Research to Practice

memory function in early Alzheimer’s disease.

KEY WORDS Alzheimer’s disease, deep stimulation, ; fornix, neuronal circuitry

INTRODUCTION Alzheimer’s disease (AD) continues to be a growing public health concern. It is estimated that there will be over 115 million new worldwide cases of AD within the next 40 years, resulting in an overwhelming health and economic burden on society.1 Given the major public health priority of AD, the Alzheimer’s Association released the National Alzheimer’s , From Act to Action, in May 2012 outlining a national strategy to address AD research, care, and Deep Brain Stimulation: services with the specific goal of finding effective ways to prevent and treat the disease by 2025. AD A Novel Strategy for Treating is characterized by progressive cognitive dysfunction often Alzheimer’s Disease beginning with an early disturbance of episodic memory and ultimately by Constantine G. Lyketsos, MD, MHS; Steven D. Targum, MD; leading to absolute functional impairment. The apparent Jo Cara Pendergrass, PhD; pathological processes causing AD and Andres M. Lozano, MD, PhD, FRCSC, FRSC include misprocessing of fibrillar amyloid leading to oligomerization, Innov Clin Neurosci. 2012;9(11–12):10–17 the deposition of amyloid plaque causing a disruption of neural network activity, a loss of synaptic ABSTRACT Therefore, Alzheimer’s disease may function, and eventual neuronal Recent studies have identified an be both a degenerative disease and death.2,3 association between memory a broader system-level disorder The United States Food and deficits and defects of the affecting integrated neuronal Drug Administration (FDA) has integrated neuronal cortical areas pathways involved in memory. In approved three cholinesterase known collectively as the default this paper, we describe the inhibitors and the N-Methyl-D- mode network. It is conceivable rationale and provide some aspartic acid (NMDA) antagonist that the amyloid deposition or evidence to support the study of memantine for the treatment of other molecular abnormalities seen deep brain stimulation of the AD. In practice, these therapies in patients with Alzheimer’s disease hippocampal fornix as a novel have had only modest, short-term may interfere with this network and treatment to improve neuronal benefits for clinical symptoms but disrupt neuronal circuits beyond circuitry within these integrated they continue to be widely used the localized brain areas. networks and thereby sustain because of a lack of alternative

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treatments.4–6 Given the current THE ROLE OF MEMORY modulation of neuronal activity understanding of the pathological NETWORKS IN ALZHEIMER’S within these interconnected route leading to AD, recent clinical DISEASE dysfunctional networks may sustain research efforts have focused on The evidence of functional or even improve cognitive function the development of several “anti- alterations in memory networks is in patients with early AD. amyloid” therapies. Attempts have commonly seen in AD patients as been made to modify the effects of well as normal elderly persons who STRUCTURAL ABNORMALITIES, amyloid production, aggregation, have no cognitive impairment.13–15 THE FORNIX, AND MEMORY clearance, or plaque deposition on Recent data have shown that both DISTURBANCES neuronal tissue. Unfortunately, normal elderly individuals and studies of AD have most of the recent Phase 2 and 3 patients with AD have defects in demonstrated the presence of trials using immunotherapies, “anti- heteromodal interconnected structural abnormalities in AD aggregants,” or related agents have cortical areas known collectively as patients that are directly associated been unsuccessful.7–10 For instance, the “.”15,16 with the cognitive and functional postmortem studies in AD patients Young show correlated disturbances experienced in AD. treated with amyloid immunization activity within this default network Neuroimaging research has shown found that cognitive dysfunction during resting states and that the occurs in and brain disease progressed deactivation of the network when widespread brain regions but with despite evidence that the much of performing many cognitive