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Physician Guidelines About These Guidelines
As an initial step in developing this document, the Orange County
Vital Aging (OCVA) team reviewed published guidelines for managing
D i s C l A i m e r
dementia from the American Geriatrics Society, the American Academy of Family Physicians, and the College of Physicians. This provided a solid These guidelines are intended to be informational only. basis for guidance with demented patients. These guidelines are not intended to be, and should Because managing cognitive health in a primary care setting requires not be considered, a substitute for medical or other early intervention against all conditions that impair cognition, these professional advice and clinical experience. Medical guidelines cover a broad spectrum of physician behavior and decision- procedures, treatments, and their outcomes are highly making. All recommendations herein are founded on published dependent on individual circumstances, and should research in the fields of patient education, risk factors that affect always be considered in the context of appropriate cognitive health, medical practice management and logistics, cognitive medical or other professional advice and clinical assessment tools and methods, diagnosing medical conditions that impair cognition, and treating medical conditions that impair cognition.
While information provided here is based on various Best practices were gleaned from the medical literature and reviewed published scientific studies and existing guidelines by the OCVA Expert Panel Physicians to finalize the guidelines. as of the time it was written, research on medical and health issues is constantly evolving, and dose schedules OCVA expert Panel Physicians
for medications are frequently revised to reflect the most up-to-date knowledge. Readers must therefore Valerie Acevedo, D.O. (Neurology) always check product information and procedure instructions with the most up-to-date, published, Alvin Chang, M.D. (Internal Medicine) product information and data sheets, provided by the Bruce Cleeremans, M.D. (Neurology) manufactures, and the most recent codes of conduct and John Gregory Duffy, M.D. (Psychiatry) safety regulations.
Sam Elsanandi, M.D. (Psychiatry) The Orange County Vital Aging Program and its members make no representations or warranties to readers, David Gehret, M.D. (Neurology) express or implied, as to the accuracy or completeness Jorge Rivero, M.D. (Family Medicine/Geriatrics) of these guidelines, including without limitation that they make no representations or warranties as to the William R. Shankle, M.D. (Neurology) accuracy or efficacy of the drug dosages mentioned in William Tsai, M.D. (Internal Medicine) thee guidelines. The Orange County Vital Aging Program James Weiss, M.D. (Internal Medicine/Pulmonary) and its members do not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be Janice Young, M.D. (Neurology) claimed or incurred as a consequence of the use and/or Guidelines on pharmacologic treatment of Alzheimer's disease are application of any of the contents of this material.
based on FDA approved "Prescribing Information." Certain portions of the prescribing information are appended with clinical expertise from the OCVA Expert Panel Physicians, to describe well-tested dosage and titration strategies. Finally, the guidelines for treating Alzheimer's disease through psycho- Table of Contents
social interventions are based on a thorough literature review by a key community partner in the OCVA Program: Cordula Dick-Muehlke, Ph.D. section 1 Clinical Path Overview
Executive DirectorAlzheimer's Family Services Center, Huntington Beach, CA section 2 Educate Your Patients
Contact Us
section 3 Select Appropriate Patients For
section 4 Select Appropriate Cognitive
Assessment Method section 5 Diagnosis
5.1 Differential Diagnostic Workup for
Alzheimer's Disease and Related Disorders 5.2 Other Differential Diagnostic Workup
section 6 Treatment
6.1 Pharmacologic Treatment Strategies
for Alzheimer's Disease 6.2 Background For Pharmacologic
Treatment of Alzheimer's Disease 6.3 Psychosocial Interventions in MCI
and Early Alzheimer's Disease section 1 OCVA Clinical Path Overview
1. educate Your Patients
Patients who are educated about the causes of memory loss, and Clinical Path Overview
who are aware of risk factors for cognitive decline, are more likely to proactively manage their cognitive health. This will help you intervene early when treatment can be most effective.
2. select Appropriate Patients For Assessment
The current medical insurance environment requires physicians to establish "medical necessity" before conducting a reimbursable cognitive assessment. The criteria are clear and easily met. The PATIENTS FOR ASSESSMENT
OCVA guidelines will help you offer the highest standards of care Healthy Brain Checklist within an economically viable model.
3. select Appropriate Cognitive Assessment method
There are 3 pathways for having your patients assessed for cognitive deficits. You may: 1. Perform an office-based assessment and earn reimbursement.
Objective cognitive assessment (e.g.
MCI Screen) positive? 2. Refer to your usual channels for neuropsychological evaluation, or 3. Refer to the OCVA memory assessment service.
4. Diagnosis
Regardless of the assessment method chosen, your patients will likely remain in your care and need further management following Diagnosis & Treatment
the assessment. The nature of this clinical management will Any abnormality found in diagnostic Non-ADRD conditions workups (e.g. history, lab work)? depend on whether or not any cognitive impairment was objectively identified in the assessment process. Negative - No Cognitive
Positive – Cognitive
But still
physician has (If Preferred)
Reassure patient, educate Pursue diagnosis of them about risk factors they underlying cause in Diagnosis & Treatment
should manage, and plan to accordance with OCVA Any abnormality found in imaging re-assess their memory in Guidelines and monitor cognition via quarterly memory assessment.
But still
5. Treatment
It is important to treat all underlying medical conditions that are causing the cognitive impairment, including Alzheimer's disease. Generally, the earlier the treatment starts, the better the outcome will be.

section 2 educate Your Patients
select Appropriate
section 3
Patients who are educated about the causes of memory loss, and who Patients For Assessment
are aware of factors that impact the risk of cognitive decline, are more As described in more detail below, many patients should have their likely to raise timely concerns about their cognitive health. Therefore, cognition assessed while many others need not. Following these basic well-educated patients are more likely to engage you constructively guidelines will ensure that you offer your patient population the highest and to receive a high standard of care from your practice.
justifiable standards of care in an economically prudent manner.
To address this opportunity, the OCVA program offers two free establishing medical Necessity
educational brochures for your practice. We encourage you to order these OCVA brochures and make them available to your patient Insurance companies, including Medicare, do not reimburse routine memory assessment without medical necessity. Any one or more of the following establishes medical necessity: About memory loss
• a cognitive concern expressed by the patient.
