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Program Written Summary
Audio-Digest Neurology
Volume 04, Issue 12
June 21, 2013

Developing Treatments for Alzheimer Disease – Christopher M. Marano, MD
When Life Imitates Work: The Bioethicist Confronts Her Mother’s Dementia – Patricia (Tia) Powell, MD

Sponsored By Albert Einstein College Of Medicine Of Yeshiva University And Montefiore Medical Center, In Joint Sponsorship With The Alzheimer’s Association, New York City Chapter; The Geriatric Mental Health Alliance Of New York; And The Consortium Of New York Geriatric Education Centers
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The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Neurology Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Highlights from the 17th Annual Symposium:
Comprehensive Approach to Dementia

Sponsored by Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, in joint sponsorship with the Alzheimer’s Association, New York City Chapter; the Geriatric Mental Health Alliance of New York; and the Consortium of New York Geriatric Education Centers

Educational Objectives

The goal of this program is to improve the treatment of dementia and provide better supportive care for patients, caregivers, and families. After hearing and assimilating this program, the clinician will be better able to:

1. Elaborate on the previous and current theories to explain the pathophysiology of Alzheimer disease (AD).

2. Summarize the attempts to develop disease-modifying treatments that target proposed causes of AD.

3. Implement features of a dementia care model that can support the patient and slow or reduce the development of cognitive and neuropsychiatric symptoms.

4. Advise patients and their families about factors that influence decisions about end-of-life care and the support services available to them.

5. Optimize the balance between emphasis of technologic or medical interventions vs the goals of patients and families.

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 faculty and planning committee reported nothing to disclose. In his lecture, Dr. Marano presents information that is related to the off-label or investigational use of a therapy, product, or device.

Developing Treatments for Alzheimer Disease

Christopher M. Marano, MD, Assistant Professor of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD

Spectrum of severity: cognitive aging; mild cognitive impairment (prodrome to dementia with multiple causes); dementia — cognitive changes become pathologic; results in cognitive and functional decline and neuropsychiatric symptoms; syndrome results from multiple causes; Alzheimer disease (AD) — brain disease; analogy to heart disease — memory loss analogous to chest pain (symptom); mild cognitive impairment analogous to angina; dementia analogous to congestive heart failure

Causes of dementia: include AD, vascular dementia (eg, large or small infarcts, chronic small vessel disease, microbleeds), Lewy body disease, and frontotemporal dementia; many cases have mixed causes; Honolulu-Asia Aging Study — among 443 Japanese-American men at autopsy, 5 distinct lesions (ie, AD pathology, vascular disease, Lewy bodies, hippocampal sclerosis, and atrophy) accounted for 90% of cognitive impairment; clinical symptoms of dementia correlated more closely with combined number of lesions than with specific type of lesion

History: first patient with AD reported in 1906 with progressive cognitive impairment and psychosis; autopsy revealed plaques and neurofibrillary tangles


Cholinergic hypothesis: primary cholinergic neurons in basal forebrain degenerate, which produces decreased cholinergic transmission to cerebral cortex; acetylcholine important in learning and memory; cholinergic loss contributes to cognitive symptoms of AD; current symptomatic treatments (cholinesterase inhibitors) based on this hypothesis

Current knowledge: neurofibrillary tangles contain hyperphosphorylated tau; extracellular amyloid plaques and soluble forms of amyloid (eg, peptides, oligomers, fibrils) present; neuronal loss and inflammatory aggravation (reactive gliosis) occur

Amyloid hypothesis: amyloid precursor protein abnormally broken down in 2 ways by β- or ϒ-secretase; abnormal breakdown produces oligomers, fibrils, and plaques; process activates glial cells and causes inflammation, death of neurons, and loss of cognitive and functional ability; treatments based on amyloid hypothesis — attempt to prevent abnormal processing of amyloid or facilitate clearance of soluble forms of amyloid, eg, with antibodies; most agents produced no difference from placebo in trials, eg, tramiprosate (Alzhemed) and R-flurbiprofen (Flurizan) inhibitors of plaque formation, bapineuzumab and solanezumab antibodies, BMS708163 (to remove plaque); other treatments produced worsening

Limitations of amyloid hypothesis: production of abnormal amyloid triggers cascade that results in symptoms of dementia; presence of amyloid does not correlate well with symptoms; findings correlated with symptoms include neurofibrillary tangles (considered marker of degeneration), neuronal loss, and loss of circuits as detected by functional magnetic resonance imaging (MRI); some patients with amyloid appear cognitively normal

Other processes involved in AD: inflammation — cytokines released by glial cells; insulin resistance — brain of patient with AD may fail to use energy properly; intranasal insulin and treatments for diabetes under investigation for AD; lipid abnormalities possible; vascular disease — important role; high blood pressure, diabetes, obesity, and smoking strongest risk factors for AD

Subtypes of AD: autosomal dominant form — 3 genes associated with early-onset familial AD

