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Bakker A, Albert MS, Krauss G, Speck CL, Gallagher M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 2015;7:688-98. Epub 2015 Feb 21 PubMed.
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University College London
This is a fantastic paper, as it illustrates the translation from rodent electrophysiological experiments into a randomized clinical study toward a novel, promising approach for the treatment of age-related memory disorders, including Alzheimer´s disease (AD). Moreover, the paper draws our attention to the critical role of neuronal hyperactivity for the earliest symptoms of AD (see Busche and Konnerth, 2015).
The study contains several very important results: (a) hippocampal networks are hyperactive in patients with amnestic mild cognitive impairment (aMCI), many of whom have early AD; (b) this hyperactivity is directly related to poor performance in a specific memory task; (c) the well-established anti-epileptic drug levetiracetam, at a dose that was more than four times lower than commonly used for the treatment of epilepsy, rescues hippocampal hyperactivity; (d) the restoration of normal activity in the hippocampus leads to improved performance in that memory task (yet not on standard neuropsychological testing).
Previous work has nicely demonstrated that CA3 hippocampal neurons become abnormally hyperactive in aging-impaired rats (Wilson et al., 2005). This excessive activity results in a failure of the neurons to encode new information rapidly. Hyperactivity of hippocampal neurons has also been shown in memory-impaired mouse models of AD (Busche et al., 2012; Siskova et al., 2014). Several studies in humans with aMCI and even presymptomatic AD have demonstrated that hippocampus hyperactivity is also apparent in macroscopic fMRI signals (O'Brien et al., 2010; Yassa et al., 2010). The direct link between hyperactivity and memory impairment has prompted further studies in animal models and humans to assess whether activity-dampening drugs like levetiracetam could be beneficial (Koh et al., 2010; Bakker et al., 2012; Sanchez et al., 2012).
By putting all these pieces of information together, the present paper strongly demonstrates that hippocampus hyperactivity is a quantitative diagnostic marker of memory impairment in early AD that responds to a treatment with a low dose of the anti-epileptic drug levetiracetam.
A surprising and unexpected finding from the present study is that the entorhinal cortex is hypoactive in aMCI, and levetiracetam normalized the activity status of that region. This effect is hard to understand and highlights the need for further studies to elucidate the precise mechanisms of action of levetiracetam in the context of AD. This may also help explain why the higher dose of levetiracetam did not rescue hippocampal hyperactivity. Moreover, this finding indicates that both hyper- and hypoactivity play a role in AD and that their specific contributions to the disease pathophysiology, and their underlying causes, are still largely unknown. Finally, it would be interesting to see whether the low dose of levetiracetam has any effect on epileptiform activity that can be associated with early AD (Vossel et al., 2013).
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.
Busche MA, Konnerth A. Neuronal hyperactivity--A key defect in Alzheimer's disease?. Bioessays. 2015 Jun;37(6):624-32. Epub 2015 Mar 14 PubMed.
Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B, Konnerth A. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2012 May 29;109(22):8740-5. Epub 2012 May 16 PubMed.
Koh MT, Haberman RP, Foti S, McCown TJ, Gallagher M. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology. 2010 Mar;35(4):1016-25. PubMed.
O'Brien JL, O'Keefe KM, Laviolette PS, Deluca AN, Blacker D, Dickerson BC, Sperling RA. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology. 2010 Jun 15;74(24):1969-76. PubMed.
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):E2895-903. PubMed.
Šišková Z, Justus D, Kaneko H, Friedrichs D, Henneberg N, Beutel T, Pitsch J, Schoch S, Becker A, von der Kammer H, Remy S. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron. 2014 Dec 3;84(5):1023-33. Epub 2014 Nov 13 PubMed.
Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, Hegde M, Cornes SB, Henry ML, Nelson AB, Seeley WW, Geschwind MD, Gorno-Tempini ML, Shih T, Kirsch HE, Garcia PA, Miller BL, Mucke L. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013 Sep 1;70(9):1158-66. PubMed.
Wilson IA, Ikonen S, Gallagher M, Eichenbaum H, Tanila H. Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci. 2005 Jul 20;25(29):6877-86. PubMed.
Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic Mild Cognitive Impairment. Neuroimage. 2010 Jul 1;51(3):1242-52. PubMed.
Massachusetts General Hospital
This new study by Dr. Gallagher and colleagues provides valuable data in multiple groups of MCI patients to support the hypothesis that a) abnormalities of neural network function are important contributors to memory deficits in MCI; b) targeting these physiologic/functional abnormalities with specific treatments can ameliorate memory deficits; c) such treatment provides benefits by normalizing hippocampal function. These results, in conjunction with a series of other findings in the field (including Bakker et al.’s prior findings, and those by Lennart Mucke and colleagues), make a strong case for the need for further studies of physiologic neural network-level abnormalities in AD and related disorders, and also for the targeting of these abnormalities for novel approaches to treatment.
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