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Vital Brain Aging Clinical Path Overview

  • Educate

  • Assess

  • The Methods

  • Diagnosis

  • Treatment













Treatment

Optimal treatment follows accurate diagnosis of any underlying medical conditions. Guidelines for performing an accurate diagnosis of conditions that impair memory are available here.

Treating Alzheimer's disease and related disorders (ADRD) requires a robust approach that includes:

  • Identification and treatment of common medical conditions
  • Pharmacologic treatment
  • Non-pharmacologic treatment

Identifying and Treating Common Medical Conditions

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 deficiency, various medications, and depression can also cause memory loss. It is important to make sure that these conditions are well controlled and monitored regularly. Treatment guidelines for those conditions are widely available from a variety of sources.

Pharmacologic Treatment of ADRD

Like many other diseases, early detection and treatment of ADRD is the key to successful treatment outcomes. For Alzheimer's disease (AD), there is a substantial body of evidence showing disease-delaying effects using combined therapy of a cholinesterase inhibitor (Exelon, Razadyne, Aricept) and memantine (Namenda). Because 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 combined therapy until they reach the hospice terminal stage of AD.

For more details, please review:

  • Pharmacologic treatment of AD
  • Rationale for Pharmacologic treatment of AD

Non-Pharmacologic Treatment of ADRD

Non-pharmacologic interventions have been recognized as important components of an optimal treatment strategy. Such interventions include, but are not limited to, life style modifications such as mental/physical exercise, and diet, as well as psychosocial intervention, careful management of co-morbid conditions such as diabetes and hypertension, and integrating community resources for patients and families.

For more details on the psychosocial components of optimal treatment, please review:

  • Psychosocial treatment of AD

Community resources that support appropriate psychological interventions are available here.

Pharmacologic Treatment of AD

For a full discussion of the background for the pharmacologic treatment strategies given below, please see Rationale for Pharmacologic Treatment of Alzheimer's Disease. Also please note that the indicated treatment efficacy will differ from patient to patient, and may not be expected for all patients with Alzheimer's disease (AD).

Overall Treatment Strategy

Although there is considerable variability between patients with AD, there is a substantial body of evidence showing disease-delaying effects using combination therapy of a cholinesterase inhibitor (Exelon, Razadyne, Aricept) and memantine (Namenda). Because these effects occur at all clinical stages of AD, it is imperative to initiate combination therapy as early as AD is detected, and to continue patients on combination therapy until they reach the hospice terminal stage of AD.

Available evidence on the efficacy of the cholinesterase inhibitors in delaying AD progression indicates that:

  • Aricept is likely to provide disease-delaying effects for 1-3 years.
  • Razadyne is likely to provide disease-delaying effects for 1-3 years.
  • Exelon is likely to provide disease-delaying effects for 1-4 years.

Therefore, after 1-3 years of treatment with Namenda plus Aricept or Razadyne, patients may benefit by switching to Namenda plus the Exelon patch, particularly if more rapid decline has recently occurred.

Step 1: Set and Manage Expectation About Treatment

Before starting new medications, it is always helpful for patients and family members to understand what to expect from these treatments. Frequently patients and caregivers have unrealistic expectations and 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 make it clear that some percentage of patients may not respond in any meaningful way to the treatment.

Therefore, setting the right expectations will help patients and family members approach the treatment process with a constructive mindset and a realistic idea about the course ahead.

Step 2: Start Cholinesterase Inhibitor (Aricept, Exelon, Razadyne)

It is important to choose the correct cholinesterase inhibitor and 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.

Aricept (donepezil HCl) Tablet
Aricept is a prescription medication to treat mild, moderate and severe AD. It is available in 5, 10, and 23 mg/day in tablet form. The starting dose is 5 mg/day and can be increased to 10 mg/day after 4-6 weeks of treatment and good tolerability. Similarly it can be increased to 23 mg/day after at least 3 months of treatment and good tolerability.

Exelon Patch (rivastigmine transdermal system)
Aricept is a prescription medication to treat mild, moderate and severe AD. It is available in 5, 10, and 23 mg/day in tablet form. The starting dose is 5 mg/day and can be increased to 10 mg/day after 4-6 weeks of treatment and good tolerability. Similarly it can be increased to 23 mg/day after at least 3 months of treatment and good tolerability.

