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Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012 May 10;74(3):467-74. PubMed.
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Lund University
This is a very interesting report showing that treatment with the antiepileptic levetiracetam improves both the task-specific hyperactivity in the DG/CA3 hippocampal circuit seen by fMRI in patients with amnestic MCI and also the cognitive task that reflects the function of this circuit. It is exciting to follow how better functional imaging can provide ever more detailed insights into the brains of living people with MCI, and now even connect therapy to improvement in a selected brain circuit. At the same time, this particular treatment provided no overall improvement on standard neuropsychological testing, including other memory tests. Mucke, Palop, and others have underscored the importance of better understanding of the neural circuitry dysfunction, in particular aberrant hyperactivity, in Alzheimer's disease.
In Parkinson's disease, research into circuitry dysfunction has led to therapies (such as lesioning of hyperactive subthalamic nucleus). It wasn't as clear why the authors wrote that some have viewed hippocampal hyperactivity in aMCI as beneficial. Dysfunctional brain circuits typically lead to imbalances, including hyper- and hypoactive circuits. The authors previously noted hypoactivity in the ERC-to-DG/CA3 circuit in aMCI (Yassa et al., 2010). One might not expect that this hypoactive ERC circuit would also benefit from low-dose levetiracetam. The relative contributions of elevated versus reduced (and also resting versus task-related) activity to the disease process remain unclear. Current evidence supports that both hyperactive (Mohajeri et al., 2002) as well as hypoactive (Tampellini et al., 2010) circuitry can negatively impact the disease process.
References:
Yassa MA, Muftuler LT, Stark CE. Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo. Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12687-91. PubMed.
Mohajeri MH, Saini K, Schultz JG, Wollmer MA, Hock C, Nitsch RM. Passive immunization against beta-amyloid peptide protects central nervous system (CNS) neurons from increased vulnerability associated with an Alzheimer's disease-causing mutation. J Biol Chem. 2002 Sep 6;277(36):33012-7. PubMed.
Tampellini D, Capetillo-Zarate E, Dumont M, Huang Z, Yu F, Lin MT, Gouras GK. Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice. J Neurosci. 2010 Oct 27;30(43):14299-304. PubMed.
View all comments by Gunnar GourasGladstone Institutes and University of California, San Francisco
Cortical and hippocampal hyperactivity of neuronal networks are early events in AD pathogenesis and are associated with early amyloid deposition in non-demented humans with and without mild cognitive impairment (MCI) (Sperling et al., 2009; Putcha et al., 2011). However, it was unclear whether such hyperactivity was a beneficial compensatory response or just a detrimental overactivation of neuronal networks. Michela Gallagher’s data clearly suggest that attenuation of hippocampal hyperactivity by levetiracetam improves memory performance in amnestic MCI patients, indicating a primary and detrimental effect of network hyperactivity in MCI patients. This is a quite remarkable and important finding that may lead to novel therapies in a short period of time.
References:
Putcha D, Brickhouse M, O'keefe K, Sullivan C, Rentz D, Marshall G, Dickerson B, Sperling R. Hippocampal hyperactivation associated with cortical thinning in Alzheimer's disease signature regions in non-demented elderly adults. J Neurosci. 2011 Nov 30;31(48):17680-8. PubMed.
Sperling RA, Laviolette PS, O'keefe K, O'brien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron. 2009 Jul 30;63(2):178-88. PubMed.
View all comments by Jorge PalopAlzheimer and Dementia Unit
In my opinion the manuscript is very thought provoking and describes a problem of great interest. However, the literature on this matter is not homogeneous.
It would be interesting to do a follow-up study of these patients. This issue needs to be more thoroughly investigated, although the cognitive results obtained with levetiracetam (LEV) are indeed very encouraging. The implications of this study are adequately discussed, and the results do support these conclusions, but a univocal interpretation of such positive results is not easy. The section on patients and methods is fairly good, except that there is no comment made about local authority approval or patient consent. There is also no discussion of adverse events. What are the main dosages of LEV utilized in the study? The limitations, namely the small number of patients, and the possibility that they are not adequately matched in a small study like this, are not fully discussed.
It has been suggested that LEV may influence the brain's metabolism in areas devoted to attention and language, similar to what has been suggested with piracetam, the other pyrrolidone derivative found to be associated with improved learning, memory, and attention. In fact, there is some evidence that piracetam enhances glucose utilization and cellular metabolism in the brain. LEV was initially studied in animal models of cognitive impairment with the primary objective of finding a drug more effective than piracetam. However, LEV was initially considered to be more effective in preventing seizures.
Our experience of LEV is clinical. We structured a clinical trial to evaluate efficacy, tolerability, and cognitive effects of levetiracetam (LEV) in patients with seizures and Alzheimer’s disease (AD). This was a prospective, randomized, three-arm parallel group, case-control study in 95 patients: LEV (n = 38), phenobarbital (PB) (n = 28), and lamotrigine (LTG) (n = 29). A four-week dose adjustment was followed by a 12-month evaluation period. The three groups were compared to a control group (n = 68) to evaluate cognitive effects. We examined drug effects cross-sectionally at baseline, six, and 12 months. LEV was well tolerated and maintained its efficacy during all long-term management of AD. LEV improved cognitive performance, specifically attention level and oral fluency items. LEV had a benign and neuropsychological side effect profile, making it a cognitively safe drug to use for controlling established seizures in patients with dementia. The mean daily dose of LEV monotherapy was 956 mg (range: 500 to 2,000 mg/day).
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