Educate Your Patients
This educational brochure explains • a cognitive concern expressed by the patient's family member the many common causes of memory or caregiver.
loss and emphasizes the importance • a concern or observation by the physician or medical staff.
of early intervention to optimize treatment efficacy, regardless of the cause of the memory loss. The purpose Office Visits for General (Non-Cognitive) Care
of this brochure is to encourage those Regardless of the purpose of the patient's visit, it makes good sense patients in your waiting room, who to be vigilant about signs of memory loss in your "at-risk" or Medicare have a memory concern, to express that population, and to assess memory when medical necessity is met. concern during their visit. You may order The Healthy Brain Checklist is a short, check-box form that should be the brochure from the OCVA Program.
provided to patients at registration for each visit to your office. This is an excellent mechanism for proactively identifying early problems and for enabling patients to document medical necessity for further risk Factors for memory loss
assessment. Patients should have their memory assessed only if they meet This educational brochure explains the many risk factors for memory loss and other cognitive impairments. It also describes strategies for managing and reducing those risks. The purpose of this brochure is to Be Aware of the "High risk" Group
help those patients who are in good cognitive health to manage their Those patients aged 50 and older, with any one or more of the risk factors and remain so. Please request materials from the OCVA following risk profiles, warrant attention. They should have the opportunity to either complete the Healthy Brain Checklist, or be engaged in a direct discussion about their cognitive health: • Personal history of stroke or head injuries• Family history of AD or related disorders• Cardiovascular risks, including high cholesterol, hypertension, obesity, and smoking All of these patients are at higher risk for cognitive problems, but do select Appropriate Cognitive
not meet medical necessity for further cognitive assessment based section 4 Assessment method
solely on their risk profile. These patients should be made aware of their increased risk and have their memory assessed only if they meet There are three pathways from which you can choose how best to have medical necessity (as outlined above).
your patients assessed for cognitive deficits. Each pathway is equally effective and physicians should choose the one that best fits within the scope and capabilities of their practice.
medicare routine Physical exams
Beginning in January 2011, CMS will honor two new reimbursement
Three Pathways to Assess Your Patients
codes*, one for a "Welcome to Medicare Visit" that can be used within 1. You may perform an office-based assessment and earn the first year of Medicare eligibility, and one for an annual "Medicare Wellness Visit". The guidelines for each of these visits stipulate that 2. You may refer to your usual channels for neuropsychological the physician assesses the patient for cognitive impairment. All of these patients should complete the Healthy Brain Checklist. 3. You may refer to the OCVA memory assessment service.
* Centers for Medicare Services established the two following codes 1. Office-Based Assessment
taking effect on January 1, 2011: Assessing memory in your office involves using a cognitive assessment instrument to objectively measure the patient's • G0438 – Annual Wellness Visit; includes a personalized prevention performance on a series of cognitive tasks, and then scoring plan of service (PPPS), first visit their performance in accordance with established means for their • G0439 – Annual Wellness Visit; includes a personalized prevention demographic peer group. There are many instruments available plan of service (PPPS), subsequent visit and several are briefly described below. Any patient you see for an Annual Wellness Visit, who indicates a concern on the Healthy Brain Checklist, should be further evaluated. • mCi screen – This is the tool recommended, but not required, for
Select Appropriate
Guidelines for such further evaluation are summarized under "Select Patients For Assessm
participating physicians in the OCVA program. It is a ten-minute, Appropriate Cognitive Assessment Method" electronically scored test of short-term memory and has the highest sensitivity for detecting mild cognitive impairment among The Healthy Brain Checklist
all tests in the published literature. It can be administered by office This short, check-box form can be completed by patients at staff and is attractively reimbursed by Medicare and most private registration in less than two minutes.
payers. It requires Internet connectivity at the point of care and a licensing fee. Instructions for establishing an account with a free Use it to identify early stage problems and to document medical trial are available at: necessity for an assessment.
Download at www.ocvitalaging.org/physician
• mini-mental state exam (mmse) – This was the original
standard for primary care assessment but is somewhat outdated and no longer reimbursed by Medicare and other payers. The primary advantage is that its 30-point scale is well known. The disadvantages are that it was designed to assess dementia (not mild cognitive impairment) and it is not sensitive for detecting subtle decline. Furthermore, it must be scored manually and there are no published norms to adjust for patient age and education level. It takes about ten minutes to administer. The testing materials section 5 Diagnosis
and scoring instructions can be purchased through:www.parinc.com.
Regardless of the results of the memory assessment (normal or abnormal), it is important to follow the guidelines that promote • Clock Drawing Test - This is another well-known standard for
ongoing cognitive vitality for your patients.
assessing severe impairment and dementia (not mild cognitive impairment). The scoring is somewhat more subjective than the Normal Assessment result
MMSE and it has equally poor sensitivity for detecting subtle decline. If the patient does not show objective evidence of memory or cognitive It is not generally reimbursed but it is free to use and usually quick impairment, and that is clinically consistent with the physician's to administer, taking from 3 to 6 minutes. A key point of difference impression, then: is that this tool tests visuo-spatial skills whereas most of the more 1. Reassure the patient and educate them about risk factors common tools assess memory. they should manage, and share the brochure "Risk Factors for • montreal Cognitive Assessment (moCA) – This is a combination of
many brief neuropsychological tests that have been assembled into 2. Advise the patient to use the risk factor identification tool for a battery with a 30-point scale like that of the MMSE. It is a relatively Alzheimer's disease and related disorders (ADrD) at the OCVA
new test with growing validation for detecting dementia but minimal website (www.OCVitalAging.org). This will make them aware of data showing an ability to detect mild cognitive impairment. For use their risks, as well as how best to manage them, according to in a clinical setting, the MoCA requires the purchase of a licensing agreement. Instructions for administering and scoring the MoCA are 3. Schedule the patient for re-assessment in 12 months to assure that they remain cognitively healthy.
www.mocatest.org. Abnormal Assessment result
2. refer to Usual Channels for Neuropsychological evaluation
If the patient shows objective evidence of memory or other cognitive If you currently refer patients with memory complaints to a particular impairment, then the cause of the problem should be diagnosed and source for neuropsychological evaluation, there is no compelling treated by using one of the following two options: reason to disrupt that established approach. However, you might 1. Order ADRD Diagnostic Work-Up consider using a simple, office-based assessment to determine which Following the National Institute of Neurological and Communicative patients should be referred. Diseases and Stroke/Alzheimer's Disease and Related Disorders The most important aspect of these guidelines is that you are vigilant Association (NiNCDs-ADrDA) diagnostic guideline for ADRD will
in identifying subtle complaints and ushering the patient forward generate an accurate diagnosis in more then 90% of cases.
along some constructive pathway toward a high standard of care.
