A perfect storm: Converging paths of epilepsy and Alzheimer's dementia intersect in the hippocampal formation

Abstract

Seizures in the human temporal lobe transiently impair cognition and steadily damage hippocampal circuitry, leading to progressive memory loss. Similarly, the toxic accumulation of Aβ peptides underlying Alzheimer's disease (AD) triggers synaptic degeneration, circuit remodeling, and abnormal synchronization within the same networks. Because neuronal hyperexcitability amplifies the synaptic release of Aβ, seizures create a vicious spiral that accelerates cell death and cognitive decline in the AD brain. The confluence of hyperexcitability and excitotoxicity, combined with the challenge of seizure detection in the human hippocampus, make epilepsy in these individuals extremely important to correctly diagnose and treat. Emerging clinical evidence reveals an elevated comorbidity of epilepsy in AD, particularly when linked to mutations in the APP/Aβ gene pathway. Experimental models in genetically engineered mice confirm and extend these findings, highlighting the presence of subclinical seizures and overlapping pathophysiologic cascades. There is an urgent need for more clinical and basic investigation to improve the early recognition of hippocampal seizures arising during the course of dementing disorders, and to validate molecular blockers of Aβ-induced aberrant excitability that can slow and potentially reverse the progression of cognitive decline.

Figure 1

Elevated co-incidence of epilepsy and Alzheimers-type dementia in the elderly. Left: Seizure disorders of all etiologies increase in the second half of life, beginning around the age of 50. The incidence ratio of epilepsy in individuals diagnosed with AD is elevated nearly 87 fold at this age. Seizure incidence at ages beyond 70 remains elevated three-fold over patients of a similar age without AD. Modified from Cloyd et al (2006), and Amatniek et al (2007)

Figure 2

Non-convulsive hippocampal seizures and network remodeling in transgenic mouse model of AD. Left: spontaneous seizure with first appearance of epileptiform discharges (arrows) in hippocampal depth electrodes and subsequent generalization in the hAPP J20 mouse. No behavioral signs were evident during or after the seizure episode. Right: seizure-related plasticity absent in wild type hippocampus is clearly demonstrated in hippocampal circuitry of hAPP J20 mice, including mossy fiber sprouting (upper), ectopic NPY expression in mossy fibers (center), and loss of calbindin staining (lower) in dentate granule cells. Modified from Palop et al. (2007).

Figure 3

Confluence of paths of epilepsy and early Alzheimer’s Disease in the human temporal lobe. Above: MRI-based volumetric analysis of TLE cases reveals atrophy in both lateral temporal and frontal cortices, overlapping regions affected in AD. Below: Regional PET based imaging demonstrates hypometabolism in the basal temporal lobe in both disorders.

Figure 4

Potentiating cytopathic effects of seizures in Alzheimer’s Disease. Above: Model depicting self-amplifying neurodegenerative cascade leading to hyperexcitability and networking reorganization. Damage is accelerated by linked effects of seizure excitotoxicity on hippocampal circuitry and augmented release of toxic Aβ peptides. Below: Comparison of hippocampal cell death at postmortem examination of genotyped PSEN1 AD patients with no overt seizure history (middle), and those with positive seizure history (right). Seizures were accompanied by extensive cell death, consistent with positive feedback model above. Modified form Velez-Pardo, (2004).