Updated 29 September 2004 Memantine: Implications for Treating Alzheimer's Steven T. DeKosky Bengt Winblad Steven T. DeKosky and Bengt Winblad led this live discussion on how the addition of memantine to the clinician's toolbox will change the management of Alzheimer's disease. Following its FDA approval last October, memantine is due to arrive in pharmacies this month. How should physicians use it? For whom should it be prescribed? What are good drug combinations? What side effects should doctors watch out for? Just how much of an improvement does this drug offer? Will this drug work for related forms of dementia? How long does its effect last? What is the best way to titrate the dose? We have posted our summary adapted from the briefing document (.pdf) that the drug's U.S. distributor, Forest Laboratories Inc., submitted to the Food and Drug Administration (FDA) last September. Our recent news story reports on the results of a trial of memantine combined with AChE inhibitors. You may also be interested in our previous live discussion on cholinesterase inhibitors. Steven T. DeKosky and Bengt Winblad led this live discussion on 29 September 2004. Readers are invited to submit additional comments by using our Comments form at the bottom of the page. View Transcript of Live Discussion — Posted 23 August 2006 Background Text The Medical Need Alzheimer's disease is the most common form of dementia in the elderly and is the fourth-leading cause of death for patients aged 65 or older. The prevalence of AD is estimated to be about four million people in the U.S. alone, and approximately one million elderly Americans have severe dementia. Moderate to severe AD represents an identifiable stage of AD and can be reliably diagnosed. A hallmark of the transition to the moderate and severe stages of AD is the progressive loss of the ability to perform activities of daily living. The current therapeutic options for AD approved by the FDA are the cholinesterase inhibitors (ChEIs), which are indicated for the treatment of mild to moderate AD. However, it is believed that seventy percent of diagnosed dementia patients already have advanced dementia symptoms. The time that the average AD patient spends in the mild stages, where episodic memory loss is the primary clinical finding, is relatively brief. Once the patient reaches the moderate stage, the remaining three to 12 years of life (depending on the age of onset, see related ARF news story) are spent experiencing further deterioration in cognition and activities of daily living (ADLs). There is no approved anti-dementia treatment in the U.S. for patients with advanced AD (MMSE <10). During the mild-to-moderate stages, cognitive skills show deterioration and this decline leads to impaired ADLs. Instrumental ADLs begin to be affected in the mild-to-moderate stages of AD, followed by pronounced deterioration in physical or self-care functions during the moderate-to-severe stage. The progressive decline in the patient's ADLs ultimately lead to nursing home placement. Decline in ADLs and cognition further burden caregivers. In severe AD, all intellectual functions are severely compromised, and the clinical picture is dominated by the patient's limited function and disruptive behavior. The estimated annual cost of patient care rises from $18,408 in mild to $36,132 in severe stages. Thus, there is a need for therapeutic agents that will slow decline, potentially reduce care costs, and delay institutionalization. Preclinical and postmortem studies of AD have associated changes in glutamatergic function with memory deficits, a hallmark of AD. Moreover, the excitotoxicity hypothesis holds that chronic glutamatergic overstimulation leads to neurodegeneration. Thus, the glutamatergic neurotransmitter pathway has been implicated in AD pathology and serves as a target for therapeutic intervention. About Memantine Memantine is a novel therapeutic agent that represents a new class of AD treatment options. Memantine has shown efficacy and safety in the symptomatic treatment of patients with moderate-to-severe AD. Memantine has recently been approved for the treatment of moderately severe to severe AD in the European Union and Australia. (Section 2.1 of the full briefing summarizes the history of the clinical development of memantine.) Memantine has been available in Germany since 1982 (originally approved for the treatment of organic brain syndrome) and is currently available outside the U.S. in 42 countries. As of February 2003, there were over 600,000 patient-years of exposure to memantine. Memantine is a low-to-moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage dependency and