These diagnostic guidelines are summarized in the following pages: 3. refer to OCVA memory Assessment service
You may wish to refer your patients to the OCVA Memory Assessment • ADRD Diagnostic Work-Up Guidelines (Section 5.1) Service at Hoag Hospital. Through this pathway, your referred • Other Diagnostic Work-Up Guidelines (Section 5.2) Select Appropriate Cognitive Assessm
patients will be assessed with the MCI Screen and the test results will be provided to you so that you can decide appropriate next steps in 2. Refer to an ADRD Specialist accordance with those results. The OCVA has also assembled a panel OCVA maintains a list of specialists who can accept referrals as needed. of experts who can receive specialty referrals as needed.
To obtain the list, please contact the program Education and Screening For more information, please contact: Education and Screening Coordinator Phone: 949/764-6288 Delivering an Alzheimer's Diagnosis
Differential Diagnostic Work-up
In recognition of the growing importance of Alzheimer's disease, the 5.1 for Alzheimer's Disease and related
National Alzheimer's Association held four regional town hall meetings with more than 800 participants, including 300 people living with the disease. The outcome of the meetings, summarized as The 2008 routine ADrD diagnostic tests include:
Report: Voices of Alzheimer's Disease, identified diagnostic challenges and dissatisfying interactions with the medical community as key a. Blood tests to exclude potentially contributing causes of challenges to address.
cognitive impairment, including: • Chemistry panel: hyponatremia, hypocalcemia, hypercalcemia, Several specific insights were voiced by the meeting participants and hypokalemia, renal dysfunction, hepatic dysfunction, published by the Alzheimer's Association as Principles for a Dignified hyperglycemia, hypoglycemia, protein wasting.
Diagnosis. These insights from families and patients with Alzheimer's disease provide suggestions on how to improve the diagnostic • CBC with differential: anemia, leukopenia, leukemia, challenges and process that both patients and physicians face. These thrombocytosis, thrombocytopenia, megaloblastosis, insights include: lymphocytopenia, lymphocytosis, monocytosis, acute infection.
• Fasting lipid panel: low HDL (<45), high LDL (>100).
• Talk to me (a patient) directly, the person with dementia.
• Vitamin D-1,25(OH)2, B12, folate: vitamin deficiencies.
• Tell the truth.
• Homocysteine: homocysteinemia (>14).
• Test early.
• TSH, free T4: hypothyroidism, hyperthyroidism.
• Take my concerns seriously, regardless of my age.
• Deliver the news in plain but sensitive language.
b. Urinalysis: proteinuria, glucosuria, ketonuria, hematuria, • Coordinate with other care providers.
c. Non-contrast MRI with volumetric assessment of hippocampus • Explain the purpose of different tests and what you hope to learn.
(CT if MRI not possible). Radiologic interpretations consistent • Give me tools for living with this disease.
with a diagnosis of: • Work with me on a plan for healthy living.
Alzheimer's Disease • Recognize that I am an individual and the way I experience this • Relatively greater atrophy in the hippocampus, medial temporal or disease is unique.
temporal lobe.
• Alzheimer's is a journey, not a destination.
• Amount of ischemic vascular disease does not explain any As a healthcare professional who touches patients' lives, you observed atrophy.
might be interested in reading the short document Principles for a • Absence of hydrocephalus, masses, or hemorrhages.
• Subtle amounts of atrophy may be missed. Therefore a negative You may download the Principles for a Dignified Diagnosis document at CT or MRI report (e.g., normal, age-related changes, mild generalized atrophy) does not exclude Alzheimer's disease if there is objective cognitive impairment.
Cerebrovascular Etiology • Extensive ischemic white matter disease.
• Well-placed lacunar infarcts or hemorrhages in the hippocampus or thalamus.
• Large infarct of the anterior, middle or posterior cerebral artery.
5.2 Other Differential Diagnostic Work Up
• Medium to large cerebral hemorrhages, or residua thereof.
Tests that can be used to further confirm cognitive impairment not Traumatic Brain Injury due to Alzheimer's disease (AD) depend upon the patient's underlying
• Focal or asymmetric patterns of atrophy, especially in inferior medical conditions and risks for possible: frontal or anterior temporal lobes.
• Small, petechial hemorrhages, especially in the white matter.
• Radiation therapy, chemotherapy, anticonvulsants, • Diffuse axonal injury, seen as focal areas of white matter anticholinergics, antipsychotics, and chronic abuse or demyelination, and blood residua.
dependence upon benzodiazepines, tranquilizers, anxiolytics or Normal Pressure Hydrocephalus • Ventriculomegaly greater than the degree of cortical atrophy.
Action: Withdrawal, reduction or substitution of the potentially
• Periventricular white matter increases in signal intensity Organ and systemic Disorders
• Ballooning of the 3rd ventricle.
• Thinning of the corpus callosum.
• Lead, mercury, carbon monoxide, organophosphate insecticides, toluene, industrial solvents.
if the routine ADrD diagnostic tests do not identify the
• Immunologic Disorders etiology, then there are two possibilities:
• Systemic lupus, temporal arteritis, cerebral arteritis. 1. The objectively established cognitive impairment is a false • Serum protein- and immuno-electrophoresis, specialized positive result and the patient does not have a progressive studies for cerebral vasculitis and immunodeficiency 2. The routine ADRD diagnostic tests were not sensitive enough Action: Refer to rheumatology or immunology.
(a false negative result), and more specialized ADRD diagnostic • Severe Pain Syndromes: MR of the spine or other affected body testing is needed. part, EMG/NCV studies. There are five approaches to differentiating between these two Action: Refer to pain specialty.
• Metabolic Syndrome a. Repeat the same cognitive test now. Look for variability in The US National Cholesterol Education Program Adult Treatment performance to identify whether the previous result was a false Panel III (2001) requires at least three of the following: positive or false negative. • Central obesity: Waist circumference ≥ 102 cm or 40 inches b. Repeat cognitive testing with the same tests in 4 to 6 months (male), ≥ 88 cm or 36 inches (female) or body mass index > to look for change. This will establish whether there is a progressive cause of cognitive impairment or not. • Fasting Lipid Panel: c. Refer to a neuropsychologist for a more comprehensive battery of tests (if not already done) that can help better determine if - Triglycerides: ≥ 150 mg/dl (≥ 1.7 mmol/L).
there is evidence of a progressive cognitive impairment and can - HDL-C < 40 mg/dL (male), < 50 mg/dL (female).
help differentiate AD from non-AD causes. - Blood Pressure ≥ 130/85 mm Hg d. Refer to an ADRD specialist. • Fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dl). Action: Refer to endocrinology, internal medicine, diabetology.
hallucinations, visual problems, executive dysfunction, aprexia.