Razadyne ER (galantamine hydrobromide extended-release) Capsule
Aricept is a prescription medication to treat mild, moderate and severe AD. It is available in 5, 10, and 23 mg/day in tablet form. The starting dose is 5 mg/day and can be increased to 10 mg/day after 4-6 weeks of treatment and good tolerability. Similarly it can be increased to 23 mg/day after at least 3 months of treatment and good tolerability.

Step 3: Add Memantine (Namenda)

Namenda (memantine HCl) is prescription medication to treat the symptoms of moderate to severe AD. It is available in 5 and 10 mg tablet.

After reaching the optimal dose of the chosen cholinesterase inhibitor, add Namenda and find the optimal dose, from 5 to 20 mg, that is well tolerated without side effects. After achieving a stable optimal dose, it is always recommended to objectively measure the treatment effect on memory and function.

Alternatively, because the terminal elimination half-life is 60-80 hours, Namenda may be given as a once a day drug. Also, the time to steady state is 3 weeks. For this reason, Namenda may be better tolerated by changing dose every 2 weeks instead of every week during titration.

Step 4: Monitor Cognition and Function Every 3 to 6 Months

After optimizing the doses of both the cholinesterase inhibitor and Namenda, schedule follow-up visits every 3-6 months and measure memory and function. See patients earlier if problems develop.

Regular monitoring is critical for:

  • Measuring treatment efficacy
  • Deciding if treatment modification is indicated
  • Identifying co-morbid conditions (see Step 5)
  • Educating patients and families about the importance of staying on treatment

Quite often, there is a misconception among patients and families that the treatment is not working because the patient is not getting better. However, in degenerative disorders such as AD, "being stable" or "getting worse at a slower rate" is a positive treatment effect that improves quality of life and can substantively reduce healthcare costs.

Regular monitoring can be quickly and accurately done within the constraints of a routine follow-up visit.

Functional Measurement
Assessment tools such as the Functional Assessment Staging (FAST), the Dementia Severity Rating Scale and the Clinical Dementia Rating Scale can be used. The FAST staging instrument which takes several minutes to complete, assesses the patient’s 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 AD. The Clinical Dementia Rating Scale takes more time to administer in clinical practice (about 10 to 20 minutes) and is more widely used in clinical research settings.

Cognitive Measurement
Cognitive assessment tools such as MCI Screen, MOCA, MMSE and Clock Drawing can be used. Note that these tests differ greatly in their sensitivity and specificity (see Select Assessment Method ). For example, the MMSE and Clock Drawing tests are not sensitive for detecting or monitoring the mild cognitive impairment stage of AD, and should be restricted to patients in the dementia stage. The MOCA is intermediate in sensitivity and specificity, and the MCI Screen has the highest sensitivity and specificity for discriminating normal aging from mild cognitive impairment and dementia. The MCI Screen has also been well validated as an effective tool for monitoring changes in mild cognitive impairment and dementia.

Depending on the structure of any given practice, reimbursement for performing cognitive assessment may be an important consideration in the selection of the most appropriate assessment tool. The MCI Screen is genrally reimbursed by Medicare and most major insurers, the MOCA and the Clock Drawing Test may each be reimbursed in some situations, and the MMSE is almost universally not reimbursed.

Step 5: Evaluate Unexpected Changes

Sudden or subacute changes, or development of symptoms that are out of sequence with that expected by FAST staging, are not typical of AD progression. The most common reasons for such changes are:

  • Infection: Urinary Tract infection, aspiration pneumonia.
  • Trauma: Unobserved falls, particularly if head injury occurred.
  • Metabolic: Dehydration due to altered patterns of eating and drinking.
  • Iatrogenic: Compliance problems, anticholinergics, anti-anxiety, tranquilizers, antipsychotics.
  • Exacerbation of an existing medical condition.
  • Development of a new medical condition.
  • Environmental: Changes in residence, light level, noise level, routine, caregiver, sleeping pattern or activity level.

Additional Information on Cholinesterase Inhibitors


Aricept (Dopnepezil)

Optimal Dosing of Aricept (donepezil): The primary mechanism of action is likely to be acetycholinesterase inhibition. However, clinically, this effect is observed to disappear within 1-2 years. One should find the highest dose among 5, 10 or 23 mg that causes no side effects. Because all of the Aricept 23 mg studies are 6 months, there are no published data to indicate that 23 mg prolongs the duration of acetylcholinesterase inhibition.

