varying levels of adjustment, including presence of microvascular complications and recent exposure to severe hypoglycemia. The most robust association was observed between DKA and executive function/psychomotor speed. Those with recurrent DKA were also 3.3 times more likely to have the lowest cognitive function (defined as 1.5 SD below the population mean) on the executive function/psychomotor speed domain.
To our knowledge, this is the first study to investigate the association between lifetime exposure to DKA and cognitive function in older adults with T1D. Our results complement previous studies in children and adolescents with T1D that have reported an association between DKA and cognitive dysfunction (specifically with memory domains),13 14 16 30 31 and a recent study reporting an increased risk of dementia associated with exposure to DKA in those with type 2 diabetes.32 It also supports findings from a small pilot study (n=38) among middle-aged adults with T1D that found evidence of a gradient association between number of DKA episodes and changes in cognitive function, brain structure and metabolite concentration.33 However, it was previously unknown if lifetime DKA exposure would be associated with cognitive function in older adulthood.
The pathways through which DKA influences cognitive function in the short term have been previously characterized in children and adolescents with T1D. DKA is associated with acute changes in the brain, including neuronal dysfunction (evidenced by reduced N-acetylaspartate/creatinine ratio)13 ,34 and cerebral edema.35 36 One study examined the neurologic impact of recurrent DKA events in T1D and found that, while neuronal function returned to baseline (pre-DKA) levels following one DKA event, after the second DKA event, neuronal function recovered partially, but did not return to prebaseline levels; they conclude that this suggests that recurrent DKA may result in progressive neurologic decline.34 Altered brain growth has been observed up to 4 years after the DKA occurrence in children with T1D.14 37 DKA has been associated with reduced cerebral blood flow, brain cell swelling, and alterations in hippocampal function in animal model studies.38 39 Taken together, these prior studies provide support that cognitive impairment due to DKA may stem from subtle cerebral injury resulting from neuronal dysfunction, reduced cerebral blood flow and/or subclinical cerebral edema.
Of note is the lack of an association between cognition and DKA in those with a single DKA event in their lifetime. Among those with T1D, as many as 58% of individuals have DKA at the time of initial diagnosis with T1D.1–3 Though data are limited, estimates suggest that approximately 20% of patients who experience DKA will go on to experience recurrent DKA40; in the present study 34% of participants who reported any lifetime exposure to DKA went on to experience recurrent DKA. Despite overall improvements in DKA-related mortality, recurrent DKA is still associated with significantly higher mortality rates and early death.40 41 It is possible that recurrent DKA has a cumulative negative impact on both mortality and brain health that single DKA does not; this is an area for future study. It is also possible that the timing of the DKA occurrence during a person’s lifetime modifies its effect on cognitive function; for example, if DKA occurs when a person is young, during a time of critical neurodevelopment, the impact of DKA may be greater than if the DKA occurs later in life. This is another important area for further research.
Another notable finding from our study was the indication that the magnitude of the association between recurrent DKA and cognitive dysfunction was strongest among individuals with childhood-onset T1D (age of onset <7 years old). The magnitude of the associations between recurrent DKA and global cognitive scores and scores on the executive function/psychomotor speed domain was nearly three times greater in those with T1D onset <7 as compared with the overall sample. Prior studies have shown that cognitive dysfunction is greater among those with childhood-onset T1D,42 yet the few studies of T1D in older adults do not have many individuals with childhood onset.8 Indeed, in our study only 33 participants (4.6%) had T1D onset <7 years old. But, among this group, recurrent exposure to DKA was associated with highly significant deficits in cognition. Whether this is a reflection of actual increased risk of cognitive dysfunction resulting from DKA or a reflection of cognitive impairment leading to increased DKA is an area for future study.
This study has a number of strengths including the large sample of ageing patients with T1D, and the ability to adjust for age at diagnosis, duration of T1D, and presence of microvascular complications and severe hypoglycemia. Additionally, the comprehensive cognitive battery allows us to examine the association of DKA with cognition on specific cognitive domains and to show that DKA may affect them differentially. A key limitation of the study is that the exposure to DKA hospitalizations is self-reported and thus may be affected by recall bias. However, this might have been reduced by the focus on severe cases of DKA (those resulting in hospitalization) rather than more mild forms of DKA. A related limitation is that we are unable to ascertain the timing of the DKA occurrences. Participants self-reported DKA exposure over their lifetime but we did not collect data on the timing of these events. Additionally, because the data in this study are cross-sectional we were unable to determine the directionality of the association between DKA and cognitive function. Individuals with poorer cognitive function may have difficulties in managing diabetes self-care and, thus, may be more likely to experience DKA. Additionally, in the present study, we did not have access to HbA1c lab data, a measure which we have previously shown to be associated with dementia risk in older adults with T1D.9 Given our inability to adjust for HbA1c, it is possible that part of the association between cognitive function and DKA may actually be explained by differences in glycemic control. Finally, the participants with T1D in the SOLID study are majority White and well educated, which potentially limits the generalizability of our findings to other populations of older adults with T1D. Despite this limitation, the SOLID study is one of the largest cohort studies of older adults with T1D to date and is well poised to contribute to our understanding of the complex nature of ageing and cognition among individuals with T1D who have been living with this disease for an average of 40 years.
In light of our findings, it is important to underscore the fact that hospitalizations for DKA, particularly for recurrent DKA, are largely preventable. For example, in the UK, structured education programs and multipronged support programs that coordinate care have been shown to reduce DKA hospitalizations.43 44 In the USA, one such example is the Novel Interventions in Children’s Healthcare program which used targeted diabetes-specific text messages to engage youth with T1D and their caregivers; participation in the program resulted in lower rates of DKA.45 A recent commentary in Diabetes Care summarizes prevention programs for DKA and highlights the need for increased prevention efforts for this serious complication.46 Of note, however, we are not aware of any DKA prevention programs that are specifically targeted to older adults with T1D; any prevention efforts in this population would need to consider the complex inter-relationships between ageing, cognitive function, self-care, hypoglycemia and DKA to ensure that efforts targeted towards reducing DKA are effective and do not increase risk for other complications.
In summary, the incidence of both T1D and DKA is increasing. People with T1D are living longer and are at risk for ageing-related health risks such as dementia and cognitive decline. In this study, we identified recurrent DKA as a potential risk factor for poor cognitive function in older adults with T1D. Understanding the long-term impact of DKA on the brain is an important first step. Future studies should identify ways to decrease exposure to DKA in T1D, especially recurrent DKA exposure.