tasks.16 an early preference for neural the amyloid had actually cleared On the other hand, older adults circuitry that affects memory. from the brain.11 In sum, these lose the expected deactivation and Regional reduction in recent clinical trials have had toggling of the default network utilization in the temporal lobe and disappointing results and generated during cognitive tasks.15,17 These posterior cingulate is a common more interest in seeking novel deficits are more pronounced in finding in emission and approaches to treat this devastating patients with AD reflecting single photon emission illness. impairment in their neuronal computerized tomography One novel strategy to treat AD is circuitry. It is conceivable that (PET/SPECT) in early AD, as well circuitry-based treatment via deep defects in the default mode as in healthy individuals at genetic brain stimulation (DBS). DBS network function, as a consequence risk for AD.20,22 These brain regions treatment has been used in of amyloid deposition or other have a propensity for fibrillar numerous central mechanisms, may be responsible amyloid deposition as visualized at (CNS) disorders, including for some of the multimodal autopsy and in vivo using Parkinson’s disease, , cognitive and behavioral deficits radiotracers, such as the Pittsburgh treatment-resistant depression, seen in patients with AD.15,18,19 compound B ([11C]-PiB) in AD , , Further, it is also possible that patients and non-demented older obsessive compulsive disorder, dysfunction caused by molecular or adults.23–27 Structural neuroimaging Tourette’s syndrome, , structural abnormalities in one studies have revealed volumetric , obesity, and most recently diseased brain area may changes in the entorhinal cortex AD.12 The National Institutes of secondarily interfere with the and hippocampus that predate the Health clinical trial registry activity in other unaffected brain development of cognitive symptoms (www.clinicaltrials.gov) lists over areas whose function is linked and subsequently track with the 150 clinical trials of DBS for within the integrated neuronal progression of disease.28,29 In fact, conditions across the CNS circuitry network. Thus, AD may be recent studies suggest that loss of spectrum. both a degenerative disease and a the integrity of the fornix, a major Clearly, alternative treatment system-level disorder affecting in- and outflow track to the options are needed for AD. This several integrated pathways linking hippocampus, may be associated article will describe the rationale select cortical and subcortical areas with early memory dysfunction. for assessing DBS as an innovative that typically work in concert to The fornix is a large axonal bundle strategy for the treatment of early serve aspects of memory and estimated to have 1.2 million axons AD. cognition. If this dual etiologic in the human.30 The importance of hypothesis is correct, the the fornix in memory function is

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supported by the observation that obsessive compulsive disorder, rechargeable and nonrechargeable fornix lesions in experimental Tourette’s syndrome, addiction, devices are available. animals and humans produce pain, and obesity. Interventions in Nonrechargeable devices typically memory deficits.30–33 The fornix these dysfunctional circuits can last 4 to 5 years. Once the batteries integrity can be measured by have local, trans-synaptic and are depleted, the pulse generator fractional anisotropy (FA) using remote effects,39,40 and, in some can be replaced in an outpatient diffusion tensor (DTI). One cases, produce striking clinical procedure without affecting the study found lower fornix FA improvements beyond what is electrodes. The level of stimulation predicted later cognitive decline in achievable with medications. DBS is is adjusted to optimize the desired individuals with amnestic mild now available in most major outcome and minimize unwanted cognitive impairment (aMCI) as medical centers. It is estimated that side effects. The activity of an well as later hippocampal volume over 85,000 patients have had entire interconnected brain loss.34,35 This finding of an early implants placed and received brain network can be