This concludes a two-part series. See also Part 1.
13 November 2009. The Society for Neuroscience annual meeting, which took place 17-21 October 2009 in Chicago, featured a rare convergence of epilepsy and Alzheimer disease researchers at a symposium focused on shared features of these two disorders. There is accumulating animal data for such a connection: At least three strains of AD transgenic mice show epileptiform activity on electroencephalography (EEG) recordings, and the data hint that the EEG changes could be a signature for impending cognitive decline (see Part 1). There is also growing suspicion that the same may be true for AD patients. In a slide talk, Jeffrey Noebels, an epilepsy researcher at Baylor College of Medicine in Houston, Texas, reviewed clinical and pathological evidence for overlap between AD and temporal lobe epilepsy (TLE). He proposed that seizures may be a common feature of AD that escapes detection by conventional EEG. Physicians spend a lot of time figuring out whether patients have AD or temporal lobe epilepsy (TLE), Noebels said, noting, “It’s actually possible to have both.”
Epidemiological data points in this direction. Epilepsy is generally a childhood disease but seems to occur more frequently in seniors with dementia (Cloyd et al., 2006). More than half of the rare early-onset AD patients with APP duplications have seizures (Cabrejo et al., 2006), and for those with very early onset of dementia (i.e., under 40 years of age), the incidence of epilepsy rises to 83 percent (Snider et al., 2005).
When made to hyperventilate, people who carry an ApoE4 allele, which puts them at increased AD risk, show epileptiform activity on EEG (Ponomareva et al., 2008). An SfN poster by Jesse Hunter, Eli Lilly and Co., Indianapolis, Indiana, and colleagues showed mouse data that seem to jibe with this. The scientists analyzed E2, E3, and E4 targeted replacement mice (i.e., transgenic mice that express a given human ApoE allele in the endogenous locus) and report that old E4 females developed seizures whereas E2 and E3 mice did not (Hunter et al. SfN poster abstract).
Meanwhile, the overall proportion of people with AD and mild cognitive impairment patients who have non-convulsive seizures remains unknown—in large part because probing the right brain regions is difficult. It is much easier to pick up epileptiform activity in mice, where the cortex is just a millimeter thick and the hippocampus is disproportionately large, Noebels said. In the human brain, surface EEG readily misses abnormal activity in the temporal lobe, the main site of early AD pathology, because this brain structure is small and deep—buried within a comparatively thick cortex. Noebels described a case where nothing showed up on a surface EEG recording, but implanted depth electrodes revealed a full-blown seizure. Mindful of these challenges, scientists at the University of California, San Francisco, launched a study earlier this year to determine the incidence of epileptiform activity in dementia patients by doing 36-hour EEG and magnetoencephalography (MEG) on study volunteers with AD and MCI, said symposium chair Lennart Mucke of the Gladstone Institute of Neurological Disease in San Francisco, California.
The notion of an interface between AD and TLE appears to be gaining traction among AD researchers. “People I talked with were fascinated by the overlap, which seems wider than is realized by the experimental and clinical evidence that has accumulated in a fairly short period of time,” Mucke told ARF. Steve Barger of the University of Arkansas, Little Rock, said the overlap with TLE might explain the vacillating clinical behavior of some AD patients, who can seem completely disoriented for a time and then snap back into an almost-normal state. “Maybe you don’t really get cognitive deficits until you get something that approaches epileptiform activity,” he said.
Helen Scharfman of the Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, proposed several potential shared mechanisms between AD and TLE. The first was inflammation. Clinical data suggest that infection is a risk factor for TLE, and animal studies have shown that cyclooxygenase-2 inhibitors can help restore long-term potentiation in an AD model (Kotilinek et al., 2008) and decrease seizures in a TLE model (Jung et al., 2006). Another common mechanism could be neurogenesis, Scharfman said. In rodents, the dentate gyrus makes new neurons after seizures (Bengzon et al., 1997), and the neurogenesis seems to contribute to hippocampal network reorganization (Parent et al., 1997). Neurogenesis is also increased early—by three to four months of age—in Tg2576 AD mice (Lopez-Toledano and Shelanski, 2007).
Some TLE models might actually be unique tools for studying AD because they model features that amyloidosis models don’t capture, Scharfman suggested. For example, the loss of basal forebrain cholinergic neurons is a common feature in AD patients, yet is hardly detectable in mouse models based on APP mutations and overexpression. However, cholinergic deficits do appear in the kindling model of TLE. (Kindling refers to repeated stimulation that leaves neurons oversensitized and prone to seizures.) The kindling model also shares a number of common dentate gyrus features with the APP/PS1 mouse, including reduced dentate hilar cells, interneuron loss, survival of granule cells, mossy fiber sprouting, and increased expression of neuropeptide Y.
The experimental and clinical support for an AD-TLE overlap begs the obvious question of whether anti-epileptic drugs can stem the network dysfunction that presumably leads to dementia. So far, this hasn’t been the case. When Mucke and colleagues treated J20 mice with the anti-epileptic drug phenytoin, a sodium channel blocker, the animals had even more seizure activity. The findings were perplexing, he said, but perhaps not so unreasonable given that some epilepsy patients with loss-of-function mutations in voltage-gated sodium channels also respond poorly to phenytoin. That observation led his team to look for sodium channel abnormalities in the cortex of their J20 mice (see Part 1).
Thus far, AD patients treated with epilepsy drugs have not fared any better. Phenytoin (sold under the trade name Dilantin) is often given to stop seizures in AD, but it tends to worsen cognition, Mucke told ARF. And a recent Phase 3 trial of the anticonvulsant valproate failed to improve neuropsychiatric symptoms in AD patients. Principal investigator Pierre Tariot of Banner Alzheimer’s Institute, Phoenix, Arizona, presented the trial results at this year’s International Conference on Alzheimer’s Disease (ICAD) in Vienna (see Tariot et al. ICAD abstract).
Much work remains to contrast and compare the mechanisms at work in epilepsy and network dysfunction in AD, Mucke said. “But at least people felt there was good reason to pay attention to that interface.”—Esther Landhuis.
This concludes a two-part series. See also Part 1.