rapid blocking/unblocking kinetics. These pharmacological features appear to allow memantine to block the sustained activation of the receptor by glutamate that may occur under pathological conditions, and to rapidly leave the NMDA receptor channel during normal physiological activation. In humans, memantine is 100 percent bioavailable after an oral dose, undergoes minimal metabolism, and exhibits a terminal elimination half-life of 60 to 80 hours (75 percent or more of the dose is eliminated intact in the urine). It rapidly crosses the blood-brain barrier with a CSF/serum ratio of 0.52. Memantine does not inhibit cytochrome P-450 (CYP 450) isoenzymes in vitro, and its pharmacokinetics are not affected by food, sex, or age. Efficacy Memantine demonstrated efficacy in the treatment of moderate-to-severe AD using a dose of up to 20 mg/day in two key double-blind, placebo-controlled trials (Trials 9605 and MD-02) of 6-month duration in patients with probable AD. Also, efficacy of 10 mg/day of memantine was shown in an earlier trial (Trial 9403) of 12-week duration in dementia patients. AD patients were defined as having Hachinski Ischemia Scale [HIS] scores ² 4; (see Panel 1 in briefing pdf). In these studies, memantine was titrated from a starting dose of 5 mg/day (weekly titration by 5 mg/day increments) to a target dose of 20 mg/day administered as 10 mg twice daily in the two six-month trials, and a target dose of 10 mg/day administered once daily in the 12-week trial. Patients were diagnosed with probable AD using National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria in Trials 9605 and MD-02, and with dementia using the Diagnostic and Statistical Manual for Mental Disorders, 3rd revised edition (DSM-III-R) criteria in Trial 9403. AD stages were identified as moderate to severe based on scores on the Mini Mental State Examination (MMSE scores of 3-14 in Trial 9605; 5-15 in Trial MD-02; and <10 in Trial 9403), Global Deterioration Scale (GDS; overall range 5-6 in Trial 9605 and 5-7 in Trial 9403), Functional Assessment Staging (FAST ³ 6a in Trial 9605), and/or Clinical Global Impression of Severity (CGI-S; range 5-7 in Trial 9403). These three key memantine clinical trials are the first to evaluate the treatment of moderate-to-severe AD. Outcome measures were chosen to reflect the symptomatology of the more severe dementia patient. Specifically, in Trials 9605 and MD-02, the Severe Impairment Battery (SIB) and the 19-item version of the ADCS-Activities of Daily Living Inventory (ADCS-ADL19), which is modified for more advanced AD patients, were used as the indices of cognitive and functional change, respectively, and a global assessment of change was made by the clinician using the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC+). When Trial 9403, the earliest of the three, was conducted, the ADCS-ADL19 and SIB instruments were not generally available. Trial 9403 used the care dependency subscale of the Behavioral Rating Scale for Geriatric Patients (BGP) as a functional assessment, along with a co-primary measure of global change, the Clinical Global Impression of Change (CGI-C). The BGP-cognitive subscale, which was a subset of items from the BGP-care dependency subscale, was retrospectively defined and analyzed as a cognitive measure. (Panel 1 in briefing .pdf summarizes efficacy of memantine as measured in cognition, function, and global status from these three trials. See simplified Table below, full table in .pdf) Efficacy Results from 3-Key, Double-Blind, Placebo-Controlled Dementia Studies Trial Randomized Patients N Treatment Duration/ Groups/ Dosage Patient Population/ Diagnostic & Inclusion Criteria Efficacy Outcome Measures (Protocol Defined Primary Endpoints) P-values for 3 Key Domains Cognition Function Global 9605 Total N=252 Memantine N=126 28-week Placebo Memantine 10mg BID Diagnosis: Probable AD (DSM-IV and NINCDS-ADRDA) Severity: Moderate to Severe MMSE 3-14 GDS 5-6 FAST ≥ 6a HIS ≤ 4 ≥ 50 years of age SIB ADCS-ADL19 (Primary) CIBIC+ (Primary) <0.001(LOCF) 0.002(OC) 0.022 (LOCF) 0.003 (OC) 0.064 (LOCF) 0.025 (OC) MD-02 Total N=404 Memantine N=203 24-week Placebo Memantine 10mg BID Diagnosis: Probable AD (NINCDS-ADRDA) Severity: Moderate to Severe MMSE 5-14 ≥ 50 years of age Ongoing donepezil therapy ≥ 6 months at a stable dose (5-10 mg/day) for the past 3 months SIB (Primary) ADCS-ADL19 (Primary) CIBIC+ <0.001(LOCF) 0.001(OC) 0.028 (LOCF) 0.020 (OC) 0.027 (LOCF) 0.028 (OC) 9403 Total N=166 Memantine N=82 12-week Placebo Memantine 10 mg QD Diagnosis: Dementia (DSM-111-R) Severity: Severe MMSE < 10 GDS 5-7 CGI-S 5-7 HIS ≤ 4 (AD patients) > 60-80 years of age BGP-Cognitive