Chronic complications of diabetes such as kidney and nerve damage or blindness and amputation are both well documented and well understood, with a plethora of research into prevention and management. However, brain health complications of diabetes are not as well understood, this according to Dr Catherine Dolan, clinical lecturer and senior registrar in psychiatry at Trinity College Dublin, who presented on the subject at the recent Diabetes Ireland Conference and Exhibition (DICE) in Croke Park, Dublin.

According to Dr Dolan, the three main brain health complications of diabetes are depression and other mental health disorders; cognitive impairment; and dementia.

“People with diabetes have an increased risk of mental health disorders, and while depression is the most common, anxiety disorders and bipolar also have a higher prevalence in people with diabetes,” she said.

People with type 1 diabetes have a three times higher prevalence of depression, while people with type 2 diabetes have twice the prevalence of depression than people without the condition. 

Dr Dolan focused on those with type 2 diabetes and the link with depression and follow-on comorbidities in her presentation at DICE 2017.

Bi-directional link

Dr Dolan explained that with the figures on prevalence documented, research is now looking into why this prevalence is so much higher in those with diabetes. She said that there is a bi-directional link, meaning that people who already have depression also run a 30% increased risk of developing type 2 diabetes and will be less motivated to engage in the complex care of the condition. Reasons for why people with depression run this higher risk of developing type 2 diabetes are most likely linked to lifestyle and obesity, she explained. 

“However, there are also shared common biological origins of both conditions,” she said.

“For example, inflammatory responses are raised in both conditions individually, and there is a disregulation in the HPA-axis (the hypothalamic-pituitary-adrenal axis) with increased glucocorticoid steroid circulating and increased inflammation having a direct effect on the brain.”

Regarding the connection between depression and diabetes, it appears that inflammation plays a major role, as does vascular damage, she said.

Furthermore, she explained that diabetes-related complications such as cerebrovascular disease can cause direct damage to the brain itself in areas like the frontal lobe, temporal lobe and the hippocampus, and this can impact on mood as well as memory.

Separating distress from depression

“Recent research has made apparent that the effort it takes to manage diabetes on a day-to-day basis can have a major impact on a person’s life and lead to increased distress,” said Dr Dolan.

“So diabetes distress is deemed to be separate to clinical depression itself and it’s very hard to tease the two apart with the current assessment methods we have, but we know that there is a significant difference between having stress in your life secondary to managing your diabetes versus a clinical depressive condition. However, both impact on the course of the disease.”

Dr Dolan made the point that comorbidity of these two conditions has a major impact on patients, carers and healthcare systems, as well as leading to worse diabetes management, morbidity and mortality.

Complications of depression

Dr Dolan said that a multitude of longitudinal studies has looked at why people with diabetes are at increased risk of depression and a lot of variables have been found. She mentioned that retinopathy is one variable that seems to increase the risk of depression in diabetes.

“Retinopathy comes out quite frequently in the literature as a variable that puts people with diabetes at a higher risk of depression and this puts more weight on the vascular theory of depression and diabetes. When microvascular damage is present as evidenced by a complication such as retinopathy, that puts a person at an increased risk of getting depression with their diabetes.”

Dr Dolan also highlighted that there is an increased risk of mortality in people with depression and diabetes compared to people with either condition alone.

Looking at the International Diabetes Federation (IDF) risk factors for diabetes, a lot of these risk factors are similar to those for depression: behavioural risk factors such as lack of exercise, unhealthy diet, being overweight; they represent a target for prevention of both diabetes and depression at a population level. 

Depression has also been found to be more difficult to treat in people with diabetes. “In people with diabetes, depression is more long-lasting, more likely to be recurrent and less responsive to antidepressant therapy,” said Dr Dolan.

She referred to a study on over 10,000 people by Katon et al in 2008,¹ which found that when compared to individuals with depression alone, the course of depression seemed to be much worse in people who also had diabetes.

“Another major risk in a person with diabetes and depression is that the risk of dementia is twice that of the risk in an individual with either condition alone,” she added.

