Alzheimer's disease

Primary care providers, geriatricians, neurologists, and psychiatrists are faced with the daunting task of treating the growing number of patients with Alzheimer's disease (AD), an illness involving neuronal loss in brain regions critical for learning and memory, language, behavior, and other cognitive functions. With the first baby boomers reaching age 65 in 2011, the increased incidence and prevalence of AD will pose an enormous economic burden on the country's healthcare system as well as on individual caregivers and families. (1) Even with existing treatments, the need for around-the-clock care in later stages of the disease creates a huge financial toll, with the 2001 estimated annual cost per patient ranging from $20,000 to $61,000 U.S. dollars (total direct and indirect costs). (2) Not surprisingly, economists predict that treatments that could delay the onset of the disease by even 1 year could reduce the societal cost by nearly $10 billion annually after 10 years. (3)

Until the recent approval of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, the only approved therapeutic strategies for AD treatment were those that target cholinergic neurotransmitter pathways. Cholinergic neurotransmission has been shown to be important for cognitive function and is disrupted in AD. (2) The use of acetylcholinesterase inhibitors (AChEIs) presumably counteracts cholinergic deficits by reducing the amount of acetylcholine that is degraded in the synaptic cleft. Clinical trials with AChEIs have demonstrated modest cognitive and global benefits (improvement in memory and at least two domains of cognitive function) as measured by improvements in patients' Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinicians' Interview Based Impression of Change with Caregiver Input (CIBIC-Plus) scores, respectively. AChEIs have been shown to be efficacious in one-half of mild to moderate AD patients (MMSE 18-26); (4) approximately one-third of patients treated with AChEIs experience a worsening of symptoms in the first 6 months, possibly requiring longer treatment before an effect, if any, can be measured. (5) AChEIs do not appear to significantly slow or modify the progression of the disease or prevent neuronal death (ie, provide neuroprotection), but are associated mainly with symptomatic improvements. AChEIs have been rigorously tested in mild to moderate AD patients, but their use can be limited by troubling significant side-effects including nausea, vomiting, dizziness, diarrhea, and anorexia (table 1).

Therapeutic strategies aimed at other pathogenic mechanisms in the disease process, eg, inflammation, oxidative injury, and b-amyloid deposition, include NSAIDs, antioxidants, herbs, statins, hormones, metal chelators, secretase inhibitors, and immunotherapy. But, clinical trials with these therapies have either been halted (b-amyloid vaccination), reported with mixed results (NSAIDs, hormones, herbs), require additional testing (antioxidants, metal chelators, statins), or are in the earliest stages of clinical trials (secretase inhibitors). (1) It is believed that b-and g-secretase inhibitors can attack one of the pathways of AD disease progression by modifying the cleavage of amyloid precursor protein (APP). APP is cleaved by both b- and g-secretase to produce the B-amyloid (AB) protein in at least two different amino acid lengths (Ab1-40 and Ab1-42), both of which have been found in senile plaques. However, clinical use of secretase inhibitors has been complicated by the lack of selectivity of these compounds. The use of secretase inhibitors is still in its infancy, but may prove to be a beneficial therapeutic strategy in the future.

More immediate, reproducible clinical benefits for treating AD symptoms have resulted from NMDA receptor antagonism. Memantine (Namenda), a low-moderate affinity, uncompetitive NMDA receptor antagonist, which has demonstrated neuroprotective characteristics in preclinical models of AD, (6) has been available in Europe for the treatment of moderately severe to severe AD since May 2002. In October 2003, the U.S. Food and Drug Administration (FDA) approved memantine for the treatment of moderate to severe AD, stages of the disease for which no drugs had been previously approved. This review presents the rationale for the emerging use of NMDA receptor antagonism as a clinically useful therapeutic strategy and provides physicians with clinical evidence supporting the use of memantine in moderate to severe AD.

Basic AD pathophysiology

Whether the cause of AD is sporadic or genetic in nature (80 versus 20%, respectively), the classic neuropathologic features are the same: deposition of extracellular Ab, formation of intracellular neurofibrillary tangles, and neuronal degeneration/loss. The extracellular deposition of an insoluble form of the B-amyloid protein contributes to neuritic (senile) plaque formation and may be associated with inflammation of the surrounding tissue and neurotoxicity. (7) Formation of neurofibrillary tangles, aggregates of a hyperphosphorylated form of the microtubule-associated protein tau, (7) and accumulation of senile plaques are accompanied by neuronal loss and atrophy in brain areas important for cognition such as the hippocampus, entorhinal cortex, and neocortex. Such neural damage can ultimately lead to mild cognitive impairment, the earliest precursor syndrome for AD and dementia (figure 1).

