Frontiers in Clinical Drug Research - Alzheimer Disorders: Volume 7

By Bentham Science Publishers

Frontiers in Clinical Drug Research - Alzheimer Disorders is a book series concerned with Alzheimer's disease AD, a disease that causes dementia, or loss of brain function. This disease affects parts of the brain that affect memory, thought, and languag

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Nov 2, 2018
• ISBN: 9781681085609

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Deep Brain Stimulation in the Treatment of Alzheimer's disease

Angelo Lavano*, Giusy Guzzi, Attilio Della Torre, Domenico Chirchiglia, Carmelino Angelo Stroscio, Donatella Gabriele, Giorgio Volpentesta

Unit of Functional Neurosurgery, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy

Abstract

Alzheimer’s disease (AD) is the leading neurological cause of dementia of advanced predominance worldwide. The pathogenic mechanisms may concern accumulations of beta amyloid and tau protein, inflammatory pathways, altered oxidative metabolism and responses to oxidative stress. The currently available therapeutic options for AD have limited efficacy. Deep Brain Stimulation (DBS) may represent a chance in order to ameliorate cognitive performances modifying cortical and hippocampal circuits. Fornix and Nucleus basalis of Meynert are the most promising targets in terms of delaying and reversing the cognitive impairment; other targets like entorhinal cortex/hippocampus, pedunculopontine tegmental nucleus, anterior thalamic nucleus are under investigation with some success. The mechanism of action and stimulation parameters remain unclear.

Keywords: Alzheimer’s disease, Brain neuromodulation, Deep Brain Stimulation, Fornix, Hippocampus, Nucleus basalis of Meynert.

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* Corresponding author Angelo Lavano: Unit of Functional Neurosurgery, Department of Medical and Surgical Sciences, University Magna Graecia, Campus S. Venuta of Germaneto, Viale Europa, 88100 Catanzaro, Italy; Tel [phone]; E-mail [e-mail]

INTRODUCTION

Alzheimer’s disease (AD) was diagnosed for the first time in 1901 by Dr. Alzheimer [1]. It is estimated that about 35 million people worldwide are affected by AD and its incidence may be the cause of an increase in ageing populations over the next decade, posing significant challenges for public health and allocation of health care resources [2, 3]. The medical therapy, currently used, includes acetyl cholinesterase inhibitors, NMDA (N-methyl D-aspartate) receptors blockers, vitamin E, that improve only temporarily the symptoms. The modest efficacy and the substantial adverse effects, such as restlessness, dizziness, motor slowing, of drugs led to find out alternative non-pharmacological options for AD [4]. It is already acknowledged that the pathological phases implicated in

AD produce a focal synaptic dysfunction that interrupts correlated brain regions generating disseminated interferences in the normal function of circuits and networks entailed in cognition [5]. Deep Brain Stimulation (DBS) is an established way of treatment in neurodegenerative and neuropsychological conditions such as Parkinson’s disease or obsessive compulsive disorder [6-11]. In the last years some investigations have been published concerning the possibility that DBS of select regions of the limbic system can improve memory processing and cognitive abilities [12, 13].

DBS TARGETS USED IN PATIENTS WITH AD

Anatomically AD has implications for many structures of the brain, but the most important circuitry is the limbic system. Selection of targets of the memory circuits with deep electrodes in AD is a new application of DBS [14]. DBS targets analysed are fornix, nucleus basalis of Meynert (NBM), entorhinal cortex (EC), pedunculopontine tegmental nucleus (PPN), anterior thalamic nucleus (ATN) and anterior limb of internal capsule/nucleus accumbens (ALIC/NAc).

Fornix

Based on the observation both on unexpected memory improvement and spatial - verbal learning in a case of bilateral hypothalamic DBS for obesity management by Hamani [15], the first phase I trial of DBS of the fornix was published in 2010 by Laxton et al. [16]. Fornix is a fiber bundle conducting nearly 1.2 million axons, which constitutes the major beaming connecting various nodes within the circuit of Papez. Six patients with early AD were treated with forniceal DBS bilaterally, over 1 year, supervising both neuropsychological assessments and FDG-PET scans. The parameters of stimulation were: 130 Hz, 90 μs pulse width, voltage between 1.0 and 10 V, monopolar mode. The authors used positron emission tomography (PET) imaging to demonstrate that this therapy was effective in reversing altered glucose consumption in the temporal and parietal lobes. Clinical evaluation with the Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-COG) and the Mini Mental State Examination (MMSE) suggested a reduction in cognitive decline rate. The follow-up PET studies after 1 year demonstrated an increasing cerebral glucose metabolism both in frontal-temporal-parietal-striatal-thalamic circuit and frontal-temporal-parietal-occipital-hippocampal circuit that was subsequently associated with improved cognitive status and quality of life [17]. Fontaine et al. [18] prove stabilization of mnesic scores and augmented metabolism in the mesial-temporal lobe after bilateral DBS of fornix in a patient with moderate AD. Bilateral low frequency stimulation of fornix (bipolar square waves of 0.2 µs duration at 5 Hz with currentintensity of 8 mA/phase) has been demonstrated to enhance MMSE in 11 patients with intractable epilepsy over a period of 4 h [19].