“One hypothesis underlying the link between diabetes and depression is that each individual disorder causes increased inflammation, and so when the conditions are comorbid there is a synergistic impact on the inflammation. This increased inflammatory burden is thought to have a direct effect on an individual’s risk of developing dementia.” 

Recognising depression

“It’s very hard to recognise depression in patients with a chronic illness, because with depression there are certain clusters of symptoms; no one symptom is specific to depression and there is a lot of crossover between symptoms of a chronic illness and depression; poor sleep and low energy levels are both symptoms of depression as well as chronic illness,” said Dr Dolan

“So it’s not surprising that there is evidence to show that there is low level of uptake and screening for depression in people with diabetes.”

Symptoms specific to depression

However, Dr Dolan pointed out that there are symptoms of depression that can help distinguish between associated symptoms of a chronic health disorder such as diabetes and clinical depression. Such psychological symptoms of depression include a pervasively depressed or sad mood, lack of interest or pleasure in activities, guilty and negative thoughts targeted at oneself, feelings of worthlessness and suicidal thoughts, all of which are not typical symptoms of a chronic health condition. 

“Negative thoughts that are pervasive, significant and impact on one’s functioning are symptoms that health professionals should be looking out for more specifically when screening for depression in individuals with diabetes,” she explained.

She said that while questions in recommended depression scales are not specific to depression in diabetes and can cause overestimation, they are easy to use and can be particularly helpful for healthcare workers who are not experienced in assessment for/or treating depression.(See Table 1 for recommended depression scales.) 

However, Dr Dolan also pointed out that no screening is of any use if there is no clear pathway for further clinical assessment and a clear pathway for actually treating a possible diagnosis of depression.

Cognitive impairment and dementia

The most common risk factor for developing dementia is ageing, and in an ageing population living an unhealthy lifestyle this risk is further increased. But in combination with possible diabetes and depression – both of which already independently increase the risk of developing dementia – this risk increase gets quite dramatic.

“Dementia is poorly recognised and is underdiagnosed,” said Dr Dolan.

“In Ireland itself, 48,000 people had dementia in 2014 and this number is estimated to treble.”

So what is the difference between normal ageing and dementia or cognitive impairment? With normal ageing cognitive abilities such as memory and information processing can gradually deteriorate over time, but not to a significant extent and it does not impact on functioning in a significant way.

“Mild cognitive impairment (MCI) is when someone can pick up that there is a problem with memory or language planning or organisation and on formal testing their results will show a score which is over 1.5 standard deviations below the expected result,” explained Dr Dolan. 

“In people with cognitive impairment, there is a 10-15% transition from MCI to Alzheimer’s disease every year, so this represents a time where if modifiable risk factors were addressed, this could delay the onset of dementia and if delayed, this could also decrease the burden on the healthcare system and the patients themselves.”

Dr Dolan referred to a study by Barnes and Yaffe in 2011² which found that half of the risk for developing Alzheimer’s disease globally are attributable to seven modifiable risk factors: 

• Diabetes

• Midlife hypertension

• Midlife obesity

• Smoking

• Depression

•
Cognitive inactivity or low educational attainment

• Physical inactivity. 

“A reduction in these risk factors would significantly reduce the number of cases of Alzheimer’s disease and represent target areas for lifestyle interventions in middle age.”

Acceleration from MCI to dementia

According to Dr Dolan, there is evidence – both high-quality and low-quality – that people with type 2 diabetes are at an increased risk of acceleration from MCI to dementia, and that they reach the endpoint of dementia much quicker than someone with MCI who doesn’t have diabetes.

“According to a study by Xu et al in 2011,³ having diabetes accelerated time from progression from mild cognitive impairment to dementia by three years compared to those without diabetes,” said Dr Dolan.

Predictors of cognitive impairment

She said predictors of cognitive impairment remain poorly understood in the literature and there are a number of indicators. In people with diabetes – a very heterogenous group of patients – it is very hard to pick up what factors increase the risk.

“But what does come out quite consistently is that the higher the persons’ burden of complications, particularly retinopathy, the higher the risk is of cognitive impairment.”

Other factors, in addition to diabetes complication burden, that increase the 10-year dementia risk in patients with diabetes include older age, depression and a lower level of education. See Table 1 for assessment of cognitive impairment.

