Update on Alzheimer's Disease

Educational Objectives

The goal of this program is to improve diagnosis and treatment of Alzheimer’s disease (AD). After hearing and as­similating this program, the clinician will be better able to:

1.   Discuss the different types of amyloid in the brain.

2.   Describe the role of amyloid plaques in AD.

3.   Explain various antiamyloid approaches to treating AD.

4.   Develop a treatment plan for the patient with AD.

5.   Refer patients with AD and their families to community resources.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Gandy is on the Scientific Advisory Boards of Epix and Diagenic. Dr. Chodosh and the planning com­mittee reported nothing to disclose.

Acknowledgements

Dr. Gandy was recorded at Advances in Psychiatry 2008: Breakthrough Treatments from Clinical Neuroscience, held October 24-25, 2008, in New York, NY, and sponsored by Mount Sinai School of Medicine. Dr. Chodosh was re­corded at New California Clinical Practice Guideline on Alzheimer’s Disease held at the Veterans Affairs Greater Los Angeles Healthcare System’s Sepulveda Campus on December 4, 2008, and sponsored by the Veterans Affairs Greater Los Angeles Healthcare System. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Anti-amyloid Drugs as Modifiers for Alzheimer’s Disease

Samuel Gandy, MD, PhD, Professor of Psychiatry and Neurology, Mount Sinai School of Medicine, New York, NY

Introduction: amyloid peptide normally made by all cells in body throughout life; for unknown reasons, in Al­zheimer’s disease (AD), amyloid peptide in interstitial spaces in brain changes shape, clumps, and forms amyloid plaques; initial plaques (also called aggregates or oligomers)  source of most toxicity associated with amyloid

Typical amyloid plaque: core composed of b-amyloid (Ab) peptide (toxic substance), resulting in neuritic dystro­phy of axons and dendrites; tau protein associated with neuritic dystrophy

Why so much focus on Ab? »3% of all AD completely genetic, and causative genes affect amyloid precursor per se or enzymes that act on it; only forms of AD understood from beginning involve amyloid-related genes; unlike com­mon form, genetic form can be produced in laboratory animals; research rationale is that drugs effective for genetic AD also effective for common form

Amyloid peptide: in amyloid plaque, initial deposition is 42-amino acid peptide (Ab42) that is clipped out of larger integral protein; amyloid precursor protein (APP) cleaves and releases amyloid from larger protein; most com­mon amyloid ends at 40th amino acid, is fairly soluble, and does not tend to aggregate; Ab42 highly aggregatable and initiates all forms of AD

a-secretase: “good” secretase; enzyme that cleaves APP, preventing formation of amyloid; however, if first cut by a-secretase rather than b-secretase, fragment left with intact amyloid peptide, which is substrate for g-secretase, which cuts within transmembrane domain to release Ab from cell; Ab “either floats around happily  …  or aggre­gates and forms plaque”

g-secretase: also called presenilin; complex enzyme comprised of quartet of polypeptides; mutation in only one polypeptide causes AD; this mutation extends C terminus so more Ab42 created

Change in shape and aggregation of Ab: amyloid peptide normally floats in spinal fluid and blood, and is “floppy” and nontoxic; for unknown reasons, sometimes folds back on itself and locks into hairpin shape, causing clump­ing with other amyloid molecules and aggregation to form plaques; once locked, very difficult to unlock; certain metals and sugars accelerate this reaction and are targets of experimental therapies

Plaque load does not correlate with cognitive status at time of death: study showed that at death, patients had widely variable scores on Mini-Mental State Examination (MMSE), but similar plaque burdens

Attacking amyloid: agents to enhance clearance of amyloid not yet in human trials

Immunotherapy: active —  vaccination; in early vaccination trials, 5% of patients developed acute allergic encephalomyelitis and trials discontinued; encephalitogenic epitope no longer used; when current vaccine used prophylactically in mice, amyloid deposition prevented; passive  —  involves intravenous infusion of synthetic im­munoglobulin (IVIg); study showed that some batches of standard IVIg from blood banks contain substantial lev­els of anti-amyloid oligomer antibodies; trials now in phases II and III

Antiamyloid aggregation drugs: also called “plaque busters”; tramiprosate (Alzhemed) failed in clinical trials; phenanthrene-based tylophorine-1 (PBT1) proved toxic; PBT2 and scyllo-inositol, which block stimulation of amyloid aggregation by metals, still in trials

Enzyme (secretase) modulators: secretase informal term for enzyme promoting secretion; a-secretase  — now known to be metalloproteinase (tumor necrosis factor-a-converting enzyme, [TACE]); pathway modulated by neurotransmitters and hormones; trials under way on overactivation of a-secretase to eliminate generation of am­yloid; b-secretase  —  now recognized as b-site  (APP)-cleaving enzyme (BACE), integral aspartyl proteinase; no evidence of toxicity with inhibition of BACE, so good target for development of new drugs; first human studies now under way; g-secretase (presenilin)  —  also an aspartyl proteinase; involved in hematopoiesis and in develop­ment and formation of somites; inhibition requires careful titration to block generation of amyloid without dis­rupting other functions; flurbiprofen seems to have allosteric effect on g-secretase and changed generation of Ab42 to Ab38 in mice, but did not slow progression of disease