manipulated in this structural abnormality in the lower stimulation to date,41 and that 8,000 way because the current acts fornix that is associated with the to 10,000 new patients are treated locally, at the site of application, eventual development of AD may each year. and remotely, at sites that are become a meaningful clinical DBS involves the neurosurgical anatomically connected. predictor of later cognitive implanting of indwelling electrodes The risks for DBS deterioration. These recent findings within specific brain circuits to are real but relatively low. There clearly link the fornix to the modulate the activity of those are potential physical adverse process of cognitive deterioration circuits. DBS can suppress effects resulting from the in AD and to later hippocampal pathological neuronal activity or neurosurgery and possible degeneration as well. drive underactive output. In this psychiatric effects (e.g., Thus, there is accumulating way, DBS can modulate brain hypomania) that require careful evidence that defects in the circuitry activity up or down based monitoring. There is approximately function of the default mode upon the specific needs. The target a one-percent incidence of serious network may occur in AD and that location for electrode placement is intraoperative events (e.g., cerebral the fornix is linked to this process. most often done by using structural hemorrhage or ). There is a These observations support the brain imaging, usually computed 5- to 10-percent risk of ongoing development of circuitry-based tomography or magnetic resonance complications related to the treatments for AD using the fornix imaging. The electrodes are hardware, such as breakage, as a preferential locale for commonly placed while the patient malfunction, and infection.42 There treatment intervention. is fully awake. Microelectrode can also be stimulation-related recordings are used to differentiate adverse effects (e.g., paraesthesias, DEEP BRAIN STIMULATION structures or nuclei and to refine dysarthria, and motor contractions) DBS is a circuitry-based lead placement as different depending on the placement of the treatment. DBS was first tested in structures have specific firing electrode. For instance, motor animal experiments over 70 years patterns or frequencies, thus effects or paresthesia would not be ago and was first approved in enabling more precise lead expected from surgery in the area Europe in 1995 and in the United placements for DBS. In an awake of the fornix. These potential States in 1997 and 2002 for subject, the final placement of the adverse effects are usually essential tremor and Parkinson’s electrodes is abetted because the reversible if the stimulation is Disease, respectively. The therapy surgeon can gauge the patient’s reduced or stopped. currently is licensed in various response to test stimulation. The regions of the world for a range of electrodes are then connected to DBS: A POSSIBLE CIRCUITRY- additional uses, including dystonia, an implanted pulse generator that BASED TREATMENT FOR refractory epilepsy, and obsessive is similar to a conventional cardiac ALZHEIMER’S DISEASE compulsive disorder.36–38 DBS also pacemaker. The pulse generator is DBS may be a useful circuitry- has been studied in the treatment subsequently programmed to based treatment for AD if the of treatment-resistant depression, deliver continuous stimulation that electrodes are placed in areas of bipolar disorder, anorexia nervosa, can last for several years. Both the brain that are implicated in

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memory, such as the hippocampal fornix (Figure 1). Although DBS of the fornix (DBS-F) is a very novel strategy, it is potentially an important therapeutic approach to slowing AD as it may slow fornix degeneration, influence hippocampal , and sustain cortical neurons and circuitry by releasing trophic factors. The use of DBS-F to treat AD is supported by rodent studies in which DBS-F treatment revealed improved memory on the Morris water maze task and increased hippocampal neurogenesis based upon histopathological studies. FIGURE 1. DBS-fornix placement The animal evidence for DBS- induced neurogenesis is provocative. One study of rodent models