• Diabetes or Pre-diabetes: Fasting glucose, HgbA1c. • Frontal Temporal Lobe Disease: Usually age of onset is 50-60 Action: Refer to diabetology, endocrinology.
years old. Primarily affects frontal and temporal lobes. Loss of language, apraxia, personality changes, disinhibition or other • Thyroid Disorders: Hypothyroidism, hyperthyroidism behavioral abnormalities, and flat or inappropriate affect are early • Cerebrovascular disease: Small and large strokes, subdural, subarachnoid, cerebral, and intraventricular hemorrhages. • Hungtington's Disease: Usually age of onset is 30-40 years old. • Orthostatic blood pressures, carotid/transcranial Doppler, Choreoathetosis, executive dysfunction, memory loss.
MR angiography, sedimentation rate, PT/PTT, coagulopathy studies. • Creutzfeld-Jakob Disease: Movement disorder, insomnia, Action: Refer to stroke neurology.
inattention, fatigue, and rapidly progressive dementia are characteristic. Any age can be affected. Abnormal periodic EEG • Cardiovascular Disease: (Coronary artery disease, Arrhythmia, Valvular Disease, Congestive Heart Disease, Cardiomyopathy): CRP, ECG, Cardiac Doppler, Holter monitor and other appropriate • Traumatic Brain Injury: Can be progressive if multiple head injuries cardiac studies. or very severe single head injury with loss of consciousness.
Action: Refer to cardiology.
• Epilepsy: EEG studies. • Sleep Disorders (Sleep Apnea, Myoclonus, REM Behavior Disorder, Action: Refer to neurology or epileptology.
• CNS Infection (HIV, Cryptococcus, cysticercosis, neurosyphyllis) Action: Refer to sleep specialist.
Action: Refer to infectious diseases.
• Pulmonary Disease (COPD, restrictive lung disease, other hypoxic • CNS Demyelination (Multiple Sclerosis, Kufs disease, Adrenoleukodystrophy, Metachromatic leukodystrophy, other Action: Refer to internal medicine or pulmonology.
storage diseases) • Kidney Disease: GFR, urinalysis. Action: Refer to neurology.
Action: Refer to nephrology.
• Liver Disease: Liver enzymes, hepatic encephalopathy.
Disorders Affecting The Central Nervous system
• Depression, Anxiety, Obsessive Compulsive Disorder: appropriate history or standardized scale evaluation.
Action: Refer to psychiatry.
• Other Psychiatric Disorders Action: Refer to psychiatry.
• Parkinson's Disease: Movement disorder followed by executive dysfunction, visual-spatial deficits and memory loss at least several years later.
• Lewy Body Disease: Marked fluctuation in level of confusion, loss of balance, difficulty walking, REM behavior disorder, visual such as mental/physical exercise, and diet, as well as psychosocial section 6 Treatment
intervention, careful management of co-morbid conditions such as Optimal treatment follows accurate diagnosis of any underlying diabetes and hypertension, and integrating community resources for medical conditions. Guidelines for performing an accurate patients and families.
diagnosis of conditions that impair memory are available in sections For more details on the psychosocial components of optimal treatment, 5 of this guideline.
Treating Alzheimer's disease and related disorders (ADrD) requires a
• Psychosocial treatment of AD (Section 6.3) robust approach that includes: Community resources that support appropriate psychological • Identification and treatment of common medical conditions interventions are available at: • Pharmacologic treatment • Non-pharmacologic treatment Pharmacologic Treatment strategies
identifying and Treating Common medical Conditions
6.1 for Alzheimer's Disease
Untreated, or not well-controlled common medical conditions, such as thyroid disease, vitamin deficiency, heart disease, and diabetes frequently cause memory loss. Similarly menopause and testosterone For a full discussion of the background for the pharmacologic deficiency, various medications, and depression can also cause treatment strategies given below, please see Section 6.2 memory loss. It is important to make sure that these conditions are "Background for Pharmacologic Treatment of Alzheimer's Disease." well controlled and monitored regularly. Treatment guidelines for those Also please note that the indicated treatment efficacy will differ conditions are widely available from a variety of sources.
from patient to patient, and may not be expected for all patients
with Alzheimer's disease (AD).
Pharmacologic Treatment of ADrD
Like many other diseases, early detection and treatment of ADRD is
Overall Treatment strategy
the key to successful treatment outcomes. For Alzheimer's disease Although there is considerable variability between patients with AD, (AD), there is a substantial body of evidence showing disease-delaying
there is a substantial body of evidence showing disease-delaying effects using combined therapy of a cholinesterase inhibitor (Exelon®, effects using combination therapy of a cholinesterase inhibitor Razadyne®, Aricept®) and memantine (Namenda®). Because these (Exelon®, Razadyne®, Aricept®) and memantine (Namenda®). Because effects occur at all clinical stages of AD, it is imperative to initiate these effects occur at all clinical stages of AD, it is imperative to initiate combined therapy as early as AD is detected, and continue patients on combination therapy as early as AD is detected, and to continue combined therapy until they reach the hospice terminal stage of AD. patients on combination therapy until they reach the hospice terminal For more details, please review: Available evidence on the efficacy of the cholinesterase inhibitors in • Pharmacologic treatment of AD (Section 6.1) delaying AD progression indicates that: • Rationale for Pharmacologic treatment of AD (Section 6.2) • Aricept® is likely to provide disease-delaying effects for 1-3 years.
Non-Pharmacologic Treatment of ADrD
• Razadyne® is likely to provide disease-delaying effects for Non-pharmacologic interventions have been recognized as important components of an optimal treatment strategy. Such • Exelon® is likely to provide disease-delaying effects for 1-4 years.
interventions include, but are not limited to, life style modifications Therefore, after 1-3 years of treatment with Namenda plus Aricept Aricept Dosing schedule
or Razadyne, patients may benefit by switching to Namenda plus the Exelon patch, particularly if more rapid decline has recently occurred.