BGP-Care Dependency (Primary) CGI-C (Primary) <0.001(LOCF) 0.001(OC) 0.012 (LOCF) 0.010 (OC) <0.001 (LOCF) <0.001 (OC) Safety Memantine has exhibited an acceptable safety and tolerability profile in 2,297 patients in 27 clinical trials involving a variety of neurodegenerative disorders (e.g., dementia, neuropathic pain, spasticity, and Parkinson's disease). This overall safety database, including studies with limited safety information, European postmarketing clinical practice experience, and other postmarketing drug experience studies, contains no evidence for rare, serious safety findings. A total of 1,748 patients were exposed to memantine in the core dementia and neuropathy safety studies. Adverse events, vital signs, and laboratory tests were systematically evaluated in the core safety trials, and electrocardiograms (ECGs) were assessed in two dementia (Trials MD-02 and 9605) studies and the two neuropathic pain studies. The core double-blind, placebo-controlled dementia trials (AD or VaD patients) included 922 placebo patients and 940 memantine patients. Approximately 80 percent of patients in both treatment groups completed the studies. Serious adverse events that were reported in more than 1 percent of either treatment group were confusion (memantine 1.6 vs. placebo 0.9 percent), inflicted injury (memantine 1.1 vs. placebo 1.7 percent), cerebrovascular disorder (memantine 1.0 vs. placebo 1.5 percent), fall (memantine 0.6 vs. placebo 1.1 percent), and agitation (memantine 0.5 vs. placebo 1.1 percent). Most of these were considered unrelated or unlikely to be related to the trial drug. The most common reason for discontinuation in both placebo and memantine patients was adverse events (11.5 percent in the placebo group and 10.1 percent in the memantine group). The most frequent adverse events (AEs) leading to discontinuation in this trial group were agitation (memantine 1.2 vs. placebo 2.0 percent), confusion (memantine 1.2 vs. placebo 1.1 percent), and cerebrovascular disorder (memantine 0.7 vs. placebo 1.1 percent). Treatment-emergent adverse events (TEAE) reported most frequently (>5 percent in incidence) by memantine-treated dementia patients and at an incidence greater than placebo patients were dizziness, confusion, headache, and constipation. None of the TEAEs were reported by >7 percent of memantine-treated patients or at a rate two times higher than in the placebo group (see Table below, or Panel two in .pdf). Most TEAEs were considered mild or moderate in severity and not related to the trial drug in either the placebo- or memantine-treated patients. The percentage of AD patients reporting TEAEs was similar in placebo- and memantine-treated groups. Patients with moderate to severe dementia had an overall TEAE profile similar to that of the entire dementia group. The profile and incidence of TEAEs (as compared to placebo) reported for AD patients receiving memantine as concomitant treatment with donepezil (Trial MD-02) was not different overall from that observed in AD patients receiving memantine alone (Trial 9605). Analyses of vital sign measurements, clinical laboratory data, and ECG results in the placebo-controlled trials revealed no clinically relevant differences between treatment groups. There was no evidence for any special safety concerns based on the preclinical safety trial results and specific assessments of possible psychotomimetic, neurologic, ophthalmologic, and cardiovascular effects from the clinical trials. In summary, the sponsor writes, memantine at its recommended dosage of 10 mg BID is well-tolerated with a safety profile similar to that of placebo treatment and is effective in providing clinical benefit for patients with moderate-to-severe AD. —Edited by Gabrielle Strobel. TEAEs in ≥ 5.0 of Patients in Either Treatment Group—Core Double-Blind, Placebo-Controlled Dementia Trials Adverse Events Placebo (N=922) n (%) Memantine (N=940) n (%) Dizziness 49 (5.3) 64 (6.8) Agitation 98 (10.6) 63 (6.7) Confusion 42 (4.6) 58 (6.2) Headache 31 (3.4) 54 (5.7) Constipation 28 (3.0) 50 (5.3) Fall 50 (5.4) 48 (5.1) Inflicted Injury 64 (6.9) 44 (4.7) Additional References—Posted 29 September 2004 Note: Please see original references in Briefing Document Full Text (.pdf) Periclou AP, Ventura D, Sherman T, Rao N, Abramowitz WT. Lack of Pharmacokinetic or Pharmacodynamic Interaction Between Memantine and Donepezil (September). Ann Pharmacother. 2004 Sep ; 38(9):1389-94. Abstract Doody, R, Wirth, Y, Schmitt, F, Möbius, HJ. Specific Functional Effects of Memantine Treatment in Patients with Moderate to Severe Alzheimer's Disease. Dement Geriatr Cogn Disord. 2004 ; 18(2):227-32. Abstract