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Brain neurotransmitters and AD

Cholinergic neurotransmission: The neurotransmitter acetylcholine plays an important role in both attention and memory. (8) The finding that cholinergic synapses in the nucleus basalis of Meynert (NBM) are lost early in AD prompted the development of AChEIs, which prevent the breakdown of acetylcholine and improve cholinergic neurotransmission in surviving neurons (see figure 2 on www.geri.com). (2) Symptomatic treatment through this cholinergic approach has been the mainstay of AD therapy; yet there is no evidence that this treatment modifies the progression of AD. (8) Furthermore, one report from autopsy results suggests that nearly 25% of patients afflicted with AD do not exhibit degeneration of the cholinergic NBM, (9) and another report indicates that cholinergic deficits may not emerge until AD has progressed beyond the initial stages. (9) These findings, in conjunction with other basic, clinical, and epidemiological research, emphasize the limitations of cholinergic monotherapy and underscore the need for the development of new treatments.

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Glutamatergic neurotransmission: Glutamatergic neurotransmission in the CNS is a brief event that occurs as a result of a presynaptic burst of glutamate--the most abundant excitatory amino acid in the central nervous system (CNS)--into the synaptic cleft. Glutamate acts on ligand-gated receptors located in the plasma membrane of the postsynaptic neuron

and include both NMDA- and non-NMDA subtypes that mediate the rapid, excitatory neurotransmission in the brain. The NMDA receptor is a voltage- and ligand-gated receptor channel that, when open, allows [Ca.sup.2+] and [Na.sup.+] to flow into the cell and [K.sup.+] to flow out. Under cellular resting conditions, [Mg.sup.2+] blocks the NMDA receptor ion channel. When glutamate and its co-agonist glycine are present in the synaptic cleft, and a concurrent depolarizing event causes [Mg.sup.2+] to exit the channel, [Ca.sup.2+] and [Na.sup.+] enter the postsynaptic neuron. (10) [Ca.sup.2+] influx can result in activation of other calcium-dependent signaling pathways that are responsible for long-term cellular changes (see figure 3 on www.geri.com). Such NMDA receptor-mediated neurotransmission has been shown to be necessary in animal models of learning and memory, (11) with disruption of this process resulting in significant loss of cognitive function. (12)

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NMDA receptor-mediated excitotoxicity in AD: Because excessive glutamatergic signaling may be toxic to neurons, a phenomenon termed "excitotoxicity," (13) regulation of synaptic glutamate is crucial for the maintenance of normal neurotransmission. Chronic overstimulation of glutamatergic NMDA receptors is thought to result in excessive [Ca.sup.2+] influx into the postsynaptic neuron. Although calcium is important for many cellular processes, excess calcium causes osmotic disturbances and inappropriate activation of catabolic enzyme pathways, ultimately leading to neuronal death. Such cell death may trigger a chain-reaction of neuronal loss due to release of additional glutamate from dying cells. (13) Excitotoxicity may therefore contribute to the widespread loss of brain cells in AD. (13)

Antagonizing NMDA receptors

High-affinity NMDA receptor antagonists, such as MK-801 and phencyclidine (PCP), which potently block the NMDA receptor ion channel, offer superb protection from excitotoxic cell death in vitro, but have yielded very poor clinical results. These antagonists produce severe side effects including hallucinations, ataxia, and memory loss. Pharmacologic studies with these agents have shown that the combination of high-affinity binding, slow blocking/unblocking rates, and insensitivity to changes in membrane potential produce such potent inhibition of the NMDA receptor that normal levels of activity (required for learning and memory) are prevented. (6) The inability of these high-affinity drugs to allow normal physiologic activity offers an explanation for the severe side effects associated with these antagonists. Lower affinity NMDA receptor antagonists, including memantine, amantadine and dextromethorphan, exhibit properties distinct from their high-affinity predecessors. Memantine, in particular, appears to demonstrate selective inhibition of pathologic receptor activation while simultaneously allowing normal physiologic function. Just as with the high-affinity antagonists, in vitro and in vivo pre-clinical studies have shown that memantine effectively protects against excitotoxic cell death. (6) Unlike high-affinity antagonists, the low-moderate affinity, uncompetitive, voltage-sensitive binding properties and fast blocking/unblocking rate of memantine appear to allow it to exit the NMDA receptor ion channel during physiologic learning conditions (see figure 4 on www.geri.com).