Potential Aricept Side Effects: Side effects occur in 9-19% of patients and are dose dependent. Loss of appetite, nausea, diarrhea, dizziness, syncope, lightheadedness and nightmares are the most common. These side effects usually resolve within 3-7 days of stopping Aricept because the elimination half-life is 70 hours. If side effects resolve, Aricept can be restarted at the next lower dose, and the side effects usually do not reappear.

For more information: www.aricept.com


Exelon (Rivastigmine)

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 compared to the upper body (i.e., 4.6 and 9.5 mg patches applied to the abdomen give 3.1 and 6.7 mg doses respectively). The FDA approved doses are 4.6 and 9.5 mg daily. However, the phase III FDA clinical trial showed further improvement in cognition for doses up to 19 mg daily, but there were more side effects above the 9.5 mg dose. When patients tolerate the 9.5 mg dose, then one can try increasing the dose to 14.3 mg (see below).

Potential Exelon Patch Side Effects: Side effects occur in 5-6% of patients and are dose dependent. Skin irritation is the most common one, followed by loss of appetite. These side effects usually resolve within two days of stopping the patch because the elimination half-life is 3 hours. If side effects resolve, the patch can be restarted at a lower dose, and the side effects usually do not reappear.

For more information: www.exelonpatch.com


Razadyne (Galantamine)

Optimal Dosing of Razadyne ER (Galantamine ER): The primary mechanism of action is likely to be the presynaptic nicotinergic receptor modulation, which increases multiple neurotransmitters to a mild degree, and stimulates three neuroprotective mechanisms—reduced cholinergic neuron damage, increased degradation of amyloid precursor protein along the non-amyloidogenic pathway (sAPP-alpha), and reduced glutamate-mediated excitotoxicity. One should therefore find the highest dose, from 8 to 24 mg, without side effects.

Potential Razadyne ER Side Effects: Side effects occur in about 4% of patients and are dose dependent. Loss of appetite, nausea, diarrhea, dizziness, syncope, lightheadedness and bradycardia are the most common. These side effects usually resolve within 2-5 days of stopping Razadyne ER because the elimination half-life is about 14-24 hours (for the non-extended release form of Razadyne, half-life is 7 hours). If side effects resolve, Razadyne ER can be restarted at the next lower dose, and the side effects usually do not reappear.

For more information: www.razadyneer.com

Additional Information on Memantine


Namenda

Optimal Dosing of Namenda: The optimal dose of Namenda is the highest one from 5 to 20 mg daily that is well tolerated. Because of Namenda’s 72-hour half-life, it can be given once daily without difficulty. It usually does not cause drowsiness, so it can be given in the a.m. If it causes drowsiness, give at bedtime.

Potential Namenda Side Effects: Side effects occur in about 5% of patients, are dose dependent, and almost always occur within 3 to 7 days after a dose increase. The most common ones are agitation, irritability, confusion or a general worsening of function. If a side effect occurs, then lower the dose by 5 mg and continue that lower dose. If side effects are mild, they may resolve on their own over a few weeks without lowering the dose.

For more information: www.namenda.com

Rationale for Pharmacologic Treatment of Alzheimer's Disease


Identifying and Treating Common Medical Conditions

~ Possible Disease Delaying Effect By 33-60% ~

Abeta42, the 42-amino acid breakdown product of the amyloid precursor protein, self-aggregates to form oligomeric clusters of Abeta42. There is an extensive body of research supporting a major role for oligomeric Abeta42 in the pathogenesis and clinical expression of Alzhemer's disease (AD).1-4 Human post-mortem studies have shown that patients receiving acetylcholinesterase (AchE) inhibitors have lower levels of cortical Abeta42 than those not receiving AchE inhibitors.5 Furthermore, animal models of AD have shown that AchE inhibition reduces Abeta42 production. Studies from the Karolinska Institute have shown that cerebrospinal fluid levels of AchE and butyrylcholinesterase, which correlate very well with brain cholinesterase levels, remain inhibited by at least 50% below baseline after 1 year of Exelon treatment of AD patients.6 Also, the type of AchE inhibited by Exelon favors protection against synaptic damage.7 In contrast, after 3 months of treatment, cerebrospinal fluid AchE levels are 200% above baseline with Aricept, and are no longer reduced by Razadyne. AchE-R, the neuroprotective, or read-through, form of AchE, is reduced relative to AchE-S, the form associated with synaptic 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 in which AD patients at all clinical stages received either no treatment (N=144, 1990-95), cholinesterase inhibitor (CheI) therapy only (N=122, 1998-2005), or Namenda plus a CheI (N=116, 1998-2005) for up to four years. Rates of cognitive and functional decline were carefully statistically analyzed. The Namenda plus CheI group showed a 33% delay in the rate of functional decline in AD patients starting with minimal functional impairment (equivalent to mild cognitive impairment), a 60% delay in AD patients starting with mild dementia, and a 50% delay in AD patients who were moderately severely demented. This finding was consistent with a 12-month, quantitative, volumetric MRI study in mild to moderately demented AD patients, in which monotherapy with either Namenda9 or a CheI10 delayed the rate of hippocampal atrophy.