Interventions Working Group for the Alzheimer's Association

Steven T. DeKosky, University of Pittsburgh School of Medicine. Dr. DeKosky serves on advisory boards for AstraZeneca, Cephalon, and Eisai Pfizer. He performs clinical research sponsored by Eisai Pfizer and Janssen. He serves as a consultant for Forest Laboratories, Eisai-Pfizer, Cephalon, Janssen, Novartis, AstraZeneca, Daiichi, and Teva Pharmaceuticals.

Lisa Gwyther, MSW, Associate Clinical Professor, Dept. of Psychiatry, Education Director, Bryan ADRC, Duke University Medical Center. No conflicts.

Zaven Khachaturian, KRA, Inc. We KRA, Inc., have consulting agreements with the Alzheimer’s Association, Toyama Chemical Co. (Japan), and GSK. No direct or specific conflicts regarding memantine, other than a theoretical one as the author of the “Calcium Hypothesis,” the presumed mode of action for memantine.

John C. Morris, MD. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. From July 2002 to July 2003, Dr. Morris participated in clinical trials of antidementia drugs sponsored by Elan, Eli Lilly, and Merck. He has also served as a consultant or received speaking honoraria for the following companies: Celera, Forest Labs, Janssen, Neurochem, Novartis, and OCC/Johnson & Johnson.

Lon S. Schneider, M.D. Consultant for Forest. He received travel reimbursement from Lundbeck Consultant for JNJ, Pfizer, and Novartis. He also received grant and clinical trials related funds from JNJ, Pfizer, Novartis.

Kathleen Anne Welsh-Bohmer, Ph.D. Professor of Psychiatry and Behavioral Sciences, Duke University.

Question—Posted 31 January 2007

My dad has been taking Reminyl for years. Recently, the nursing home doubled the dose, and he has been much more agitated. That made me wonder whether he should try memantine. He has never tried memantine and he is definitely in the moderate to severe stage of AD or dementia. My question is, would he start that with the Reminyl? Would it be best to eliminate Reminyl altogether and start memantine? Or perhaps reduce the Reminyl and add the memantine?

Reply by Doug Galasko—Posted 31 January 2007

The only published study on the combination of Namenda with a cholinesterase inhibitor is the one that was used by Forest as part of their package to obtain FDA-approval for Namenda in moderate to severe AD. That study combined memantine (Namenda) with donepezil versus donepezil alone, and found benefits regarding slower progression of cognitive test scores and ADL scores. The combination was well-tolerated with no suggestion that behavioral symptoms were related to using both medications. In principle, memantine could be combined with a different cholinesterase inhibitor, for example, galantamine or rivastgmine, although there have not been published clinical trials to formally make this comparison. There is an ongoing clinical trial to investigate the combination of rivastigmine and memantine, sponsored by Novartis.