® (donepezil HCl) Tablet Aricept is a prescription medication to treat mild, moderate and severe step 1: set and manage expectation About Treatment
AD. It is available in 5, 10, and 23 mg/day in tablet form. The starting Before starting new medications, it is always helpful for patients and dose is 5 mg/day and can be increased to 10 mg/day after 4-6 weeks of family members to understand what to expect from these treatments. treatment and good tolerability. Similarly it can be increased to 23 mg/ Frequently patients and caregivers have unrealistic expectations and day after at least 3 months of treatment and good tolerability.
don't realize that "not getting worse" means that the medications are working. Since AD is a progressive degenerative disease, "stabilizing" the symptoms can be a positive outcome. Patients should also understand that finding the right combination of medications and dosages is a process that may take months. Finally, physicians should Stop Aricept: related side
effects should resolve
make it clear that some percentage of patients may not respond in any No side effect / within 3-5 days.
meaningful way to the treatment.
Wel tolerated for 4-6 weeks • If side effects resolve Therefore, setting the right expectations will help patients and family (Aricept-related), then use alternate cholinesterase members approach the treatment process with a constructive mindset inhibitor or go back to the and a realistic idea about the course ahead.
prior dosage.
step 2: start Cholinesterase inhibitor
• If side effects do not resolve, they are not Aricept-related, (Aricept®, exelon®, razadyne®)
No side effect / Wel tolerated and medical evaluation to It is important to choose the correct cholinesterase inhibitor and for 3 months or longer.
identify the cause of the side effects is indicated.
its maximum, well-tolerated dose within the approved range. This process may take weeks to months, and it is always recommended to objectively measure the treatment effect on memory and function after achieving a stable optimal dose. For more details, please see: • Aricept Dosing Schedule• Exelon Dosing Schedule• Razadyne Dosing Schedule Loss of effect
Consider switching to other after 1-3 years?
step 3: Add memantine (Namenda®)
After reaching the optimal dose of the chosen cholinesterase inhibitor,
add Namenda and find the maximal dose, from 5 to 20 mg, that is well *Take at dinner or bedtime.
tolerated without side effects. After achieving a stable optimal dose, it If nightmares or vivid dreams is always recommended to objectively measure the treatment effect on occur, then take it in the a.m.
memory and function. For more information, please see: • Namenda Dosing Schedule exelon Patch Dosing schedule
razadyne er Dosing schedule
® (rivastigmine transdermal system) Razadyne® ER (galantamine hydrobromide extended-release) Exelon Patch is a prescription medication to treat mild to moderate AD. It is available in 4.6 and 9.5 mg/day. The starting dose is 4.6 mg/ Razadyne ER is a prescription medication to treat mild to moderate day and can be increased to 9.5 mg/day after a minimum of 4 weeks of AD. It is available in 8, 16 and 24 mg/day. The starting dose is 8 mg/ treatment and good tolerability.
day and can be increased to 16 mg/day after a minimum of 4 weeks of treatment and good tolerability. Similarly, it can be increased to 24 mg/day after a minimum of 4 weeks of treatment and good tolerability.
Remove Exelon patch:
side effects should
resolve within 2 days.
• If side effects resolve No side effect / Wel tolerated for (Exelon-related), reapply the a minimum of 4-6 weeks patch over the abdomen. Stop Razadyne ER:
This will reduce the actual No side effect / Wel tolerated Related side effects
dose to 3.1 mg and 6.7 mg in for a minimum of 4 weeks should resolve within
4.6 mg and 9.5 mg patch, 2-5 days.
respectively. If not well tolerated, then use alternate • If side effects resolve (Razadyne-related), then use alternate • If side effects do not resolve, they are not Exelon-related, cholinesterase inhibitor and medical evaluation to or go back to the prior identify the cause of the side No side effect / Wel tolerated effects is indicated.
for a minimum of 4 weeks Loss of effect
• If side effects do not after 1-4 years?
resolve, they are not Consider switching to other Razadyne-related, and medical evaluation to identify the cause of the *Apply the patch to the upper body (chest, shoulder, side effects is indicated.
Stay on Exelon Patch back) each a.m., and remove the previous day's patch. Rotate the site to avoid skin irritation.
Loss of effect
Consider switching to other after 1-3 years?
*Take after breakfast or dinner to avoid GI upset.
Stay on Razadyne ER Namenda Dosing schedule
Namenda Dosing schedule
(Possible alternative approach) (Recommended by manufacture) Alternatively, because the terminal elimination half-life is 60-80 hours, Namenda (memantine HCl) is a prescription medication to treat Namenda may be given as a once a day drug. Also, the time to steady the symptoms of moderate to severe AD. It is available in 5 and state is 3 weeks. For this reason, Namenda may be better tolerated by 10 mg tablets.
changing dose every 2 weeks instead of every week during titration. One 5 mg tablet in am Stop Namenda: Related
side effects should
resolve within 3-14 days.
No side effect / • If side effects resolve Wel tolerated for 2 weeks (Namenda-related), then the One 5 mg tablet in am & one 5 mg tablet at night* dose should be reduced by 5mg. If this does not work, patient may not be able to tolerate Namenda.
• If side effects do not resolve, One 10 mg tablet in am & one 5 mg tablet at night they are not Namendarelated, and No side effect / Wel tolerated for 2 weeks medical evaluation to identify the cause of the side effects is indicated.
One 10 mg tablet in am & one 10 mg tablet at night No side effect / Wel tolerated for 2 weeks *For patients with severe renal impairment, 5 mgtwice daily is the recommended dose.
*Take in am. If experiences drowsiness, take at bed time.
step 4: monitor Cognition and Function every 3 to 6 months
Depending on the structure of any given practice, reimbursement for performing cognitive assessment may be an important After optimizing the doses of both the cholinesterase inhibitor and consideration in the selection of the most appropriate assessment namenda, schedule follow-up visits every 3-6 months and measure tool. The MCI Screen is generally reimbursed by Medicare and memory and function. See patients earlier if problems develop.
most major insurers, the MOCA and the Clock Drawing Test may Regular monitoring is critical for: each be reimbursed in some situations, and the MMSE is almost • Measuring treatment efficacy universally not reimbursed. • Deciding if treatment modification is indicated step 5: evaluate Unexpected Changes
• Identifying co-morbid conditions (see step 5)
Sudden or subacute changes, or development of symptoms that are • Educating patients and families about the importance of staying out of sequence with that expected by FAST staging, are not typical of AD progression. The most common reasons for such changes are: Quite often, there is a misconception among patients and families • Infection: Urinary Tract infection, aspiration pneumonia.
that the treatment is not working because the patient is not getting • Trauma: Unobserved falls, particularly if head injury occurred.
better. However, in degenerative disorders such as AD, "being stable" • Metabolic: Dehydration due to altered patterns of eating and or "getting worse at a slower rate" is a positive treatment effect that improves quality of life and can substantively reduce healthcare costs. • Iatrogenic: Compliance problems, anticholinergics, anti-anxiety, Regular monitoring can be quickly and accurately done within the constraints of a routine follow-up visit.