Sankar et al., observed with structural MRI bilateral hippocampal volume increases in two of six AD patients that underwent to bilateral fornix DBS. Following this treatment, in one patient hippocampal volume was maintained three years after diagnosis. Mean hippocampal atrophy was significantly slower in the DBS group compared to the AD group, correlated strongly with hippocampal metabolism and with volume change in the fornix and mammillary bodies, suggesting a circuit-wide effect of stimulation. This is the first in-human evidence that, in addition to modulating neural circuit activity, DBS may potentially change the natural course of brain atrophy in a neurodegenerative condition [20]. Lozano et al., considered ON/OFF bilateral DBS of the fornix in a randomized, double-blind trial in 42 patients with mild AD. They evaluated cognitive performance and cerebral glucose metabolism up to 12 months post-implantation, showing that DBS for AD was linked to the improved cerebral glucose metabolism. There were no further variations in cognitive functions for patients in its entirety, while it is conceivable a possible deterioration in patients aged<65 years with stimulation.

Nucleus Basalis of Meynert

The first case report of DBS for dementia traces back approximately to thirty years ago and Nucleus basalis of Meynert (NBM) was targeted. In 1984 Turnbull implanted a unilateral electrode into the left NBM by frontal approach in a 74-year-old patient with moderate AD [21]. The modulation of NBM can enhance the behavioural state and boost memory, attention and perception. Patients eligible for NBM DBS trials are those who have already tested cholinesterase inhibitors before, have minimal cortical atrophy on imaging, lack of significant comorbidities and lucid intervals and capacity to consent. In one 71-year-old patient with Parkinsonian Dementia Disease, Freund et al. [22] performed bilateral monopolar low frequency DBS of Ch4i subsector of NBM was (1 V, 20 Hz, 120 μs) associated with bilateral STN stimulation. NBM DBS enhances substantially cognitive and memory functioning: after surgery score on Auditory Verbal Learning Test for immediate episodic memory and learning (AVLT - sum) demonstrated improvement of immediate episodic memory and score on Auditory Verbal Learning Test for long term memory (AVLT - recog) improvement of long term memory performance. Cognitive profits have been supported for 2 months during chronic stimulation (time locked). This expansion in cognitive and behavioral functions can be ascribed to the strengthening of leftover cholinergic projections in the memory circuits [23].

Entorhinal Cortex/Hippocampus

Neuropsychological details counsel that the verbal learning is a function of the left medial temporal lobe while non-verbal learning is the prerogative of the right medial temporal lobe. Starting from this examination, in 2012, Suthana et al. [24] observed that bilateral DBS of the hippocampus or entorhinal cortex in seven pharmacologically intractable temporal lobe epilepsy patients may enhance memory functions. Improved spatial memory was observed when the medial temporal lobe was stimulated. This finding is the proof that improvement could be registered in patients with other memory disorders like Alzheimer’s disease. Fell et al. evaluated in a pilot study the effects of low frequency stimulation of EC and hippocampus in 11 patients with temporal lobe epilepsy. A linear relationship of stimulation on correctly remembered words was reported [25].

Pedunculopontine Tegmental Nucleus

In a small group of six Parkinsonian patients Stefani et al. were the first to stimulate simultaneously both the subthalamic nucleus (STN) and the pedunculopontine tegmental nucleus (PPN). PPN-ON/STN-OFF stimulation condition (bipolar contacts 0-1/4-5, 25 Hz, 1.5 to 2.4 V and 60 μs pulse width) elicited better results in both executive and attentive functions, associated with augmented glucose consumption in prefrontal and frontal bilateral cortical areas, including both lateral and more antero-medial cortices. Moreover, during PPN-ON stimulation, a more recognizable reduction of FDG (fluorodeoxyglucose) was observed in the left ventral striatum. These data would corroborate the hypothesis of a positive effect of 25 Hz PPN-DBS on Parkinsonian patients' cognitive profile, probably due to a facilitatory effect exerted by PPN on both associative and limbic circuits [26].