Biomarkers: challenges — progression from changes in amyloid to development of symptoms may take decades; symptoms change slowly; trials costly; clearing amyloid from brain accomplished in humans but did not affect symptoms; biomarkers needed to accelerate development of treatment; candidates — use of amyloid markers approved for research; positron emission tomography (PET) markers for inflammation under investigation; arterial spin labeling to evaluate vasculature; PET ligand detects tau and phospho-tau in cerebral spinal fluid, although less sensitive than florbetapir and Pittsburgh Compound-B that detect amyloid; MRI detects loss of volume; magnetic resonance spectroscopy can reveal brain chemistry; PET evaluates metabolism of brain to look for receptors and loss of circuitry; diffusion tensor imaging reveals structural integrity of different parts of brain; attempts under way to identify clinical phenotypes

Additional treatment candidates: anti-tau agents in trials; bexarotene (anticancer agent) shown to upregulate apolipoprotein and shuttle amyloid in mice; anti-inflammatory agents; agents that influence use of glucose (eg, intranasal insulin, metformin, glitazones); phase II trial under way to evaluate deep brain stimulation of fornix (feeds into hippocampus and degrades in early AD); near- and medium-term approaches include attempts to extend time course of mild cognitive impairment

Dementia care: effective care and treatment model for AD currently available; care involves multidisciplinary teams of psychiatrists, neurologists, geriatricians, nurses, occupational therapists, and social workers

Cache County Dementia Progression Study: epidemiologic study of individuals >65 yr of age; 328 individuals developed dementia over 10 yr

Findings: progression variable (many patients progressed slowly); women and individuals with earlier onset progressed faster; education and apolipoprotein E did not necessarily correlate with progression; potentially modifiable factors included neuropsychiatric symptoms, medical comorbidity, level of activity, and closeness and coping style of caregivers

Rate of progression: latent class analysis of changes in Mini-Mental State Examination scores over time among 335 patients with probable AD found 33% progressed fairly linearly and rapidly; 10% progressed extremely rapidly; 55% showed only slight change over 10 yr

Neuropsychiatric symptoms: nearly universal; prevalence determined over 5 yr with Neuropsychiatric Inventory (lists symptoms, eg, delusions, hallucinations, agitation, depression); found 100% of patients had some symptoms (depression, apathy, anxiety, delusions, and agitation most prominent); greater number of symptoms correlated with shorter time to severe dementia

Other factors: cognitive stimulation also shown to affect cognitive and functional decline early in disease; patients with mild dementia progressed more slowly if engaged in activities; effect not seen in more severe disease; closer relationship with caregiver slowed progression as determined by Clinical Dementia Rating Scale

Dementia care model: treat disease (not currently possible); treat cognitive and neuropsychiatric symptoms; provide supportive care for patient, family, and caregiver

Supportive care for patient: provide comfort and emotional support; address safety concerns (eg, driving, living alone, medications, falls), structure (including proper approach and communication), and predictability of environment; provide activity and stimulation; plan and assist with decision making; manage medical comorbidities; provide good nursing care in advanced disease

Provide support for caregiver: emotional support and comfort; education; instruction in skills required; problem solving; crisis intervention; respite

Disease-modifying treatment: management of vascular risk factors before symptoms develop only current option

Treatment of symptoms: cholinesterase inhibitors and memantine approved (well tolerated with modest benefit); neuropsychiatric symptoms — treat and try to prevent symptoms through caregiver techniques and supportive care; rule out delirium; try de-escalation, distraction, and structured activity; limit medications and polypharmacy; all antipsychotics carry warning about increased risk for death and have poor efficacy; treatments for depression (eg, sertraline) also show poor efficacy

Treatments in development: methylphenidate for apathy; antidepressants (eg, citalopram) possibly helpful for agitation; serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine, duloxetine) in trial; dextromethorphan (approved for pseudobulbar symptoms) combined with antiarrhythmic quinidine in trial; β-blockers (eg, prazosin) also under investigation

When Life Imitates Work: The Bioethicist Confronts Her Mother’s Dementia

Patricia (Tia) Powell, MD, Professor of Clinical Epidemiology, Division of Bioethics; Professor of Clinical Psychiatry; Director, Montefiore Einstein Center for Bioethics; and Director, Einstein Cardozo Master of Science in Bioethics, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY

Humor: represents efficient and effective therapeutic and coping mechanism; helps to process fear and anxiety

Speaker’s grandmother: suffered from dementia and had pacemaker placed 12 yr before death; children agreed to placement but later came to believe pacemaker prolonged suffering and regretted decision

Course of speaker’s mother’s disease: before developing dementia herself, speaker’s mother informed children that she did not wish to receive pacemaker if it prolonged time of disability; mother repeated instructions as her dementia emerged; cognitive deficits became more apparent after husband died of cancer; progressing symptoms included agitation and paranoia and prevented her from living outside institution even with 24-hr caregivers; assisted living worked well for period of time; serious medical problems provoked long hospital stays (including long period in intensive care) and rehabilitation facility; thereafter went to skilled nursing facility; required constant supervision and hand feeding; began to stop breathing; caused by heart block where normal conductivity of electrical pathways in heart did not function; condition treatable with pacemaker