An open-label extension study to one of the original memantine clinical trials was reported by Reisberg et al. (2006). In that study, 175 (96.7 percent) of 181 subjects who completed the 28-week randomized trial entered the open-label study for a further 24 weeks. The mean age was 75 years old, and most subjects were female. Nearly 90 percent of the study population was Caucasian. The mean MMSE score was about 7. The group that were previously taking placebo and switched to memantine showed a significant benefit in functional, global, and cognitive efficacy assessments compared with their mean rate of decline during placebo treatment. Data suggested that the group in treatment for 12 months continued to show clinical benefit even though they declined on outcome measures. Memantine was well-tolerated for 12 months of treatment overall. This indicates sustained beneficial effects from memantine in AD.

What is not clear is whether memantine helps patients with milder AD. Unpublished clinical trials using memantine at this stage yielded equivocal overall results. This does not mean that milder patients will never show a response to memantine; it simply means that the likelihood of their doing so is smaller than it is for moderate to severe dementia.

Question from Lauretta W.—Posted 6 February 2004

My husband began using Memantine (brought in from a buyers club in NY) from Germany over a year ago. He used 10 mg bid. In 9 days he began speaking again and eating again without help. A year later the disease progressed to the point where he had lost 30 lbs and was not eating or drinking. We considered a feeding tube and then decided against it, but increased his medication first to 3 [doses] a day, and then 4 [doses of 10 mg] per day. At 4 per day he began eating by himself and started to gain weight again. His doctor is refusing to prescribe any more than 2 a day without literature saying it would be okay to do. I feel it is a matter of life or death. Do you have anything I could send to my doctor to help convince him? My husband is 55 and in great health otherwise.

Reply from Bengt Windblad— Posted 6 February 2004

There are no published data on memantine doses above 20 mg in AD. Some of the older studies in "organic brain syndrome" used higher doses, but it is difficult to recommend more than 20 mg/d based on these sometimes poorly documented studies. In neuropathic pain, on the other hand, we have (so far unpublished) data showing that efficacy of memantine in pain is better with 40 mg/d - but adverse-event rates clearly increase and more patients drop out than with 20 mg/d. Overall, we are not very happy with the recommendation of higher doses in dementia patients. Based on the mode of action, we do not expect a major increase in efficacy with higher doses in this indication and, in contrast, the safety and tolerability profile may worsen. (There probably is a U-shaped dose-response curve with very high doses worsening cognition via an impairment of the physiological function of the NMDA receptors). Things seem to be different in pain, and perhaps for patients with a high BMI / body weight (as plasma levels decrease with weight).

Question from J.M.— Posted 25 March 2004

My husband was diagnosed with "probable early stage AD" two years ago. Since that time, his regimen includes Reminyl to offset cognitive losses and Paxil to dampen anxiety-driven personality deficits. About a year ago, he began using .5mg of clonapine to minimize his nocturnal myoclonic jerking. His only other medical condition is a "non-pathologically induced prostate enlargement" which is easily managed by Proscar, a supplemental hormone.

With that said, we continued down the AD road, all the while researching both the disease and alternative treatments. We discovered Memantine about a year or so ago and have tracked it with the hopes of adding it to his regimen. His geriatric psychiatrist agreed to this once it was officially approved for use by the FDA. During this last month, Alan successfully titrated Namenda and it is now another part of his daily regimen at 10mg twice a day. Based on our research and the discovery that Memantine could enhance activity of SSRI drugs, we went one step further and also reduced his Paxil during the titration process.

The results are phenomenal. His first response was increased energy and renewed interest in activities and socialization. He is much calmer and is able to concentrate with minimal distraction. He can follow abstract conversation with more ease as well as learn and retain new information. The latest thing we noticed was that he no longer waivers upon rising, even when he is fatigued during the evening.

So... What is my question? I would like to know how our geriatric psychiatrist could reach researchers like Dr. John Morris, to present his clinical findings which would, as I understand it, help argue for the need for additional studies related to long-term use of Namenda. Admittedly, my husband is his first patient to be prescribed Namenda but since our doctor is the head of our local hospital's psychiatric facility, this information may prove to be beneficial to many.

Any help you could provide would be welcome. — J.M.

My husband (58) has moderately severe AD and it was recommended that we apply to the Special Access Program for Memantine. He was denied on the grounds that "he's an epileptic." He is not, but does take Epival "off label" as an aid in controlling agitation as well as a prophylatic against potential seizures which the Dr says are common in advancing AD. Is it the disorder of epilepsy or the interaction of drugs which precludes the use of Memantine?

