Elsevier

Epilepsy & Behavior

Volume 26, Issue 3, March 2013, Pages 343-351
Epilepsy & Behavior

Review
Shared cognitive and behavioral impairments in epilepsy and Alzheimer's disease and potential underlying mechanisms

https://doi.org/10.1016/j.yebeh.2012.11.040Get rights and content

Abstract

Seizures in patients with Alzheimer's disease (AD) have been examined by many investigators over the last several decades, and there are diverse opinions about their potential relevance to AD pathophysiology. Some studies suggest that seizures appear to be a fairly uncommon co-morbidity, whereas other studies report a higher incidence of seizures in patients with AD. It was previously thought that seizures play a minor role in AD pathophysiology because of their low frequency, and also because they may only be noticed during late stages of AD, suggesting that seizures are likely to be a consequence of neurodegeneration rather than a contributing factor. However, clinical reports indicate that seizures can occur early in the emergence of AD symptoms, particularly in familial AD. In this case, seizures may be an integral part of the emerging pathophysiology. This view has been supported by evidence of recurrent spontaneous seizures in transgenic mouse models of AD in which familial AD is simulated. Additional data from transgenic animals suggest that there may be a much closer relationship between seizures and AD than previously considered. There is also evidence that seizures facilitate production of amyloid β (Aβ) and can cause impairments in cognition and behavior in both animals and humans. However, whether seizures play a role in the early stages of AD pathogenesis is still debated. Therefore, it is timely to review the similarities and differences between AD and epilepsy, as well as data suggesting that seizures may contribute to cognitive and behavioral dysfunction in AD. Here we focus on AD and temporal lobe epilepsy (TLE), a particular type of epilepsy that involves the temporal lobe, a region that influences behavior and is critical to memory. We also consider potential neurobiological mechanisms that support the view that the causes of seizures in TLE may be related to the causes of cognitive dysfunction in AD. We suggest that similar underlying mechanisms may exist for at least some of the aspects of AD that are also found in TLE.

This article is part of a Special Issue entitled “The Future of Translational Epilepsy Research”.

Highlights

► Remarkably, Alzheimer’s disease (AD) and epilepsy have some common characteristics. ► Similarities also exist in animal models of the two diseases. ► Psychiatric symptoms of AD share some characteristics of comorbidities in epilepsy. ► Overlapping mechanisms have been suggested for some aspects of AD and epilepsy.

Introduction

Disorders or conditions that affect synaptic function are often associated with seizures or are risk factors for epilepsy, including traumatic brain injury, autism, schizophrenia, and Alzheimer's disease (AD). This is not surprising, considering that the brain is made up of over 1 billion neurons, and each neuron can form tens of thousands of synapses. Such a complex structure requires numerous cellular and circuit mechanisms to regulate neuronal network activity and maintain stable function that also can adapt to environmental demand [1]. Although the brain can generally meet this challenge, disorders that impact synaptic function may overcome the capacity to maintain normal function. Changes to synaptic function may result in seizures by numerous mechanisms, creating an imbalance between excitation and inhibition either directly or indirectly, e.g., by inducing maladaptive compensatory responses.

Focusing on synaptic regulation is important in AD, which has been referred to as a “disease of synaptic failure” [2], [3]. It also is considered to be central in epilepsy, and therefore, it may not be surprising that seizures have been described in patients with AD [4], [5], [6], [7]. The fact that patients with AD have recurrent spontaneous seizures, which defines ‘epilepsy,’ has also been noted [6], [8], but the role of epilepsy in AD pathophysiology has largely been unexplored. Seizures have traditionally been attributed to neuronal loss in the late stages of disease, and may, therefore, be a possible epiphenomenon of little pathophysiological relevance. However, as discussed in this review, recent studies have provided more experimental support for the idea that there is a greater connection between epilepsy and AD than previously recognized. These experimental studies, particularly those utilizing mouse models of AD, support the idea that seizures may contribute in a critical fashion to the emergence of AD symptoms, i.e., cognitive impairment, in early stages of AD [9]. Notably, epilepsy and AD also have similar psychiatric co-morbidities, suggesting that seizures may influence a wider range of brain function in AD than memory impairment. This article reviews the evidence that cognitive and psychiatric symptoms of AD and TLE are not merely byproducts of widespread temporal lobe pathology in both conditions but may share underlying mechanisms.

Section snippets

Seizures in patients with AD

The occurrence of seizures in patients with AD has been thoroughly reviewed recently [4], [5], [6], [7]. The incidence of unprovoked seizures is 5–10-fold greater in sporadic AD than in reference populations, and as much as 87-fold greater in patients with “early” disease onset (before 60 yrs of age [5], [6], [10], [11], [12]). In autosomal dominant forms of AD, the relationship between seizures and AD is most remarkable. In these forms of AD, there are either mutations in amyloid precursor

Cognitive and behavioral impairments in patients with AD and TLE

One of the reasons that the idea of seizures in AD has gained so much interest is that TLE and AD can appear quite similar in their cognitive and behavioral impairments. These impairments are considered “co-morbidities” in TLE and include deficits that span multiple cognitive domains and a wide range of ‘emotional’ symptoms ranging from mood disorders such as depression to anxiety. Clinically, AD is characterized by a progressive loss of cognitive function, particularly regarding episodic

Psychiatric symptoms in patients with AD and TLE or epilepsy

Changes in behavior are common in both epilepsy and in AD [94], [95], [96]. Almost all people (over 90%) diagnosed with AD develop neuropsychiatric symptoms at some stage during disease progression [94], [95], [96], typically at early stages. Indeed, regression analyses indicate that in patients with AD, there are significant associations between mood disorders [97]. Similarly, depression, anxiety, and other neuropsychiatric symptoms are common in people with epilepsy [94], [95], [98].

That such

Conclusions and avenues for future research

Identifying similarities and differences between epilepsy and AD is important because it could help define new targets for drug development in these diseases. Broadening the target pool is greatly needed in epilepsy because the antiepileptic drugs that are currently available often fail to stop seizures or have adverse side effects. In AD, new drugs are also sorely needed, because disease-modifying therapeutics are currently not available, and the numbers of affected individuals are growing

Acknowledgments

JC is grateful for support from the Alzheimer's Association and the Margaret Q. Landenberger Research Foundation. HS acknowledges support from NIH, the Alzheimer's Association, and the New York State Office of Mental Health.

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