Accelerated cognitive aging

Epilepsy is not only characterized by seizures, but is also associated with cognitive problems. For example, global cognitive decline is reported in the context of chronic medication-resistant epilepsy, which may indicate a negative effect of accumulative seizures on the brain. However, it is largely unknown what percentage of patients is at risk for decline.

Recent interest is focused on the identification of risk factors and characterization of how cognitive functions develop in people with epilepsy. Evidence is found that the cognitive trajectory of patients with epilepsy over time differs from processes of cognitive ageing in healthy people, especially in adulthood-onset epilepsy.

In 1889, Gowers introduced the concept of ‘epileptic dementia’. It has been suggested that this type of cognitive deterioration almost exclusively occurs in the context of the childhood-onset chronic (often medication-resistant) epilepsies where accumulation of medication and seizures over decades leads to gradual decline of the higher cognitive functions. The final cognitive outcome of this ‘chronic accumulation model’ of decline can be similar to the cognitive outcome in some forms of dementia.

However, in daily clinical practice clinicians also encounter another possible form of cognitive decline that is less well described in literature. In a subgroup of adult patients with epilepsy who complain about cognition and a quite sudden inability to meet the demands of daily (working) life, cognitive functioning appears to be globally deteriorated. These patients do not fulfil the diagnostic criteria of epileptic dementia or a progressive neurological disease such as Alzheimer’s, nor neuropsychologically, nor clinically. The majority of these patients have an adult-onset epilepsy , so that they do not fit into the ‘chronic accumulation model’ of decline either. Cognitive deterioration in this subgroup may be ‘cascadic’ rather than progressive, thus: deterioration takes place in a relatively short period of time, and not as a consequence of chronicity. It these people with epilepsy on which we mainly focus within Neu3CA.

Cognitive deterioration in this group develops in a stepwise ‘second hit model’ when epilepsy affects an already vulnerable brain. The model predicts loss of cognitive reserve capacity due to e.g. traumatic brain injury (TBI) or old age leading to a cascade of events after a second hit, i.e. epilepsy. Processes of ageing may be accelerated due to this loss of brain plasticity and cognitive reserve capacity for which we coin the term ‘Accelerated Cognitive Ageing’.

Drawing

Graphical representation of Accelerated Cognitive Ageing. The dashed blue line represents the cognitive ageing trajectory without pathology. With increasing age, cognitive functioning is declining until the minimal cognitive threshold is reached. Two alternative cognitive ageing trajectories are shown. The yellow line depicts the cognitive trajectory after one hit (e.g. TBI). There is decline in cognitive function which recovers. Recovery is, however, not complete and results in a loss of functional reserve. This is followed by a normal rate of subsequent ageing. The solid red line represents Accelerated Cognitive Ageing in the second-hit model. After a second hit (e.g. epilepsy), cascadic deterioration takes place and does not recover due to the diminished cognitive reserve capacity. In combination and interaction with the expected changes of normal ageing, cognitive ageing is accelerated and the patient’s cognitive profile resembles that of an older individual. Published in: Breuer et al., 2016

We believe that the concept of accelerated cognitive ageing can be helpful in providing a framework understanding global cognitive deterioration in epilepsy. Moreover due to the cascadic character of the deterioration trajectory (in a short time period) in these patients, it offers a very promising model to study ageing.

The aim of the Neu3CA program is to find specific brain abnormalities for accelerated cognitive aging and to develop treatment options for these patients. Thus, we aim to broaden the scope of epilepsy treatment options from merely seizure management to continuously protecting/preserving cognition. In a broader context, we expect that insights into accelerated cognitive aging are also relevant to understand and slow down healthy cognitive aging in the general population.