found that electrical stimulation of the Papez circuit (of which the fornix and hippocampus are part) using parameters analogous to clinical high frequency DBS reversed memory impairment by corticosterone treatment and produced hippocampal neurogenesis.43,44 Entorhinal cortex (EC) stimulation increased new granule cell formation in mice that were integrated into hippocampal networks engaged by spatial memory in a maturation dependent manner.45 EC stimulation facilitated spatial memory formation at six weeks but not at one week before or after FIGURE 2. DBS-fornix affects FDG-PET hypometabolism training. The time delay to special memory is consistent with the time course of incorporation of adult- generated neurons into spatial neuronal network that affects derived from a small, open-label memory circuits. Importantly, the memory. Phase 1 trial that was conducted in facilitation of spatial memory by EC Toronto by Laxton et al.46 Six AD stimulation was prevented by A PRELIMINARY, OPEN-LABEL patients received DBS-F blocking neurogenesis. Taken STUDY OF DBS IN EARLY neurosurgical implants and were together, these data suggest that ALZHEIMER’S DISEASE treated for 12 months with deep DBS can induce neurogenesis, The DBS-F treatment strategy brain stimulation. As shown in which in turn can facilitate for early AD is supported by some Figure 2, follow-up PET scan improvement in the integrated promising but preliminary results studies over the next year revealed

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increases in cortical glucose interpreted with caution. Further, scans of glucose and metabolism that were correlated these patients had very mild AD at magnetic resonance scans of with improved cognitive measures the time of DBS implantation. hippocampal volumes/fornix white in some of these patients.46 The However, these findings do suggest matter integrity, respectively. finding of increased glucose that the underlying DBS Although a small study, the findings metabolism is a striking contrast to mechanism of action may involve will be informative and generate the well-documented, longitudinal up-regulation of processing, more research investigating this metabolic decline generally seen in capacity, and/or sustained integrity novel approach to treat patients AD patients.20,47 After 12 months, of these neuronal circuits. Hence, a with early AD. the DBS-F treatment produced a circuitry-based treatment like DBS sustained increase in glucose may be helpful for patients with SUMMARY utilization in the posterior cingulate early AD. In this paper, we have explored cortex and the precuneus; these the possibility that AD be are important components of the CURRENT RESEARCH FOR DBS considered a circuit disorder as brain default mode network that IN EARLY ALZHEIMER’S well as a degenerative disease and are most affected in early AD and DISEASE that it may be possible to improve where significant amounts of beta- Currently, Clinicaltrials.gov lists or sustain cognitive function in amyloid deposition is known to six distinct clinical trials evaluating early AD, particularly memory occur.33,48,49 Furthermore, using the role of DBS in memory within the integrated cognitive electromagnetic tomography disorders being conducted in networks involving the (sLORETA) these investigators Europe and the United States. hippocampus and cortex, by demonstrated that DBS drove Double-blind studies of patients stimulation at the level of the neural activity in the “memory with DBS implants are possible fornix. This novel strategy circuit,” including the entorhinal because the brain stimulation can supplements our thinking about the and hippocampal areas, and be turned on or off. Therefore, etiology of AD and does not activated the default mode patients who have had surgical discount the prevalent amyloid network. The activated regions implants can be randomly assigned hypotheses. In fact, the possibility included the anterior cortical (left to “active-on” or “sham” stimulation that DBS may be effective suggests anterior cingulate, bilateral groups during the double-blind that a dual treatment regimen that superior and middle frontal gyrus, treatment period. One currently addresses both amyloid issues and and