• Exacerbation of an existing medical condition.
Functional Measurement • Development of a new medical condition.
Assessment tools such as the Functional Assessment Staging • Environmental: Changes in residence, light level, noise level, (FAST), the Dementia Severity Rating Scale and the Clinical routine, caregiver, sleeping pattern or activity level. Dementia Rating Scale can be used. The FAST staging instrument which takes several minutes to complete, assesses the patient's Additional Information on Cholinesterase Inhibitors level of severity and provides a variety of useful other pieces of information, such as the patient's developmental age, approximate MMSE score, and expected duration per FAST stage for untreated Optimal Dosing of Aricept (donepezil): The primary mechanism of action AD. The Clinical Dementia Rating Scale takes more time to is likely to be acetylcholinesterase inhibition. However, clinically, this administer in clinical practice (about 10 to 20 minutes) and is more effect is observed to disappear within 1-2 years. One should find widely used in clinical research settings.
the highest dose among 5, 10 or 23 mg that causes no side effects. Cognitive Measurement Because all of the Aricept 23 mg studies are 6 months, there are Cognitive assessment tools such as MCI Screen, MOCA, MMSE no published data to indicate that 23 mg prolongs the duration of and Clock Drawing can be used (see section 4). Note that these
acetylcholinesterase inhibition. tests differ greatly in their sensitivity and specificity. For example, Potential Aricept Side Effects: Side effects occur in 9-19% of patients the MMSE and Clock Drawing tests are not sensitive for detecting and are dose dependent. Loss of appetite, nausea, diarrhea, dizziness, or monitoring the mild cognitive impairment stage of AD, and syncope, lightheadedness and nightmares are the most common. should be restricted to patients in the dementia stage. The MOCA These side effects usually resolve within 3-7 days of stopping Aricept is intermediate in sensitivity and specificity, and the MCI Screen because the elimination half-life is 70 hours. If side effects resolve, has the highest sensitivity and specificity for discriminating Aricept can be restarted at the next lower dose, and the side effects normal aging from mild cognitive impairment and dementia. The usually do not reappear.
MCI Screen has also been well validated as an effective tool for monitoring changes in mild cognitive impairment and dementia. For more information: www.aricept.com Additional Information on Memantine Optimal Dosing of Exelon Patch: The optimal dose is the highest well- tolerated dose, ranging from 3.1 mg to 14.3 mg per day. The dose of the patch is approximately 1/3 lower when applied over the abdomen Optimal Dosing of Namenda: The optimal dose of Namenda is the highest compared to the upper body (i.e., 4.6 and 9.5 mg patches applied to the one from 5 to 20 mg daily that is well tolerated. Because of Namenda's abdomen give 3.1 and 6.7 mg doses respectively). The FDA approved 72-hour half-life, it can be given once daily without difficulty. It usually doses are 4.6 and 9.5 mg daily. However, the phase III FDA clinical trial does not cause drowsiness, so it can be given in the a.m. If it causes showed further improvement in cognition for doses up to 19 mg daily, drowsiness, give at bedtime.
but there were more side effects above the 9.5 mg dose. When patients Potential Namenda Side Effects: Side effects occur in about 5% of tolerate the 9.5 mg dose, then one can try increasing the dose to 14.3 patients, are dose dependent, and almost always occur within 3 to mg (see below).
7 days after a dose increase. The most common ones are agitation, Potential Exelon Patch Side Effects: Side effects occur in 5-6% of patients irritability, confusion or a general worsening of function. If a side effect and are dose dependent. Skin irritation is the most common one, occurs, then lower the dose by 5 mg and continue that lower dose. If followed by loss of appetite. These side effects usually resolve within side effects are mild, they may resolve on their own over a few weeks two days of stopping the patch because the elimination half-life is 3 without lowering the dose.
hours. If side effects resolve, the patch can be restarted at a lower dose, For more information: www.namenda.com and the side effects usually do not reappear. For more information: www.exelonpatch.com Background For Pharmacologic
6.2 Treatment of Alzheimer's Disease
Abeta42, the 42-amino acid breakdown product of the amyloid Optimal Dosing of Razadyne ER (Galantamine ER): The primary mechanism precursor protein, self-aggregates to form oligomeric clusters of of action is likely to be the presynaptic nicotinergic receptor Abeta42. There is an extensive body of research supporting a major modulation, which increases multiple neurotransmitters to a mild role for oligomeric Abeta42 in the pathogenesis and clinical expression degree, and stimulates three neuroprotective mechanisms—reduced of Alzheimer's disease (AD).1-4 Human post-mortem studies have
cholinergic neuron damage, increased degradation of amyloid shown that patients receiving acetylcholinesterase (Ache) inhibitors
precursor protein along the non-amyloidogenic pathway (sAPP-alpha), have lower levels of cortical Abeta42 than those not receiving AchE and reduced glutamate-mediated excitotoxicity. One should therefore inhibitors.5 Furthermore, animal models of AD have shown that find the highest dose, from 8 to 24 mg, without side effects. AchE inhibition reduces Abeta42 production. Studies from the Potential Razadyne ER Side Effects: Side effects occur in about 4% of Karolinska Institute have shown that cerebrospinal fluid levels of patients and are dose dependent. Loss of appetite, nausea, diarrhea, AchE and butyrylcholinesterase, which correlate very well with brain dizziness, syncope, lightheadedness and bradycardia are the most cholinesterase levels, remain inhibited by at least 50% below baseline common. These side effects usually resolve within 2-5 days of stopping after 1 year of Exelon treatment of AD patients.6 Also, the type of AchE Razadyne ER because the elimination half-life is about 14-24 hours (for inhibited by Exelon favors protection against synaptic damage.7 In the non-extended release form of Razadyne, half-life is 7 hours). If side contrast, after 3 months of treatment, cerebrospinal fluid AchE levels effects resolve, Razadyne ER can be restarted at the next lower dose, are 200% above baseline with Aricept, and are no longer reduced and the side effects usually do not reappear. by Razadyne. AchE-R, the neuroprotective, or read-through, form of AchE, is reduced relative to AchE-S, the form associated with synaptic For more information: www.razadyneer.com.
