The+International+Journal+of+Neuropsychiatricmedicine%2C+Creativity+and+Dementia.unlocked

7/29/2019 The+International+Journal+of+Neuropsychiatricmedicine%2C+Creativity+and+Dementia.unlocked

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CNS Spectr13:2 (Suppl 2) MBL Communications

CNS SPECTRUMS

T H E I N T E R N AT I O N A L J O U R N A L O F N E U R O P S Y C H I AT R I C M E D I C I N E

ABSTRACT

Alzheimers disease research is beginning to yield promising treatments and prevention strategies. Current Alzheimers dis-

ease treatments benefit symptoms, but do not appreciably alter the basic disease process. The new generation of Alzheimers

disease medications, however, will likely include disease-modifying treatments, which will slow disease progression or stop

it entirely. These new treatments pursue four points of intervention: increasing the clearance of amyloid-42 (A42) proteins in

the brain, blocking A42 production, decreasing A42 production, and decreasing A42 aggregation. Neurogenerative therapies

are being explored as well, suggesting future treatments may not only stop disease progression but also reverse it. Risk fac-

tors for developing Alzheimers disease and factors associated with a lower risk of Alzheimers disease have been identified.

Future Alzheimers disease management may come to resemble routine cardiovascular disease prevention and management,

which involves the control of modifiable risk factors and the use of medications that decrease or stop underlying pathology.

The hope is that such management will arrest the disease process before cognitive symptoms have begun. Like other neuro-

logic illnesses, Alzheimers disease has a profound impact on creativity. Alzheimers disease attacks the right posterior partof the brain, which enables people to retrieve internal imagery and copy images. Alzheimers disease patients may lose the

ability to copy images entirely. However, people with Alzheimers disease can continue to produce art by using their remain-

ing strengths, such as color or composition instead of shapes or realism. Studying art and dementia is a model for identifying

the strengths of psychiatric patients. Remarkably, art emerges in some patients even in the face of degenerative disease. In

this expert roundtable supplement, Jeffrey L. Cummings, MD, offers an overview of recent advances in Alzheimers disease

research. Bruce L. Miller, MD, discusses creativity in patients with neurologic illnesses. Daniel D. Christensen, MD, discusses

emerging Alzheimers disease therapies. Debra Cherry, PhD, discusses the advocacy needs of Alzheimers disease patients

and their caregivers. In addition, a testimonial of the impact of Alzheimers disease on an accomplished artist is featured.

www. cnsspectrums.com

EXPERT ROUNDTABLE SUPPLEMENT

CREATIVITY AND DEMENTIA:

EMERGING DIAGNOSTIC AND TREATMENT

METHODS FOR ALZHEIMERS DISEASE

AUTHORS

Jeffrey L. Cummings, MD, Bruce L. Miller, MD,

Daniel D. Christensen, MD, and Debra Cherry, PhD2CME


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EXPERT ROUNDTABLE SUPPLEMENTAn expert panel review of clinical challenges in psychiatry and neurology

CNS Spectr13:2 (Suppl 2) MBL Communications February 20082

Accreditation StatementThe Semel Institute at UCLA is accredited by the

Institute of Medical Quality and the California MedicalAssociation to provide continuing medical education

for physicians. The Semel Institute atUCLA takes responsibility for the con-

tent, quality, and scientific integrity ofthis CME activity.

Credit DesignationThe Semel Institute at UCLA designates this educa-

tional activity for a maximum of 2 hours of Category Icredit in Continuing Medical Education and the AMAsPhysician Recognition Award. Each physician should claimonly those hours of credit that he/she actually spent in theeducational activity. This credit may also be applied to the

CMA Certification in Continuing Medical Education.

Needs Assessment

UCLA has surveyed conference participants andprofessionals in the community through an annualneeds assessment and has found an educationalneed for a more holistic discussion on Alzheimersdisease. This need encompasses information on theselection of treatments for this disorder, demonstra-tion of the human spirit and creativity of those livingwith Alzheimers disease, as well as the role of thecommunity in helping to provide a better future for allthose who suffer from this illness. This supplementwill specifically address all of these unmet needs andwill provide a personal perspective on the illness.There are unmet needs in recognition of dementia,diagnosis of Alzheimers disease and mild cognitiveimpairment (MCI), use of clinical and technological

diagnostic methodologies, and Alzheimers diseasetreatment. These deficiencies in clinical practiceadversely impact patient care and patient and care-giver quality of life. Major advances have occurredin the recognition of dementia, diagnosis of MCI andAlzheimers disease, and treatment of Alzheimersdisease. Despite this progress, many patients gounrecognized until late in their disease, and availabletreatments are underutilized. Research advancesrequire translation into clinical practice where they

can maximally impact the care of patients.

Target AudienceThis activity is designed to meet the educational needs of

psychiatrists and neurologists.