In contrast to the disease-delaying effect of combined therapy, the Atri et al. study showed that AD patients receiving no treatment showed the same rate of decline as patients receiving CheI monotherapy. An independent study by the Pfizer global research team provided further information about the treatment effect of CheI monotherapy.11 They performed a meta-analysis of randomized, placebo-controlled, CheI trials for up to 12 months, and found no difference between placebo and Aricept or Razadyne in the rate of cognitive decline. There was only one double-blind, placebo controlled, randomized trial of Exelon lasting 12 months, which suggested a delay in rate of cognitive decline.

Longer duration studies of rivastigmine (Exelon) support that it may delay AD progression, at least in certain sub-populations. A re-analysis in 2010 of the randomized, placebo-controlled, Exelon study lasting up to 4 years found a 25% reduction in the rate of conversion from MCI to AD for Exelon-treated patients, particularly females.12,13 A 5-year open label extension study of Exelon in 32 AD-treated patients showed stabilization in cognition, function and severity for 2-3 years. Of the 8 patients who remained in the study at 5 years, 2/3 of them had started in the high dose Exelon group.14 A 2-year study comparing Exelon to Aricept found that moderate-to-severe AD patients under 75 years old declined less in severity and functional abilities on Exelon. AD patients over 75 years old responded the same to Exelon and Aricept over 2 years.15 Two open label extension studies, each lasting two years, compared the course of Exelon-treated AD patients vs. the expected cognitive decline from historical, untreated AD controls. Both studies found clinically meaningful reductions in the rate of cognitive decline on Exelon that influenced overall severity.16 These longer duration Exelon studies provide the strongest support for a disease-delaying effect among the cholinesterase inhibitors.

Longer duration studies of galantamine (Razaydne) also support that it may delay AD progression. A 3-year open label extension of a randomized, double-blind trial of Razadyne vs. placebo showed a 50% reduction in the rate of cognitive decline compared to expected rate of decline on placebo using a matched patient sample.17

Longer duration studies of Aricept indicate that it may delay AD progression for up to 3 years in certain subgroups. The rate of conversion from MCI to AD dementia over 3 years was reduced in a subset of depressed AD patients.18 A 1-year, open label extension in severe AD patients treated with Aricept found that they did not decline in behavior or functional abilities, but that these benefits were lost if treatment was discontinued for 1 month or longer.19 A 1-year, double-blind, placebo-controlled trial of MCI patients treated with Aricept showed no difference in functional abilities and overall severity over the 2 years, but did show a slight reduction in rate of cognitive decline.20 A 3-year open label extension of mild-to-moderate AD patients treated with Aricept showed cognitive and functional decline over the study that did not differ between patients initially treated during the first six months of the study (the duration of the randomized part of the trial) with Aricept or placebo.21 Another 3-year open label extension study of AD patients treated with Aricept found small but statistically significant reductions in the rates of cognitive and functional decline, but not global decline.22 Another open-label study of Aricept for up to 4 years found reduced rates of cognitive and functional decline for the first 2 years, but no change in rates of institutionalization at 3 years.23 Overall, Aricept appears to slightly delay cognitive and/or functional decline for not longer than 2-3 years.

Although the above findings are not absolute, they suggest that the largest disease-delaying effect among the CheIs is with Exelon, both in terms of amount and duration of delay (i.e., the only CheI with 5-year data for at least some patients). The evidence for Aricept and Razadyne suggests a smaller disease-delaying effect that can last for up to 2-3 years. More importantly, the Harvard study indicates that combined therapy with Namenda and a CheI delays rate of cognitive and functional decline at all clinical stages of AD by 33% to 60%, which means that one should attempt to detect AD as early as possible and maintain combined therapy as long as possible. A reasonable strategy, therefore, would use any of the CheIs with Namenda during the first two to three years, depending upon the patient's course, and switch to one of the other CheIs and when patients begin to show a more rapid decline.

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