Anterior Thalamic Nucleus

According to Gao, bilateral anterior thalamic nucleus (ATN) stimulation in rats increased glucose utilization in the target region, the thalamus and hippocampus, and decreased glucose consumption in the cingulate cortex and frontal cortex [27]. In 2011, Oh examined the cognitive outcomes at least 12 months after bilateral DBS of the ATN for controlling epilepsy in nine patients with intractable epilepsy who were not candidates for resective surgery. Bilateral ATN DBS directly activated both the limbic and the thalamo-cortical pathway, with significant advantages in verbal memory or verbal fluency after chronic stimulation. Thus, bilateral DBS of the ATN is responsible for metabolic activation of the target area and changes in energy metabolism in remote brain regions via efferent or afferent fibers [28].

Anterior Limb of Internal Capsule/Nucleus Accumbens

Modulation of ventral capsule, ventral striatum and nucleus accumbens are entailed in motivation and is a part of reward circuitry. The stimulation of these neural pathways might strengthen the cognitive and behavior functions in patients with AD [29]. The initial stimulating results of the study involving bilateral DBS of anterior limb of internal capsule/nucleus accumbens (ALIC/NAc) in patients with AD are yet to be published.

DISCUSSION

AD is a neurodegenerative disorder that affects behaviour and cognition clinically and many structures in the limbic system even anatomically. Neuroimaging studies have highlighted widespread structural and metabolic aberrations, mainly in areas associated with memory functions [30]. In pathogenesis of AD accumulations of beta amyloid and tau protein, inflammatory cascades, abnormal responses to oxidative stress and alteration in oxidative metabolism are implicated [4, 8-10]. At molecular level, these proteins are responsible for the loss of synaptic functions, faulty metabolism, altered cell repair and cell death. These molecular alterations lead to neuronal loss and cerebral atrophy in different regions of the brain involving frontal, temporal, parietal, hippocampus and entorhinal cortex. AD also disrupts the neural connections between the cortical and subcortical areas [4, 7, 9].

Interest in the potential role of neurosurgery for patients with diagnosis of dementia has gradually increased: encapsulated cell biodelivery (ECB) implant and Deep Brain Stimulation (DBS) represent a new strategy.

Several animal studies have shown that delivery of nerve growth factor (NFG) – a neurotrophin that is involved in cholinergic synaptic remodeling in the adult CNS - in basal forebrain (anterior part of the brain, cerebral hemispheres, thalamus and hypothalamus) by ECB could arrest or even reverse the neuronal degeneration process. In 2012 Wahlberg et al. demonstrated the restorative role of ECB implants in patients with AD [31].

The results of DBS on the neural circuitry in diseases like Parkinson’s disease, primary dystonia, Obsessive Compulsive Disorders, Major Depression and Tourette syndrome have prompted researchers to translate its potential utility to AD [32-36]. Several targets have been explored as potential targets to enhance memory functions in the circuit of Papez that is one of the major pathways of the limbic system and is primarily involved in the cortical control of emotions and in storing memory. In the so-called memory circuit the entorhinal cortex projects to the hippocampus via the perforant pathway that projects to the dentate gyrus, to the subiculum and to the CA3 and CA1 subfield of the hippocampus. From the hippocampus the information proceeds through the subiculum to the fimbria and the fornix. The pre-commissural branch of the fornix projects to the anterior cingulated cortex via the septal nuclei, the nucleus basalis of Meynert and the ventral striatum. The post-commissural branch of the fornix projects to the anterior thalamic nucleus and the mammillary bodies. Because the mammillo-thalamic tract couples the mammillary bodies and the anterior thalamic nucleus, the hippocampus can have direct as well as indirect effect on the thalamus [37].

As recent data suggest system-level defects characterized by alterations in memory circuits, it is reasonable to expect that external stimulation of subareas within the circuitry will ameliorate symptoms. Stimulation of the memory circuit activates hippocampus and the para-hippocampalgyrus and thus improves hippocampus-dependent memory functions. The anterior thalamic nucleus plays an important role in the Papez circuit. Previous studies in rats have shown that high current stimulation of the ATN interrupted the acquisition of contextual fear conditioning and reduced performance on a spatial alternating task; stimulation of this area also modulates regional cerebral metabolism as detected by FDG-microPET [27]. Stimulation of the nucleus basalis of Meynert (NBM) should improve or stabilize memory and cognitive performance in patients with AD. Medial temporal structures, including the hippocampus and the entorhinal cortex, have long been known to be important in memory formation and recall [24]. Previous studies in refractory epileptic patients have shown that entorhinal stimulation enhanced the memory of spatial information when applied during learning. The CA1 region of the hippocampus is another interesting target. A rodent model study showed that application of high-frequency stimulation to isolated hippocampal slices significantly increased synaptic plasticity in the CA1 region and promoted a twofold increase of non-amyloidogenic α-secretase activity.