“A consistent finding in neuroimaging studies is brain shrinkage. Cortical atrophy, which is seen in Alzheimer’s disease, is also seen in individuals with type 2 diabetes at an increased rate compared to the non-diabetic population. 

“A predictor of this atrophy is HbA1c level; the higher this is, the quicker the acceleration of the brain shrinkage. It is thought that diabetes actually increases or accelerates brain ageing,” she said.

Hyperglycaemia

Improved diabetes control, particularly in mid-life, is an important dementia prevention target in individuals with type 2 diabetes. 

“It’s been shown that a 1% higher HbA1c level can be associated with lower test scores. Hyperglycaemia in the acute phase can also impact on working memory and attention, and that can be an issue in the acute phase but over time it can also be quite toxic to neurons and can cause damage to sensitive areas of the brain responsible for cognition.”

Hypoglycaemia

“There is twice the risk of dementia in older adults with type 2 diabetes who experience severe hypoglycaemia,” stated Dr Dolan.

Is Alzheimer’s actually type 3 diabetes?

“It was thought that the brain wasn’t an insulin-sensitive organ, but recently it has been shown that there are areas in the brain that are insulin-sensitive and in particular in areas that are responsible for regulation of mood and cognition, including the hippocampus,” revealed Dr Dolan.

“This insulin resistance in the brain can cause direct damage to vulnerable areas.”

This, said Dr Dolan, has led to the suggestion that Alzheimer’s may be looked at as a ‘type 3 diabetes’.

Impact on diabetes management

If someone has a problem with their memory or organisational skills, it is going to impact on how they manage a very complex condition like type 2 diabetes. 

“Poor diabetes control, leading to increased risk of complications and more difficult-to-manage disease, are all very relevant issues in diabetes management related to memory problems or other cognitive deficits occurring in individuals with diabetes. So when do we consider cognitive impairment?

“We should be suspicious if patients start missing their appointments, if there is a change in their behaviour, if they’re not taking their medication or do not refill prescriptions, and while such issues could be associated with a number of patients, it’s in particular when you notice a change in behaviour in a patient that you know well that you need to become suspicious,” said Dr Dolan.

“The IDF recommends the Montreal cognitive assessment tool, which is freely available. There are quite specific instructions and all healthcare professionals can use it. When you reach a certain score you should consider referring the patient to primary care, a geriatrician, a psychiatrist or a neurologist as appropriate.

“The Mini-Cog is another freely available test, which is easily used and there are good instructions on how to use it.

When it comes to management of cognitive impairment in patients with type 2 diabetes, Dr Dolan said early detection is key. This will facilitate management to be tailored to the individual for more support, more education for family members, carers and the patient themselves, to make it easier for all involved to manage.

“Reassessing the targets for glycaemic management with older patients may be necessary with less stringent targets. More intensive glycaemic control has not been shown to be beneficial in older adults and may be detrimental,” said Dr Dolan.

“However, practical measures such as written instructions, visual aids and close contact with primary care and specialist teams can help in making it as simple as possible to manage the condition.”

Reducing healthcare burden

“Ultimately it comes down to prevention, especially in midlife and in the younger population. We need to encourage healthy lifestyle behaviours if we want to reduce the burden on the healthcare system,” said Dr Dolan.

“We can’t control ageing, but having a healthier midlife is a major target for prevention of chronic illnesses that will have  major impact on the management of the ageing population. 

“If we could prevent or delay the development of diabetes and/or depression, by lifestyle factors, early screening and treatment, that would decrease the risk overall for comorbid diabetes and/or depression, cognitive impairment and dementia.”

References

1. Katon W, Fan MY, Unützer J, Taylor J, Pincus H, Schoenbaum MJ. Depression and diabetes: a potentially lethal combination Gen Intern Med. 2008 Oct;23(10):1571-5
2. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011 Sep;10(9):819-28
3. Xu W, Caracciolo B, Wang H-X, et al. Accelerated Progression From Mild Cognitive Impairment to Dementia in People With Diabetes. Diabetes. 2010 Nov;59(11):2928-35