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Memantine efficacy and safety

The clinical efficacy of memantine has been reliably demonstrated in several double-blind, placebo-controlled trials. In a 28-week U.S. clinical trial, (14) patients with moderate to severe AD (MMSE 3 to 14) were administered 20 mg/d (10 mg/bid), memantine, or placebo. Day-to-day function and global outcomes were assessed using a modified 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) and the Clinician's Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus). Cognition was measured using the Severe Impairment Battery (SIB). At week 28, patients receiving memantine exhibited significantly less global (observed cases analysis [OC]), functional (OC and last observation carried forward analysis [LOCF]), and cognitive decline (OC and LOCF; figure 5). The most commonly reported side effects (incidence greater than 10%) of agitation, urinary incontinence, and insomnia occurred at similar rates in both placebo- and memantine-treated patients, with agitation more frequently reported in the placebo group.

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In a 24-week open-label extension of this trial during which all patients were treated with memantine, those who were switched from placebo showed a favorable alteration in global, functional, and cognitive decline compared to the rate of decline on initial placebo treatment. (15) Similar to the placebo-controlled phase of the study, and as expected in later stages of AD, the most commonly reported side effects (incidence greater than 10%) of agitation and urinary tract infection occurred at similar rates in patients maintained on memantine and in those switched to memantine. (14,15)

A 24-week U.S. clinical trial in patients with moderate to severe AD assessed the efficacy of memantine (10 mg/bid) in a moderate to severe AD population who had already been treated with donepezil at least 6 months and who continued donepezil therapy throughout the memantine study period. (16) Function in ADLs, cognition, and global functioning were measured using the ADCS-ADL (19), the SIB, and the CIBIC-Plus, respectively. At study endpoint, patients receiving memantine/donepezil exhibited less functional and global decline than those treated with placebo/donepezil. Furthermore, patients receiving memantine/donepezil demonstrated improvement in cognition above baseline compared to patients receiving placebo/donepezil (figure 6). Table 2 summarizes the key clinical trials used in support of the New Drug Application (NDA) for memantine. These studies, (14,16,17) as well as pharmacokinetic and German post-marketing data, (18,19) demonstrate that memantine therapy either alone or in combination with donepezil, is efficacious and safe for the treatment of AD.

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Consistent with the clinical benefits seen in memantine-treated patients, a pharmacoeconomic analysis of the 28-week trial revealed that memantine therapy correlates to an average reduction in patient management costs of $1,090/month for society and $824/month for the caregiver due to lower rates of institutionalization and reduced caregiver time, respectively. (20) While these figures do not include the cost of treatment, the average cost of memantine ($120/month) is roughly 11% less than that of donepezil and 20% less than that of other commonly prescribed AChEIs. (21)

Clinical administration of memantine

Memantine (Namenda) is currently available in U.S. pharmacies. The recommended target dose is 20 mg/d (10 mg bid), with an upward titration from 5 mg qd over the course of several weeks (table 3) administered with or without food. (22)

Conclusion

The progressive cognitive decline seen in AD is devastating to patients, their families and caregivers, and presents a huge public health concern that will grow as the U.S. population ages. Many underlying mechanisms at work in this disease have been elucidated, even though the initial cause is still unknown. NMDA receptor-mediated glutamate excitotoxicity, which can cause neuronal loss and cognitive impairment, has emerged as a likely contributing factor. Safely preventing NMDA receptor-mediated excitotoxicity requires an antagonist that blocks pathologic activation of NMDA receptors while allowing normal physiologic function required for learning and memory.

Clinical trials have demonstrated the efficacy, safety, and tolerability of memantine, a low-moderate affinity, uncompetitive NMDA receptor antagonist, for the effective treatment of symptoms related to moderate to severe AD. Functional, cognitive, and global symptomatic decline in patients who received memantine was significantly reduced compared to placebo. Based on its proposed mechanism of action, memantine may prove even more beneficial when administered either prophylactically or in earlier stages of the disease, although clinical evidence for neuroprotection has yet to be established.

Preliminary cognitive and global results from a clinical trial of memantine monotherapy in mild to moderate AD patients have been promising, indicating that memantine may provide therapeutic benefits at all stages of the disease. Although this review has focused on NMDA receptor antagonism with memantine as a clinically useful therapeutic approach to AD, a multi-faceted treatment strategy ultimately may prove to be the most beneficial, with patients receiving a combination of pharmacotherapeutic agents aimed at the many divergent yet overlapping pathways involved in AD.

References

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(21.) MDDB-Select for Windows. Version 3.12. Chicago, IL: Wolters Kluwer Health, Inc.; 2004.

(22.) NamendaTM (memantine hydrochloride) Prescribing Information, Forest Laboratories, Inc.: St. Louis, MO.

Dr. Farlow is professor, Department of Neurology, Indiana University School of Medicine, Indianapolis. Disclosure: Dr. Farlow discloses that he has received consulting fees, honoraria, and grant funding from Forest Pharmaceuticals, Inc.

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