Conclusions: so far, evidence favors using antiamyloid strategies as prophylaxis, not treatment; amyloid-related mu­tations cause early-onset familial AD (EOFAD); in mouse models, human EOFAD genes can cause AD that can be cured with amyloid vaccines, antiaggregants, and/or secretase modulators; however, not known whether these re­sults apply to humans

Dimebolin (Dimebon): first used as antihistamine in Russia; found to improve cognition in old rats for up to 18 mo; now in human studies worldwide and looks promising; trials will be completed in »1 yr

Guidelines for Management of Alzheimer’s Disease

Joshua Chodosh, MD, MSHS, Associate Professor of Medicine, David Geffen School of Medicine at the University of Cal­ifornia, Los Angeles, and Staff Physician and Assistant Chief of Staff/Patient Safety, Veterans Affairs Greater Los Angeles Healthcare System ,  Geriatric Research, Education, and Clinical Center

Introduction: 2008 guidelines from Alzheimer’s Association (available at www.alz.org/national/docu­ments/NATLguidelineONEPAGE.pdf)

Assessment: conduct and document assessment and monitor changes in 1) daily functioning, including feeding, bath­ing, dressing, mobility, toileting, continence, and ability to manage finances and medications; 2) cognitive status, using reliable and valid instrument; 3) comorbid medical conditions that may present with sudden worsening in cognition or function, or as change in behavior; 4) behavioral symptoms, psychotic symptoms, and depression; 5) prescription and nonprescription medications (at every visit); 6) living arrangement, safety, care needs, and abuse and/or neglect; 7) need for palliative and/or end-of-life planning

Reassess frequently: at least every 6 mo; sudden change in behavior or increase in rate of decline should trigger ur­gent visit to clinician

Identify support: identify primary caregiver and assess adequacy of family and other support systems, paying par­ticular attention to caregiver’s mental and physical health; identify contact person if ³1 family member accompa­nies patient to visits or cares for patient

Assess capacity: assess patient’s decision-making capacity and determine whether surrogate identified

Identify culture and values: identify patient’s and family’s culture, values, primary language, literacy level, and de­cision-making process

Treatment: develop and implement ongoing treatment plan with defined goals; discuss with patient and family 1) use of cholinesterase inhibitors, N-methyl-D-aspartic acid (NMDA) inhibitor, and other medications, if clinically in­dicated, to treat cognitive decline; 2) referral to early-stage groups or adult day services for appropriate structured activities, such as physical exercise and recreation (exercise shown to improve cognitive function)

Treat behavioral symptoms and mood disorders: use nonpharmacologic approaches, such as environmental modifi­cation, task simplification, and appropriate activities; refer patient to social service agencies or support organiza­tions, including Alzheimer’s Association MedicAlert Safe Return program for patients who may wander

Nonpharmacologic treatment first: use medications targeted at specific behaviors only after nonpharmacologic ap­proaches have failed; side effects from medications may be serious and significant

Overall medical management: provide appropriate treatment for comorbid medical conditions

End-of-life care: arrange for appropriate services and for palliative care, as needed

Patient and family education and support: integrate medical care with education and support by connecting patient and caregiver to support organizations for linguistically and culturally appropriate educational materials and re­ferrals to community resources, support groups, legal counseling, respite care, consultation on care needs and op­tions, and financial resources; organizations include Alzheimer’s Association (800-272-3900; www.alz.org), Family Caregiver Alliance (800-455-8106; www.caregiver.org), or local social service department

Diagnosis and treatment: discuss diagnosis, progression, treatment choices, and goals of AD care with patient and family in manner consistent with their values, preferences, culture, educational level, and patient’s abilities

Care of early-stage patients: pay particular attention to special needs of early-stage patients, involving them in care planning, heeding their preferences and wishes, and referring them to community resources

Decision-making throughout stages of AD: discuss patient’s need to make care choices at all stages through use of advance directive and identification of surrogates for medical and legal decision-making

End-of-life decisions: discuss intensity of care and other end-of-life decisions with patient and involved family members while respecting their cultural preferences

Legal considerations: as soon as possible after making diagnosis of AD, discuss importance of basic legal and finan­cial planning as part of treatment plan

Capacity evaluations: use structured approach to assessment of patient’s capacity; be mindful of relevant criteria for particular kinds of decisions

Elder abuse: monitor for evidence and report all suspicions of abuse (physical, financial, neglect, isolation, aban­donment, abduction) as required by state law

Driving restrictions: report diagnosis of AD to appropriate agency in accordance with local or state law

Suggested Reading

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