damage. The neuroprotective/neurodestructive ratios of Exelon, Aricept, and Razadyne are 1.4, 0.6 and 0.4 respectively.7 The longest prospective clinical study was done at Harvard by Atri et al.,8 Longer duration studies of galantamine (Razadyne) also support in which AD patients at all clinical stages received either no treatment that it may delay AD progression. A 3-year open label extension of a (N=144, 1990-95), cholinesterase inhibitor (Chei) therapy only (N=122,
randomized, double-blind trial of Razadyne vs. placebo showed a 50% 1998-2005), or Namenda plus a CheI (N=116, 1998-2005) for up to four reduction in the rate of cognitive decline compared to expected rate of years. Rates of cognitive and functional decline were carefully statistically decline on placebo using a matched patient sample.17 analyzed. The Namenda plus CheI group showed a 33% delay in the rate Longer duration studies of Aricept indicate that it may delay AD of functional decline in AD patients starting with minimal functional progression for up to 3 years in certain subgroups. The rate of impairment (equivalent to mild cognitive impairment), a 60% delay in AD conversion from MCI to AD dementia over 3 years was reduced in a patients starting with mild dementia, and a 50% delay in AD patients who subset of depressed AD patients.18 A 1-year, open label extension in were moderately severely demented. This finding was consistent with severe AD patients treated with Aricept found that they did not decline a 12-month, quantitative, volumetric MRI study in mild to moderately in behavior or functional abilities, but that these benefits were lost if demented AD patients, in which monotherapy with either Namenda9 or a treatment was discontinued for 1 month or longer.19 A 1-year, double- CheI10 delayed the rate of hippocampal atrophy.
blind, placebo-controlled trial of MCI patients treated with Aricept In contrast to the disease-delaying effect of combined therapy, the Atri showed no difference in functional abilities and overall severity over the et al. study showed that AD patients receiving no treatment showed 2 years, but did show a slight reduction in rate of cognitive decline.20 A the same rate of decline as patients receiving CheI monotherapy. An 3-year open label extension of mild-to-moderate AD patients treated independent study by the Pfizer global research team provided further with Aricept showed cognitive and functional decline over the study information about the treatment effect of CheI monotherapy.11 They that did not differ between patients initially treated during the first six performed a meta-analysis of randomized, placebo-controlled, CheI months of the study (the duration of the randomized part of the trial) trials for up to 12 months, and found no difference between placebo and with Aricept or placebo.21 Another 3-year open label extension study of Aricept or Razadyne in the rate of cognitive decline. There was only one AD patients treated with Aricept found small but statistically significant double-blind, placebo controlled, randomized trial of Exelon lasting 12 reductions in the rates of cognitive and functional decline, but not months, which suggested a delay in rate of cognitive decline. global decline.22 Another open-label study of Aricept for up to 4 years Longer duration studies of rivastigmine (Exelon) support that it may found reduced rates of cognitive and functional decline for the first 2 delay AD progression, at least in certain sub-populations. A re-analysis years, but no change in rates of institutionalization at 3 years.23 Overall, in 2010 of the randomized, placebo-controlled, Exelon study lasting up Aricept appears to slightly delay cognitive and/or functional decline for to 4 years found a 25% reduction in the rate of conversion from MCI not longer than 2-3 years.
to AD for Exelon-treated patients, particularly females.12,13 A 5-year Although the above findings are not absolute, they suggest that the open label extension study of Exelon in 32 AD-treated patients showed largest disease-delaying effect among the CheIs is with Exelon, both stabilization in cognition, function and severity for 2-3 years. Of the 8 in terms of amount and duration of delay (i.e., the only CheI with patients who remained in the study at 5 years, 2/3 of them had started in 5-year data for at least some patients). The evidence for Aricept and the high dose Exelon group.14 A 2-year study comparing Exelon to Aricept Razadyne suggests a smaller disease-delaying effect that can last for found that moderate-to-severe AD patients under 75 years old declined up to 2-3 years. More importantly, the Harvard study indicates that less in severity and functional abilities on Exelon. AD patients over 75 combined therapy with Namenda and a CheI delays rate of cognitive years old responded the same to Exelon and Aricept over 2 years.15 Two and functional decline at all clinical stages of AD by 33% to 60%, which open label extension studies, each lasting two years, compared the means that one should attempt to detect AD as early as possible and course of Exelon-treated AD patients vs. the expected cognitive decline maintain combined therapy as long as possible. A reasonable strategy, from historical, untreated AD controls. Both studies found clinically therefore, would use any of the CheIs with Namenda during the first meaningful reductions in the rate of cognitive decline on Exelon that two to three years, depending upon the patient's course, and switch to influenced overall severity.16 These longer duration Exelon studies one of the other CheIs and Namenda when patients begin to show a provide the strongest support for a disease-delaying effect among the more rapid decline. care manager who can assess family needs, help caregivers navigate Psychosocial interventions in mCi
the health care system and community resources, and serve as a coach and early Alzheimer's Disease
has been shown to improve caregiver quality of life, social support, mastery of caregiving, and confidence.41,42 Additionally, quality of care, Psychosocial interventions are a key component of treatment for as measured by adherence to guidelines, was dramatically higher in the non-cognitive symptoms of MCI and early Alzheimer's disease. patients who were assigned a care manager than those who were not.42 According to two recent literature reviews, 35-85% of individuals with MCI exhibit behavioral abnormalities.24,25 Individuals with MCI Caregiver Education exhibit an average of 2.3 neuropsychiatric disturbances, with some Caregiver education has proven benefits for both the caregiver and experiencing as many as 9.6 symptoms.26 There is no typical profile of person with MCI or early AD. Studies have investigated a variety of neuropsychiatric disturbances in MCI or mild AD as these symptoms educational programs, which vary in content (e.g., caregiver self-care, are heterogeneous and unpredictable.27 Across studies, depression, behavior management), format (single- or multiple-session), and apathy, anxiety, and irritability are the most common neuropsychiatric complexity (i.e., offered independently or as part of a multicomponent symptoms in MCI.24,25 Compared to cognitively intact older adults, intervention). Key outcomes for caregivers include significant persons with mild AD were at significantly greater risk for apathy (Odds improvements in knowledge of Alzheimer's disease,43 ability to Ratio = 42) and depression (OR = 17).28 Neuropsychiatric disturbances, cope with the dementia,43 depression,44,45 anger,46 burden,45 use of like the cognitive and functional symptoms of MCI and AD, worsen with adaptive coping strategies,44 self-efficacy46 and response to difficult disease severity.29 behaviors.45 Additionally, caregiver education can also significantly Psychosocial interventions to alleviate neuropsychiatric symptoms reduce the actual frequency of behavior problems,47 with key patient are critical given their deleterious consequences, including increased outcomes including stabilization,43 and significantly reduced agitation risk of conversion from MCI to AD,30 greater functional dependence,31 heightened risk for institutionalization,32 shorter survival time,33 and higher levels of burden and depression among caregivers.34 Early-Stage Groups Early stage groups that incorporate education and support for evidence Base for Key early Psychosocial interventions