A. Reply from Lon Schneider

Memantine belongs to a class of drugs known as NMDA antagonists. Some NMDA antagonists may be pro-convulsant. That is, they may tend to increase the likelihood of or cause seizures in people who have epilepsy. The available NMDA antagonists, memantine, dextromethorphan, and amantadine, however, are probably less likely to worsen epilepsy although they have not been systematically evaluated for this effect. In memantine clinical trials in patients with moderate to severe Alzheimer's disease there does not appear to be an increased risk for seizures, although the numbers studied are few.

Divalproex (brand names Epival in Canada and Depakote in the US) is an anticonvulsant medication used to treat seizures and migraine headaches. Divalproex, however, is also approved by the FDA as a mood stabilizer to treat mood swings and hyperactivity in people with bipolar depression. It is helpful for treating what are known as manic episodes. Some physicians use divalproex to treat agitation and aggression in people with dementia, although it is not officially approved for this use and some clinical trials have been not shown efficacy.

Seizures occur in some people with advancing Alzheimer's dementia. Many experts however would not use an anticonvulsant such as divalproex as a prophylactic in order to protect against possible seizures for several reasons: (1) it cannot be predicted who with Alzheimer's disease will get seizures; (2) a single seizure may not require ongoing use of anticonvulsants; (3) physicians try to minimize medications used; (4) anticonvulsants have side effects including sedation, somnolence, and confusion, and in the case of divalproex there may be other side effects such as liver toxicity and a decrease in blood platelets needed for clotting. As with all medications used to treat behavioral symptoms in people with dementia, divalproex should be tapered and discontinued at intervals to assess whether it is helping.

There is no known contraindication to combining divalproex with memantine. In the absence of detailed information and an examination, we cannot speak specifically about whether memantine or divalproex is indicated in any particular person.

Comment by Bengt Winblad—Posted 1 July 2004

Question: Is Memantine's effectiveness sufficient to replace Aricept, or are both required for effective treatment?—Posted 12 July 2004

This is a serious question, since my mother is not wealthy, and each of these drugs costs about $150/month.

My mother, age 85, was diagnosed with probable AD two years ago. She has been taking Aricept for two years with good effect. She has good function for ADL, and is able to function without much assistance, however she had major memory impairment, some confusion and some agitation. Her physician has now suggested Memantine.

Reply from Steven T. DeKosky—Posted 12 July 2004

Memantine has never been tested in a direct “head to head” test against Aricept. The double-blind, placebo-controlled studies of memantine either have been done vs. placebo, or as an add-on people taking Aricept already. In the latter case, everyone was on Aricept and randomized to either memantine or placebo. Those studies showed evidence that in moderate to severe AD adding it to the Aricept results in some improvement on average.

The level of severity of the dementia is also important. Memantine is still in testing in mild to moderate AD, and approved for use in moderate to severe AD. Aricept is approved for (and has been extensively tested in) mild to moderate AD and studies are underway or just completed looking at its effectiveness in moderate to severe AD. If the patient has moderate to severe AD the studies have shown a benefit, albeit a small one, for memantine alone. However there is no perfect way to know if substituting memantine for Aricept would be equivalent or better.

Disclosure: I consult for both Pfizer and Forest Laboratories.

It's sad that pharma's hype about Alzheimer drugs leads families that cannot afford these top shelf drugs to feel so guilty. Patients know that a drug exists for their loved one and believe it would be negligent to withhold it. The industry preys upon the dire needs of AD victims by charging them outrageous prices for drugs that do little or nothing. Even if a percentage of patients gets a tiny bit better, that in no way dents the tragedy of the disease, salvages the person's dignity, or improves prognosis. These drugs are the emperor's new clothes. They not only let pharma reap billions, but they assuage the physicians' sense of helplessness before his or her patients. Most physicians base their judgement of drug efficacy on a simple enquiry of a family member as to whether they see improvement. On the basis of an anecdotal remark the physician is all too ready to place a significant financial burden on the family.

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