1 Christopher Marano, M.D. Assistant Professor Division of Geriatric Psychiatry and Neuropsychiatry Department of Psychiatry and Behavioral Sciences Johns.

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Christopher Marano, M.D.

Assistant Professor

Division of Geriatric Psychiatry and Neuropsychiatry

Department of Psychiatry and Behavioral Sciences

Johns Hopkins University School of Medicine

Johns Hopkins Bayview Medical Center

Alzheimer’s Disease:What’s New on the HorizonMarch 25, 2015

Objectives

• Briefly review symptoms and causes of dementia

• Briefly review current treatments for Alzheimer’s dementia

• Future directions for Alzheimer’s treatment– Seeing amyloid in the living brain– Potential disease-modifying treatments– Can we prevent Alzheimer’s?

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What is Dementia?

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• Loss of thinking, memory and reasoning skills to a degree that seriously affects the ability to carry out daily activities

http://www.nia.nih.gov/HealthInformation/Publications/forgetfulness.htm Accessed 5/13/2009

What Causes Dementia?

• Dementia itself is not a disease, but a group of symptoms (called a syndrome) caused by certain diseases or conditions

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What Causes Dementia?

• The 2 most common causes of dementia are:

1. Alzheimer’s Disease – 60-70%

2. Vascular Dementia – 10-20%• Alzheimer’s and Vascular Dementia

often exist together (Mixed dementia)

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Dementia is Common

Prevalence of severe (Mini-Mental State Examination score, <=9), moderate (Mini-Mental State Examination score, 10–17), and mild (Mini-Mental State Examination score, >=18) Alzheimer disease, in each of 3 age groups, in the community population providing data for these estimates.

Hebert: Arch Neurol, Volume 60(8).August 2003.1119–11226

Dementia is Common

Projected number of persons in US population with Alzheimer disease by age groups, 65 to 74 years old, 75 to 84 years old, and 85 years and older, using the 2000 US Census Bureau middle-series estimate of population growth.

Hebert: Arch Neurol, Volume 60(8).August 2003.1119–11227

Dementia is Costly

• Alzheimer's and dementia triple healthcare costs for Americans age 65 and older

• The direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses is more than $148 billion each year

• Alzheimer’s is the seventh-leading cause of death.

8Alzheimer’s Association, 2009 Alzheimer’s Disease Facts and Figures

What is Alzheimer’s Disease?

• Named after Dr. Alois Alzheimer.• 1906: discovered changes in the brain of a woman

who died from an unusual mental illness• Symptoms included memory loss, language

problems, and unpredictable behavior• After her death, he examined her brain and found

many abnormal clumps (amyloid plaques) and tangled bundles of fibers (neurofibrillary tangles).

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What is Alzheimer’s Disease?

• Plaques and tangles in the brain are two of the main features of AD

• Progressive loss of brain cells• Damage to the brain begins up to 10 to

20 years before symptoms develop

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Plaques and Tangles

11http://www.memorydisorder.org/research/amyloid/images/klnk/plaques.jpg

Symptoms of Dementia

• Four “A”s of Dementia1. Amnesia (Memory)

2. Aphasia (Language)

3. Apraxia (Doing things)

4. Agnosia (Recognizing the world)• Plus loss of executive function (Getting

things done)

12Rabins, Lyketsos, Steele. Practical Dementia Care 2nd Edition , OUP, 2006

Behavioral (or Neuropsychiatric) Symptoms of Dementia

• Delusions• Hallucinations• Agitation or

aggression• Depression or

dysphoria• Anxiety• Elation or euphoria

• Apathy or indifference

• Disinhibition• Irritability or lability• Motor disturbance• Nighttime behaviors• Appetite and eating

Cummings et al., Neurology, 199413

Symptoms of Alzheimer’sDisease

• Cognitive and functional symptoms are disease hallmarks

• However:– Neuropsychiatric symptoms are nearly universal– Associated with multiple adverse consequences

including worse quality of life, greater disability, accelerated cognitive or functional decline, greater caregiver burden, earlier institutionalization, and accelerated mortality1

141. Rabins PV, Lyketsos CG, Steele CD. Practical Dementia Care. Oxford University Press, New York, 2006

Current State of Care:Four Pillars of Dementia Care

1. Treat the Disease

2. Treat the Symptoms– Cognitive Symptoms– Neuropsychiatric Symptoms

3. Support the Patient

4. Support the Caregiver

Rabins, Lyketsos, Steele. Practical Dementia Care 2nd Edition, OUP, 200615

Treat the Disease

• No true disease modifying agents for Alzheimer’s Disease currently

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Treat the Symptoms:Cognitive (1)

• Cholinesterase inhibitors: – donepezil (Aricept), rivastigmine (Exelon),

galantamine (Razadyne)– Increase the amount of acetylcholine in the brain– Modest benefit (1-2 points on average in the 30-

point Mini-Mental State Examination [MMSE])– Generally well tolerated but some potential serious

side effects: slowed heart rate, passing out, falls, hip fracture

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Treat the Symptoms:Cognitive (2)

• Memantine (Namenda)– Different mechanism than the

cholinesterase inhibitors– FDA approved for moderate to severe

disease– Same modest benefit as cholinesterase

inhibitors– Usually well-tolerated

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Treat the Symptoms:Behavioral (1)

• Prevention through good care• Medications

– Antidepressants: Used for mood and agitation

– Antipsychotics:• Can be effective for agitation• High potential for side effects• Slightly increased risk of death (FDA Black Box

Warning)