both individuals with MCI or early Alzheimer's disease and their care partners have proven beneficial in the literature. While early Caregiver Counseling and Support stage groups vary, they typically include parallel support sessions In a series of studies, Mary Mittelman and her colleagues at New for persons with early memory loss and their care partners, and an York University demonstrated that early access to a combination of educational component. A recent randomized controlled clinical trial counseling (i.e., 2 family and 4 individual sessions), a caregiver support demonstrated that participation in an early stage group can improve group, and ad hoc telephone consultation lowered the rate of nursing quality of life for the person with MCI or early AD, as evidenced in home placement by 28.3%, delayed institutionalization by 557 days,35 significantly reduced depression and behavioral symptoms, improved and resulted in other significant benefits for caregivers, including family communication, enhanced feelings of self-efficacy, and better reduced depression,36 better self-rated health,37 improved satisfaction emotional and social functioning.49 with support network,38 and greater tolerance for a loved one's memory and behavior problems.39 Cognitive StimulationA number of studies have now demonstrated that cognitive stimulation can have additive effects over and above those accrued Effective management of MCI and early AD requires an integrated by the acetylcholinesterase inhibitors and Namenda. In Requena et approach to care that encompasses medical care, psychosocial al.,50 persons with mild AD who received a combination of cognitive interventions, community services, and family resources.40 Access to a stimulation and 10 mg of Aricept showed less decline on measures of overall mental status (MMSE), cognitive functioning (ADAS- examples – Psychosocial interventions as a
Cog), and functional abilities (FAST) across 2 years than their peers Component of Treatment in mCi and early AD
receiving no treatment or medication alone. Subsequently, Niu et al.51 demonstrated that cognitive stimulation significantly improved apathy 1. A 56-year-old male corporate executive with multiple domain and depression/dysphoria in persons with mild-to-moderate AD. In MCI who can no longer work or drive, is spending a lot of time MCI, a 4-week cognitive intervention that included activity planning, sleeping at home, and exhibits depressed affect. Patient is receiving self-assertiveness training, relaxation techniques, stress management, acytelcholinesterase inhibitor and anti-depressant. Patient has high use of external memory aids, memory training, and motor exercise, degree of insight into how MCI has affected him. Caregiver is highly resulted in significant improvements on measures of activities of daily motivated to seek services for patient and self.
living, mood, and verbal and nonverbal episodic memory.52 Options • Refer patient for individual counseling for cognitive stimulation include computer-based programs and • Refer patient and caregiver to early stage support group participation in an early stage day program.
• Educate couple regarding need for meaningful, purposeful, and pleasurable activity, and suggest options such as volunteering and early stage day program Given the changes in motor53 (e.g., walking speed, standing balance) and higher level functional abilities54 that are already evident in MCI • Educate couple regarding benefits of cognitive stimulation and and early AD, in addition cognitive decline and neuropsychiatric options, including at-home computer-based programs and early symptoms such as depression, exercise can play an important role in stage day program maintaining physical, mental and emotional well-being. In MCI, walking • Promote exercise for positive benefits on cognition and mood 150 minutes per week for 6 months resulted in significant improvement 2. A 75-year-old homemaker with amnestic MCI being cared for by her on the ADAS-Cog,55 better than that achieved by Aricept alone over 81-year-old spouse who is physically frail and has multiple chronic the same period.56 Aerobic exercise (e.g., treadmill, stationary bike) health conditions. Patient will not acknowledge memory loss, is sufficient to elevate heart rate to 75-85% of reserve improved cognitive resistant to services, and husband feels overwhelmed.
function, particularly executive skills, in women with MCI.57 In AD, • Refer for care management support to assist caregiver to physical activity has also been associated with reduced depression,58 assess both patient's and caregiver's needs, assist with patient's better physical health52 and longer survival time.59 Among older resistance and problem-solving, and coordinate care and adults, other health benefits of exercise have been documented for community resources for patient and/or caregiver depression,60 quality of life,61 falls,62 cardiovascular function,63 and disability.64 • Promote use of caregiver support group and educational opportunities related to caregiving Purposeful and Pleasurable Activities 3. A 65-year-old man with early AD, living alone, estranged from Given the gradual loss of ability to engage in previously meaningful family, and relying on support of neighbor. Patient retains some work and leisure activities, and the high frequency of apathy and insight into his condition, but insists on living alone, has been the depression in MCI and early AD, it is critical to encourage affected victim of a scam, and continues to drive short distances. It appears individuals to become involved in purposeful and pleasurable activities. patient may be missing medications. Patient has minimal resources. Simply increasing the frequency and intensity of pleasurable activities • Refer to Adult Protective Services due to self-neglect for possible in AD has been shown to alleviate depression.65 In MCI and early AD, conservatorship and coordination of services. individuals may be able to continue participating in some activities • Report patient to DMV for driving evaluation/license revocation. relatively independently with encouragement and support (e.g., appropriate transportation) by caregivers. Early stage day programs, however, offer a venue for meaningful, pleasurable activities, cognitive stimulation, and peer support, while relieving the caregiver. 14. Farlow MR, Lil y ML; ENA713 B352 Study Group. Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer's disease for up to 5 years. BMC Geriatr 2005; 5:3.
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06/11-LT-3M-HM-CS 2189 06/11-LT-3M-HM-CS Orange County Vital Aging Program

Source: http://www.ocvitalbrainaging.com/pdf/guideline.pdf;jsessionid=8DEDCECD57B52C1520ACC7BB5EC86EC5