left insula), temporal cortical enrolling double-blind, “active-on” neuronal circuitry for AD patients (bilateral superior, middle and versus “sham” DBS study may be on the horizon. medial temporal cortices), and (clinicaltrials.gov NCT01608061) is parietal cortical regions (left a Phase 2b study for patients with REFERENCES precuneus, bilateral posterior mild AD (defined as meeting 1. Wimo A, Prince M. Alzheimer’s cingulate, left fusiform gyrus, right diagnostic criteria of probable AD Disease International: World supramarginal gyrus, right inferior based on the National Institute of Alzheimer Report 2010: The parietal lobule) and the bilateral Aging Alzheimer’s Association Global Economic Impact of cerebellum. Guidelines, obtaining an ADAS-Cog . London, United Clinical evaluation using the 11 item score of 12–24, and a CDR Kingdom: Alzheimer’s Disease conventional Alzheimer Disease Global Score of 0.5–1). All patients International (ADI); 2010. Assessment Scale cognitive will be on standard medical 2. Hardy JA, Selkoe D. The amyloid subscale (ADAS-COG) and the Mini treatment for AD and will be hypothesis of Alzheimer’s disease: Mental State Examination (MMSE) randomly assigned to DBS-F progress and problems on the suggested possible slowing in the activation either following surgery road to therapeutics. Science. rate of progressive cognitive or after a 12-month delay, and 2002;19;297(5580):353–356. decline in these mild AD followed for 24 months post- 3. Lyketsos CG, Szekely CA, Mielke patients.50,51 It is important to note operatively. Comprehensive safety, MM, et al. Developing new that this was a small open-label clinical, cognitive, and treatments for alzheimer’s study without any placebo control neuroimaging assessments will be disease: The who, what, when, group, and the results must be performed, including serial PET and how of biomarker-guided

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and biomarkers in early Alterman RL, et al. Deep brain trial of deep brain stimulation of alzheimer’s disease and mild stimulation for Parkinson disease: memory circuits in Alzheimer’s cognitive impairment. Clin an expert consensus and review disease. Ann Neurol. Pharmacol Ther. of key issues. Arch Neurol. 2010;68(4):521–534. 2009;86(4):438–441. 2011;68:165. 47. Alexander GE, Chen K, Pietrini P, 29. Risacher SL, Saykin AJ, West JD, 37. Sankar T, Tierney TS, Hamani C. et al. Longitudinal PET evaluation Alzheimer’s Disease Novel applications of deep brain of cerebral metabolic decline in Neuroimaging Initiative (ADNI), stimulation. Surg Neurol Int. dementia: a potential outcome et al. Baseline MRI predictors of 2012;3:26. measure in Alzheimer’s disease conversion from MCI to probable 38. Lozano AM. Deep brain treatment studies. Am J AD in the ADNI cohort. Curr stimulation therapy. Br Med J. . Alzheimer Res. 2012;344:e1100 2002;159(5):738–745. 2009;6(4):347–361. 39. Moro E, Lang AE, Strafella AP, et 48. Greicius MD, Srivastava G, Reiss 30. Powell, TP, Guillery, RW, Cowan al. Bilateral AL, Menon V. Default-mode WM. A quantitative study of the stimulation for huntington’s network activity distinguishes fornixmamillo-thalamic system. J disease. Ann Neurol. alzheimer’s disease from healthy Anat. 1957;91(4):419–437. 2004;56(2):290–294. aging: evidence from functional 31. Tsivilis D, Vann SD, Denby C, et 40. Mayberg HS, Lozano AM, Voon V, MRI. Proc Natl Acad Sci U S A. al. A disproportionate role for the et al. Deep brain stimulation for 2004;101(13):4637–4642. fornix and mammillary bodies in treatment-resistant depression. 49. Buckner RL, Andrews-Hanna JR, recall versus . Neuron. 2005;45(5):651–660. Schacter DL. The brain’s default Nat Neurosci. 41. Medtronic. Parkinson’s disease. network: Anatomy, function, and 2008;11(7):834–842. http://www.medtronic.com/patient relevance to disease. Ann N Y 32. Wilson CR, Baxter MG, Easton A, s/parkinsons-disease/index.htm. Acad Sci. 2008;1124:1–38. Gaffan D. Addition of fornix Accessed Dec 1, 2012. 50. Ito K, Ahadieh S, Corrigan B, transection to frontal-temporal 42. Oh MY, Seong KH, Abosch A, et Alzheimer’s Disease Working disconnection increases the al. Long-term hardware-related Group, et al. Disease progression impairment in object-in-place complications of deep brain meta-analysis model in memory in macaque monkeys. stimulation. Neurosurgery. 