Although we rely on a small series, the fornix is the current target most frequently chosen for treating dementia with 2.5-3.5 V, 130 Hz and 60-90 μs as stimulation parameters: DBS of this target improves memory functions and slows progression of memory loss in AD patients mainly in those affected by mild cognitive impairment [15, 16, 18]. As to other potential target, there are investigations dealing with the effects of low-frequency (20-50 Hz, 1-3 V, 120-210 μs) DBS in the NBM for treating patients with Parkinsonian Dementia Disease and Senile Dementia of Alzheimer’s type, stressing results regarding memory and other cognitive functions like attention, visual processing or practical symptoms [19, 27]. NBM DBS also improves memory performance, as a result of Ach release from the NBM. The nucleus basalis of Meynert may be a promising target structure in dementia thanks to its afferent and efferent projections and its pool of 90% cholinergic neurons [23, 35]. Other potential DBS targets under evaluation in patients with dementia are the entorhinal cortex (0.5-1.5 mA, 50-130 Hz,300-450 μs as stimulation parameters) [24], the pedunculopontine tegmental nucleus (2.4 mA, 25 Hz and 60 μs) [26] and the anterior thalamic nucleus (1.5-3.1 mA, 100-185 Hz, 90-150 μs) [28], because at least in some areas of cognition such as spatial orientation, executive functions and attention, slight improvements appeared to occur in humans. Currently there are six clinical trials (ranging from March 2007 to May 2012) for DBS in AD that are listed by the National Institutes Health of Clinical Trial registry. One of these is a double-blind design (stimulation on/off), which should prove to be very informative in evaluating the effectiveness of DBS as a therapeutic technique in AD [30].

For AD patients undergoing DBS, very few adverse effects are described so far. Independently of the target structure stimulated, patients recovered quickly from surgery and only rarely experienced cognitive deterioration caused by the operation. Generally chronic stimulation was well tolerated, except for sensations of warmth, flushing and sweating.

The mechanisms underlying the effects of DBS in AD are still uncertain. Increase in neuritic arborization with restoration of functional connectivity, induction of hippocampal neurogenesis, increase of neurotrofic grown factors (NGF) release and acetylcholine release in hippocampus may be activated by fornix or NBM DBS [32, 35].

The promotion of neurogenesis has been demonstrated in animal studies involving the electrical stimulation of fornix, anterior thalamic nucleus and entorhinal cortex and stimulation-induced memory enhancement may depend on the ability of electrical neural stimulation to induce the development of functional mature hippocampal neurons.

In addition to the aforementioned potential mechanism that can be at the basis of long-term effects (arrest or slowing of cognitive decline), DBS can induce a modulation of oscillatory rhythms which may be responsible for the immediate effects of stimulation on cognition (enhancement of memory functions)by means of theta phase activity resetting in the hippocampus [24, 35].

Neuroethical aspects concerning the use of DBS in AD and/or cognitive impairments represent a challenge for clinical research. Taking into account that DBS is a surgical procedure, it requires an informed consent. The ability to express or to sign an informed consent in a patient affected by dementia or cognitive disorder may be lack and the surgical procedure is not explainable only on the basis of the clinical diagnosis [38]. Also the decision-making capacity ofcaregivers to give consent in difficult situations poses ethical and legal questions [39, 40].

CONCLUSION

AD is a multifactorial disease with significant financial and health-care impact. Medical therapy is of modest advantage and associated with significant side effects. In selected patients with AD, DBS of key regions of memory circuit with tailored stimulation parameters can delay cognitive decline, enhance memory functions and improve overall quality of life. Fornix and NBM are the most promising targets for DBS in terms of delaying and reversing the cognitive deterioration. Other potential targets for DBS treatment of AD have been assessed and include the nucleus basalis of Meynert, the entorhinal cortex, the pedunculopontine nucleus, ATN with encouraging results. Moreover, DBS in AD patients seems to be feasible and safe, even if the debate on the ethical issues moves clinical research to reevaluate this technique within the framework of cognitive degenerative disorders, with strict protocols and inclusion criteria. However, long-term randomized controlled trials are required to validate the efficacy of neurostimulation, to determine the most optimal target and stimulation parameters, to define mechanisms through which DBS produces therapeutic effects in AD patients, and to check for possible adverse effects in the long period.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The author (editor) declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

ASS234: A New and Promising Anti-Alzheimer Agent

Alejandro Romero¹, *, Eva Ramos¹, Ana P. Fernández², Julia Serrano², Ricardo Martínez-Murillo², José Marco-Contelles³