Cardiologist’s perspective: cardiologist advocated placement of pacemaker; family objected because of mother’s wishes, but cardiologist implied decision motivated by neglect or ignorance; insisted he would only consider deactivating pacemaker if all children and he agreed (contradicted mother’s directive that speaker serve as health care proxy); mother stated preference as “whatever doctor thinks best”; patient or caregiver can decide when to withdraw most treatments; anticipated difficulty of deactivating pacemaker appeared inconsistent

Decision to implant pacemaker: speaker acquiesced to wishes of some siblings and agreed to implantation; Heart Rhythm Society recently provided guidelines on deactivation or termination of devices that support heart rhythm and function (guidelines clearly support option of deactivating pacemaker); outcome — before procedure, mother refused pacemaker and procedure canceled; symptoms increased over several weeks with no evidence of anxiety, pain, or suffering; mother placed on hospice status and died several weeks later

Family’s perspective: making decision about pacemaker and death extremely difficult despite clear instructions from mother and family’s good health literacy, shared values, and adequate finances; situation complicated by medical recommendations that did not align with family’s values and preferences

Available support: humor allows honest discussion of fears; religion and community may provide powerful support for patients and caregivers (who have increased rates of depression, stress, and mortality); Resources for Enhancing Alzheimer’s Caregiver Health (REACH) study — evaluated interventions that affect quality of life for caregivers; found measurable benefit from culturally attuned interventions (eg, phone conversations, role playing, problem solving techniques, breathing exercise); Conversation Project — encourages families to discuss end-of-life choices; provides film of family conversation on website (; advance directive document helpful but often insufficient without such conversations; Dr. Angelo Volandes — developed series of videos with clear and balanced information about several illnesses (eg, dementia) that allows patients to make better informed choices; speaker recommends video dealing with dementia

Patient engagement: defined as patient’s sense of involvement in and understanding of diagnosis, options, and treatments; patients who show more engagement have better outcomes and more satisfaction; highly engaged patient Jessie Gruman (author of AfterShock) has written article about difficulties with illness and paperwork associated with insurance

Current situation: patient engagement, advance directives, and other developments remain insufficient to address problems associated with culture of medicine; clinicians may focus on fixing specific health problem without addressing overall needs of patient or family

Proposed changes: love of technology among Americans creates presumption that technologic approach always best (eg, pacemaker highly effective technology); financial incentives may influence whether clinicians use available technologies; speaker advocates — promoting conversations about patient’s goals rather than technical or medical solutions; improving communication skills among clinicians; helping individuals focus on values and goals for treatment and perspectives on death and disability; health care providers may focus on interventions that have poor efficacy and serious side effects; important to explore informal and nontechnologic tools and supports that help patients and caregivers; patients need help in understanding course of chronic diseases


Drs. Marano and Powell spoke at the 17th Annual Symposium: The Comprehensive Approach to Dementia, held March 7, 2013, in New York, NY, and sponsored by Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, in joint sponsorship with the Alzheimer’s Association, New York City Chapter; the Geriatric Mental Health Alliance of New York; and the Consortium of New York Geriatric Education Centers. To learn more about CME activities presented by Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, please visit The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Suggested Reading

Anonymous: Encouraging news in Alzheimer’s prevention and treatment. Research continues to underscore the value of cardiovascular health in relation to brain function. Duke Med Health News 19:4, 2013; Chaufan C et al: Medical ideology as a double-edged sword: the politics of cure and care in the making of Alzheimer’s disease. Soc Sci Med 74:788, 2012; Corbyn Z: New set of Alzheimer’s trials focus on prevention. Lancet 381:614, 2013; Friedrich MJ: New research on Alzheimer treatments ventures beyond plaques and tangles. JAMA 308:2553, 2012; Frisch S: Caring for the caregiver. Minn Med 96:16, 2013; Gitlin LN et al: Nonpharmacologic management of behavioral symptoms in dementia. JAMA 308:2020, 2012; Griffin WS: Neuroinflammatory cytokine signaling and Alzheimer’s disease. N Engl J Med 368:770, 2013; Gusmano M: End-of-life care for patients with dementia in the United States: institutional realities. Health Econ Policy Law 7:485, 2012; Haight TJ et al: Relative contributions of biomarkers in Alzheimer’s disease. Ann Epidemiol 22:868, 2012; Kozauer N, Katz R: Regulatory innovation and drug development for early-stage Alzheimer’s disease. N Engl J Med 368:1169, 2013; Lemmens C: End-of-life decisions and demented patients. What to do if the patient’s current and past wishes are in conflict with each other? Eur J Health Law 19:177, 2012; Leuzy A, Gauthier S: Ethical issues in Alzheimer’s disease: an overview. Expert Rev Neurother 12:557, 2012; Mitka M: PET imaging for Alzheimer disease: are its benefits worth the cost? JAMA 309:1099, 2013; Mullane K, Williams M: Alzheimer’s therapeutics: continued clinical failures question the validity of the amyloid hypothesis — but what lies beyond? Biochem Pharmacol 85:289, 2013; Torjesen I: Dementia patients should have more say in their end of life care, NICE says. BMJ 345:e5590, 2012; Wolff J: Dementia, death and advance directives. Health Econ Policy Law 7:499, 2012.

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