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Support the Patient

• Comfort and emotional support • Safety: driving, living alone, medications, falls• Structure

– Proper approach and communication– Safe predictable place to live with help with daily

activities as needed• Activity and stimulation • Planning/assistance with decision making• Management of medical problems

Support the Caregiver (1)

• 2/3 patients with dementia live at home and majority cared for by family

• Caregiver distress is common– Studies show symptoms of depression or

distress are 2-3x higher compared to general population

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Support the Caregiver (2)

• BUT there are positives– Many (probably majority) do not report

significant emotional distress

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Support the Caregiver (3)

• Caregiver Distress Symptoms– Grief– Anger– Demoralization– Guilt– Fatigue

• Distress ≠ “Clinical Depression”

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Support the Caregiver (4)

• Emotional support and comfort (including support groups)

• Education• Instruction in the skills of caregiving• Problem solving and crisis intervention• Respite and time away• Attention to personal needs and wants• Be on the lookout for depression

Future Directions:The Promise of Research

• Four building blocks toward a cure:1. Discovery of potential treatments

2. Ability to test if the therapies work

3. Research teams to test the therapies

4. Patients willing to help find the cure by being in studies

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Visualizing Amyloid in theLiving Brain

• Florbetapir (Amyvid) PET Scan• FDA-approved in 2012• Limitations:

– What does a positive scan mean? (especially without a disease modifying treatment)

– Not reimbursed by insurance as of yet

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Typical Negative andPositive Florbetapir Scans

Yang L et al. N Engl J Med 2012;367:885-887.

Altering Amyloid in the Brain

• Potential future treatments currently being tested that remove, decrease the production or change the composition of amyloid in the brain

• Vaccines, antibodies, enzyme inhibitors

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A Preliminary Study of Carvedilolfor the Treatment of Alzheimer’s Disease

• Carvedilol is a beta-blocker long used to treat heart disease

• May reduce the aggregation of amyloid• Currently enrolling participants for a 6-

month trial at Johns Hopkins Bayview

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SNIFF: Study of Nasal Insulin to  Fight Forgetfulness

• Growing  evidence that insulin has multiple functions in brain and that poor insulin regulation may contribute to development of Alzheimer’s

• Examine effects of intranasally-administered insulin in amnestic mild cognitive impairment or mild Alzheimer's disease

• Currently enrolling participants for a 18-month study at Johns Hopkins Bayview

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DIADS-3: Venlafaxine for Depression in Alzheimer’s Disease

• Large studies of various depressants in patients with both AD and depression fail to show a benefit compared to placebo

• Venlafaxine (Effexor) is a commonly used antidepressant that acts on 2 different brain chemicals (serotonin and norepinephrine)

• Currently enrolling participants for a 12-week study at Johns Hopkins Bayview

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Challenges in Developing Better Treatments for Alzheimer’s

• May need to start much earlier– Amyloid deposition starts years before symptoms

• We may not be able to remove enough amyloid safely (adverse events)

• Amyloid may not cause the symptoms of dementia

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Can We Prevent Alzheimer’sDisease? (1)

• Potentially modifiable dementia risk factors are vascular risk factors– Smoking– Hypertension in midlife– High body mass index (overweight) in

midlife– High cholesterol in midlife– Diabetes

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Can We Prevent Alzheimer’sDisease? (2)

• How to lower vascular risk factors: Control hypertension, cholesterol, stop smoking, weight loss

• Mediterranean diet : unsaturated fats and anti-oxidants

• Education and exercise are cognitive protective factors so:– Participate in mental and physical exercise

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Key Components of the Mediterranean Diet

• Eating a generous amount of fruits and vegetables

• Consuming healthy fats such as olive oil and canola oil

• Eating small portions of nuts• Drinking red wine, in moderation (flavinoids =

anti-oxidants)• Consuming very little red meat • Eating fish on a regular basis

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Mental Health Resources for Seniors and Families

• Primary Care Physician• Specialist care with a neurologist,

psychiatrist or geriatrician if needed• Local Department of Aging• Local Health Department

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Mental Health Resources for Seniors and Families

• Alzheimer’s Association www.alz.org– Greater Maryland Chapter

1850 York Road, Suite D,Timonium, MD 21093

410-561-9099

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Mental Health Resources for Seniors and Families

• National Library of Medicine MedlinePlus

www.medlineplus.gov• Alzheimer’s Disease Education and

Referral (ADEAR) Center 800-438-4380 (toll-free)www.nia.nih.gov/Alzheimers

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Mental Health Resources for Seniors and Families

• Eldercare Locator800-677-1116 (toll-free)www.eldercare.gov

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Johns Hopkins Memory and Alzheimer’s Treatment Center

• Located at Johns Hopkins Bayview Medical Center Campus• Interdisciplinary program involving neuropsychiatrists, neurologists,

and geriatric medicine specialist physicians• Evaluation and ongoing treatment working closely with primary care

physicians • Assess “cognitively concerned” individuals with or without

progressive memory disorders• On-campus state of the art 3 Tesla MRI scanning and brain PET to

assist in differential diagnosis

Johns Hopkins Memory and Alzheimer’s Treatment Center

• Comprehensive caregiver & family support & education

• Supportive interventions provided by dementia-care specialist nurses,

• Access to clinical trials of research therapies for Alzheimer’s disease and related conditions

For more information:410-550-6337

www.hopkinsmedicine.org/memory

Contact information forclinical trials at Johns Hopkins

Wendy Golden at (410) 550-9022

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Comments or Questions

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Thank You

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