¹ Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain

² The Neurovascular Research Group, Department of Translational Neurobiology, Cajal Institute (CSIC), Madrid, Spain

³ Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry (CSIC), Madrid, Spain

Abstract

Physiopathological events associated with the development and progression of Alzheimer's disease (AD) are complex and require new therapeutical approaches. Consequently, N-((5-(3-(1-benzylpiperidin-4-yl) propoxy)-1- methyl-1H-indol-2-yl) methyl)-N-methylprop-2-yn-1-amine (ASS234), synthesized as a new multitarget-directed molecule, has focused a great interest in this field. In vitro, it is able to cross the blood-brain barrier and has less toxicity than donepezil. It acts simultaneously as a reversible inhibitor of both human acetyl and butyrylcholinesterase, and as an irreversible inhibitor of human monoamine oxidase A and B. It inhibits both Αß1-42 and Αß1-40 self-aggregation and possesses antioxidant and neuroprotective properties. Recently, it was demonstrated that ASS234 is able to induce the wingless-type MMTV integration site family (Wnt) signaling pathway, which is involved in neuroprotective activities related to AD and it also promotes the induction of several key antioxidant genes that counteract oxidative stress. In vivo experiments, ASS234 exhibited a reduction of amyloid plaque burden and gliosis in the cortex and hippocampus and significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Herein, we summarize the neuroprotective effects of ASS234 in counteracting several steps in the pathological processes of AD.

Keywords: AChE, Alzheimer disease, ASS234, BuChE, Gene expression, MAO-A/B, Neuroprotection, Oxidative stress, Wnt signaling pathway.

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* Corresponding author Alejandro Romero: Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain; Tel: [phone]; E-mail: [e-mail]

INTRODUCTION

Alzheimer's disease (AD) is the most common neurodegenerative disorder at any age worldwide, which involves progressive memory loss and dementia [1]. Initially, the extracellular deposit of β-amyloid (Aβ) intraneuronal and accumulations of hyperphosphorylated tau (pTau) (neurofibrillary tangles) were the main hypotheses for this disease [2-4]. However, both molecular manifestations do not fully explain all of the disturbances in AD development, which, in the last years, has come under sharp criticism. It is clear that AD is a multifactorial disorder and it seems to result from a complex interaction of multiple environmental and genetic factors [5]. Besides these, numerous other mechanisms, such as disturbances in the structure and functions of mitochondria [6], chronic oxidative stress (OS) [7], neuroinflammation [8], metal ion metabolism disorders [9], abnormalities of lipid metabolism [10] and/or deregulation of the Cyclin-dependent kinase 5 (Cdk5) [11] are involved.

In this complex scenario, the scientific community is exploring multiple approaches to modify the natural course of this disease. Until now, four acetylcholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) and one NMDA receptor antagonist (memantine) have been FDA-approved for this pathology. However, these drugs had not produced the expected results. Combination or hybridizing therapy is an alternative strategy to address the complex pathophysiology of AD through multiple pathways at several steps, offering a higher efficacy. Consequently, the design and synthesis of molecules able to interact with two or more targets, the so called multitarget-directed ligands (MTDLs), have raised a great interest in this field as a powerful drug design alternative and run parallel to drug combination for the treatment of AD [12, 13].

In this chapter, we summarize the interesting perspectives given by the studies carried out with the multipotent monoamine oxidase (MAO) A and B plus cholinesterase inhibitor N-((5-(3-(1-benzylpiperidin-4-yl) propoxy)-1- methyl-1H-indol-2-yl) methyl)-N-methylprop-2-yn-1-amine (ASS234) by several in vitro and in vivo experimental studies through enzymatic and other specific targets.

Design and Synthesis of ASS234 Strategy

Possibly, the multifactorial and complex nature of AD is the main cause that no effective drug exists in clinics, even after more than a century of the first diagnosed case of AD. Consequently, multiple new therapeutic strategies have been conceived to find the statement drug, among them, of particular interest and acceptation is the multi-target directed ligand (MTDL) [2] approach, based on the "one molecule, multiple targets" paradigm [14]. Thus, the idea was that a single drug acting on a specific target might not be adequate for AD therapy. Thereby, the MTDL approach has captured an increasing attention in many laboratories, which have reported a large number of ligands able to bind several biological targets simultaneously [12, 15-19].

Thus, based on our previous developments of monoamine oxidase inhibitors (MAOIs) to treat neurodegenerative diseases [20], our choice was to design new potential hybrids able to inhibit both MAO and cholinesterase (ChE) for AD treatment. Consequently, novel