2002; alzheimer’s disease. Alzheimers Eur J Neurosci. 50:1268-1276. Dement. 2010;6(1):39–53. 2008;27(7):1814–1822. 43. Toda H, Hamani C, Fawcett AP, et 51. Stern RG, Mohs RC, Davidson M, 33. Browning PG, Gaffan D, Croxson al. The regulation of adult rodent et al. A longitudinal study of PL, Baxter MG. Severe scene hippocampal neurogenesis by alzheimer’s disease: learning impairment, but intact deep brain stimulation. J measurement, rate, and recognition memory, after Neurosurg. predictors of cognitive cholinergic depletion of 2008;108(1):132–138. deterioration. Am J Psychiatry. inferotemporal cortex followed by 44. Hamani C, Stone SS, Garten A, et 1994;151(3):390–396. fornix transection. Cereb Cortex. al. Memory rescue and enhanced 2010;20(2):282–293. neurogenesis following electrical FUNDING: There was no funding for the 34. Mielke M, Okonkwo O, Oishi K, et stimulation of the anterior development and writing of this article. al. Fornix integrity and in rats treated with hippocampal volume predict corticosterone. Exp Neurol. FINANCIAL DISCLOSURES: Dr. Lyketsos has memory decline and progression 2011; 232(1):100–104. received grant support (research or CME) to AD. Alz Demen. In Press. 45. Stone SS, Teixeira CM, Devito from NIMH, NIA, Associated Jewish 35. Mielke MM, Kozauer NA, Chan LM, et al. Stimulation of Federation of Baltimore, Weinberg KC, et al. Regionally-specific entorhinal cortex promotes adult Foundation, Forest, Glaxo-Smith-Kline, diffusion tensor imaging in mild neurogenesis and facilitates Eisai, Pfizer, Astra-Zeneca, Lilly, Ortho- cognitive impairment and spatial memory. J Neurosci. McNeil, Bristol-Myers, Novartis, National alzheimer’s disease. Neuroimage. 2011;31(38):13469–13484. Football League, Elan, Functional 2009;46(1):47–55. 46. Laxton AW, Tang-Wai DF, Inc. Dr. Lyketsos has 36. Bronstein JM, Tagliati M, McAndrews MP, et al. A phase I been a consultant/advisor to Astra-Zeneca,

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Glaxo-Smith Kline, Eisai, Novartis, Forest, International, PRA International, Prana BrainCells Inc., and Functional Supernus, Adlyfe, Takeda, Wyeth, Biotechnology Ltd., ReViva, Roche Labs, Neuromodulation Inc., Chief Medical Lundbeck, Merz, Lilly, Pfizer, Genentech, Sophiris, Sunovion, Takeda, Targacept, Advisor at Prana Biotechnology Ltd., and a Elan, NFL Players Association, NFL Benefits Theravance, and Transcept; Dr. consultant in psychiatry at the Office, Avanir, Zinfandel, and BMS. Dr. Pendergrass has no conflicts relevant to Massachusetts General Hospital; Jo Cara Lyketsos has received honoraria or travel the content of this article; and Dr. Lozano Pendergrass, PhD is Vice President of support from Pfizer, Forest, Glaxo-Smith is a consultant to Medtronic, St Jude, and Clinical Operations at Clintara LLC; and Kline, Health Monitor; Dr. Targum has Boston Scientific, co-founder Functional Andres M. Lozano MD, PhD, FRCSC, FRSC, received grant support or has been a Neuromodulation Inc, and has intellectual is Dan Family Professor and Chairman of consultant or medical advisor to Acumen, property in the field of DBS. Neurosurgery at the University of Toronto Acadia Pharmaceuticals, Alkermes Inc., and RR Tasker Chair in Functional AstraZeneca, BioMarin, BrainCells Inc., AUTHOR AFFILIATIONS: Constantine G. Neurosurgery (Toronto Western Hospital), CeNeRx, Cephalon, CTNI MGH, EnVivo Lyketsos, MD, MHS, is Elizabeth Plank and Canada Research Chair in Pharmaceuticals, Euthymics, Forest Althouse Professor, Department of Neuroscience. Research, Functional Neuromodulation inc, Psychiatry and Behavioral Sciences, Johns Eli Lilly and Company, Johnson & Johnson Hopkins University and Chair of Psychiatry ADDRESS CORRESPONDENCE TO: PRD, INC Research, Medtronics, at Johns Hopkins Bayview Medical Center; Dr. Steve Targum, 505 Tremont St., #907, Methylation Sciences Inc., NeoSync, Steven D. Targum, MD, is Scientific Boston, MA 02116; E-mail: Neurophage, Novartis Pharmaceuticals, Director at Clintara LLC, Chief Medical [email protected] Novartis Bioventures, Nupathe, Parexel Officer at Methylation Sciences Inc.,

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