This is an interesting paper coming from an excellent research group. I agree that neural networks and synaptic plasticity are at the center of Alzheimer disease (Ashford and Teter, 2002), but in interpreting the relevance of this study to AD, we should also keep several issues in mind. This work is in mice, which only model a small part of the Alzheimer pathology. Further, β amyloid is associated with vulnerability to Alzheimer disease, but the dementia is due to a tauopathy, so any potential connection between Aβ and tau effects hinted at in the bigenic mice needs to be more specifically explored.

In my clinical experience, the epileptic issues in AD are less than described here. Alzheimer patients rarely have seizures, and the ones we reported in the literature were related to anti-cholinesterase drugs (Piecoro et al., 1998).

The concept of looking at a whole neural network and seeing how it responds to amyloid stress is very interesting. At the same time, the...  Read more

This is an interesting paper coming from an excellent research group. I agree that neural networks and synaptic plasticity are at the center of Alzheimer disease (Ashford and Teter, 2002), but in interpreting the relevance of this study to AD, we should also keep several issues in mind. This work is in mice, which only model a small part of the Alzheimer pathology. Further, β amyloid is associated with vulnerability to Alzheimer disease, but the dementia is due to a tauopathy, so any potential connection between Aβ and tau effects hinted at in the bigenic mice needs to be more specifically explored.

In my clinical experience, the epileptic issues in AD are less than described here. Alzheimer patients rarely have seizures, and the ones we reported in the literature were related to anti-cholinesterase drugs (Piecoro et al., 1998).

The concept of looking at a whole neural network and seeing how it responds to amyloid stress is very interesting. At the same time, the development of the plaques and tangles seems to be more of a local phenomenon affecting components of the network than a problem at the system level of networks.

I was a coauthor on a paper cited in this study (Mark et al., 1995). We were not primarily interested in seizures. Rather, our idea was that excitotoxicity would stress neuroplastic mechanisms (possibly involving GSK3) and exacerbate Alzheimer pathology development—which might in turn be reduced by valproate. Valproate seemed potentially useful because it is known to affect the brain. Along these lines, it could be considered that β amyloid could increase the excitability in neural networks, and reduction of that excitability could reduce the predilection for tauopathy to develop. We clearly need more data. At this point, it still remains doubtful to me that that increase of excitability is the hallmark of the amyloid pathologic mechanism.

View all comments by John (Wes) Ashford

This article raises a number of interesting issues with regard to improving the understanding and treatment of Alzheimer disease (AD). The authors demonstrate that β amyloid aberrantly increased neuronal excitability in cortex and hippocampus, which led to a series of neuronal structural and electrophysiologic alterations in the entorhinal cortex and hippocampus that are found in AD pathology. Such β amyloid-induced changes were either genetically induced in transgenic mouse models of AD, or exogenously induced by kainic acid administration in non-transgenic mice. Furthermore, reduction of neuronal tau structural microtubular proteins reduced the amount of disruption. The authors also showed that these animals exhibited abnormal excitatory EEG activity from cortical and hippocampal electrodes, often without clinically overt seizure activity.

The relevance of these basic research findings to treatment of AD patients is that EEG activity may be a useful marker for the expression and treatment-mediated control of these pathophysiologic changes. The EEG signature from scalp...  Read more

This article raises a number of interesting issues with regard to improving the understanding and treatment of Alzheimer disease (AD). The authors demonstrate that β amyloid aberrantly increased neuronal excitability in cortex and hippocampus, which led to a series of neuronal structural and electrophysiologic alterations in the entorhinal cortex and hippocampus that are found in AD pathology. Such β amyloid-induced changes were either genetically induced in transgenic mouse models of AD, or exogenously induced by kainic acid administration in non-transgenic mice. Furthermore, reduction of neuronal tau structural microtubular proteins reduced the amount of disruption. The authors also showed that these animals exhibited abnormal excitatory EEG activity from cortical and hippocampal electrodes, often without clinically overt seizure activity.

The relevance of these basic research findings to treatment of AD patients is that EEG activity may be a useful marker for the expression and treatment-mediated control of these pathophysiologic changes. The EEG signature from scalp electrodes will certainly appear different from that produced by cortical and hippocampal electrodes, as well as from that produced by hippocampal slice recordings. Even so, there is almost certain to be a scalp signature that can be identified with the appropriate EEG analytical methodology (Sneddon et al., 2005). The nature of the scalp EEG signature could be studied by performing scalp recordings in animals who have also had cortical and hippocampal recordings, and by performing hippocampal and cortical plus scalp electrode recordings in AD or perhaps epileptic patients.

Such a scalp EEG signature, once identified by proper EEG analytic methodology, would serve as a useful index of how well a given treatment is retarding AD pathophysiology. This is particularly relevant now that clinically safe β amyloid-lowering agents have been developed and may be FDA-approved soon. While reversal of cognitive and functional impairment in AD would be optimal, it is much more likely that treatment will delay or perhaps halt AD progression, such that an EEG measure of the degree to which this occurs could help guide physicians in optimizing each patient's treatment.

Such an EEG tool would certainly be useful in deciding whether to continue therapy with memantine (Namenda) and with cholinesterase inhibitors in very mildly impaired AD patients. In many cases, there is no clear symptomatic improvement. Because evidence exists both for and against disease-delaying effects for cholinesterase inhibitors (Farlow et al., 2005; Geldmacher et al., 2006; Doody et al., 2001; Raskind et al., 2004; Birks et al., 2006) and for NMDA receptor modulators (i.e., memantine) (Kirby et al., 2006; Bullock 2006), it is useful to identify potential disease-delaying effects in each patient. Given findings by Palop et al. about aberrant neuronal excitatory activity contributing to the progression of AD pathophysiology, it would be important to know if memantine, which minimizes aberrant excitatory glutamatergic activity and may reduce the formation of abnormally phosphorylated tau protein (Degerman Gunnarsson et al., 2007), is forestalling the progression of AD pathophysiology even if symptoms do not improve. Similarly, given the recent findings that cholinesterase inhibitors can beneficially modulate amyloid precursor protein metabolism to potentially reduce β amyloid formation in AD (Nordberg, 2006), and that the three FDA-approved cholinesterase inhibitors have different mechanisms and different potencies in this regard, it would be useful to be able to measure the effect of a given cholinesterase inhibitor on the AD pathophysiology of a given patient. Such translational research from cortical and hippocampal electrophysiology to scalp EEG recordings could have substantial benefits for AD patients and their treating physicians.

References:
1. Sneddon R, Shankle WR, Hara J, Rodriquez A, Hoffman D, Saha U. EEG detection of early Alzheimer's disease using psychophysical tasks. Clin EEG Neurosci. 2005 Jul 1;36(3):141-50. Abstract

2. Farlow MR, Lilly ML; ENA713 B352 Study Group. Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer's disease for up to 5 years. BMC Geriatr. 2005 Jan 19;5:3. Abstract

3. Geldmacher DS, Frolich L, Doody RS, Erkinjuntti T, Vellas B, Jones RW, Banerjee S, Lin P, Sano M. Realistic expectations for treatment success in Alzheimer's disease. J Nutr Health Aging. 2006 Sep-Oct ;10(5):417-29. Abstract

4. Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD, . Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Arch Neurol. 2001 Mar 1;58(3):427-33. Abstract

5. Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol. 2004 Feb 1;61(2):252-6. Abstract

6. Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD001190. Review. Abstract

7. Kirby J, Green C, Loveman E, Clegg A, Picot J, Takeda A, Payne E. A systematic review of the clinical and cost-effectiveness of memantine in patients with moderately severe to severe Alzheimer's disease. Drugs Aging. 2006 Jan 1;23(3):227-40. Abstract

8. Bullock R. Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: the evidence to date. Alzheimer Dis Assoc Disord. 2006 Jan-Mar;20(1):23-9. Review. Abstract

9. Degerman Gunnarsson M, Kilander L, Basun H, Lannfelt L. Reduction of phosphorylated tau during memantine treatment of Alzheimer's disease. Dement Geriatr Cogn Disord. 2007 Jan 1;24(4):247-52. Abstract

10. Nordberg A. Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease. Alzheimer Dis Assoc Disord. 2006 Apr-Jun ;20(2 Suppl 1):S12-8. Abstract

View all comments by William Rodman Shankle