Learning Objectives Update practitioners in psychiatry, neurology, and

primary care on the state of the art in understandingand treating Alzheimers disease.

Promote community awareness regarding thehuman toll of this debilitating disease.

Discuss future treatments of Alzheimers disease.

Faculty Affiliations and DisclosuresJeffrey L. Cummings, MD, is the Augustus Rose

professor of neurology, professor of psychiatry, direc-tor of the UCLA Alzheimers Disease Research Center,and director of the Deane F. Johnson Center forNeurotherapeutics at the University of California, Los

Angeles. Dr. Cummings has provided consultation for orreceived research support from Abbott, Adamas, Avanir,CoMentis, Eisai, Forest, Lundbeck, Medivation, Memory,Myriad, Neurochem, Novartis, Ortho-McNeil Neurologic,Pfizer, Prana, sanofi-aventis, and Takeda.

Bruce L. Miller, MD, is professor of neurology, A.W.& Mary Margaret Clausen distinguished chair, andclinical director of the Memory and Aging Center atthe University of California, San Francisco, School ofMedicine. Dr. Miller has served on the speakers bureausof Novartis and Pfizer.

Daniel D. Christensen, MD, is clinical professor ofpsychiatry and neurology and adjunct professor ofpharmacology at the University of Utah School ofMedicine in Salt Lake City. Dr. Christensen has servedas a consultant for Bayer, Bristol-Myers Squibb, DesignerGenes, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, MyriadGenetics, Novartis, NPS, Pfizer, RiboMed, Solvay, andWyeth; has served on the advisory boards of Eisai,GlaxoSmithKline, Myriad, and Pfizer; has served on thespeakers bureaus of Abbott, Bayer, Bristol-Myers Squibb,Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Pfizer,Solvay, Upjohn, and Wyeth; and has received grant orresearch support from Abbott, Bristol-Myers Squibb,Designer Genes, Eccles Institute of Human Genetics,GlaxoSmithKline, Janssen, Myriad Genetics, Novartis,NPS, Organon, Pfizer, RiboMed, Solvay, and Wyeth.

Debra Cherry, PhD, is the executive vice presidentof the California Southland Chapter of the Alzheimers

Association in Los Angeles. Dr. Cherry reports nofinancial, academic, or other support that may pose a

conflict of interest.

Acknowledgment of Commercial SupportFunding for this activity has been provided by an edu-

cational grant from Myriad Pharmaceuticals, Inc.

To Receive Credit for this ActivityRead this supplement, reflect on the information

presented, and complete the CME posttest and evalu-ation form on pages 22 and 23. The posttest is alsoavailable at www.ArtAndAlzheimers.com.

To obtain credit, you should score 70% or better.Early submission of this posttest is encouraged tomeasure outcomes for this CME activity. Please sub-mit this posttest by February 28, 2010 to be eligible

for credit.

Release Date: February 1, 2008Termination Date: February 28, 2010

The estimated time to complete this activity is 2hours.


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UPDATE ON ALZHEIMERS DISEASE: ONEHUNDRED YEARS AFTER DR. ALOIS ALZHEIMERBy Jeffrey L. Cummings, MD

Dr. Cummings is the Augustus Rose professor of neurology, professor of psychiatry, director of the UCLA Alzheimers Disease Research Center,

and director of the Deane F. Johnson Center for Neurotherapeutics at the University of California, Los Angeles.

Disclosures: Dr. Cummings has provided consultation for or received research support from Abbott, Adamas, Avanir, CoMentis, Eisai, Forest,

Lundbeck, Medivation, Memory, Myriad, Neurochem, Novartis, Ortho-McNeil Neurologic, Pfizer, Prana, sanofi-aventis, and Takeda.

IntroductionAlzheimers disease was first described by

Alois Alzheimer in 1906, and first appeared in the

medical literature in 1907.1 The medical commu-

nity has been ruminating about Alzheimers dis-

ease for over 100 years, and only recently have

Alzheimers disease therapies begun to emerge.

However, many vital questions remain, pertinent

not only to physicians but to the public at large.

For example, how likely is it that a particular indi-

vidual will develop Alzheimers disease? What

can one do to avoid getting Alzheimers disease?

What are the current and promising treatments

for Alzheimers disease? While there are grey

areas, the Alzheimers disease field is beginning

to find solid answers to these questions. There

are risk factors that individuals can control, and

emerging treatments are cause for optimism.

Risk Factors for Alzheimers DiseaseA striking phenomenon is occurring in the

aging population. Only 1% of patients 60 years

of age have Alzheimers disease, but the rates

of occurrence double in frequency every 5 years

after age 60 (Slide 1).2 Approximately 40% of

people 85 years of age have Alzheimers dis-

ease.2 There is a huge concern that this phenom-

enon will overstress Medicare resources if we

do not find a way to reduce the incidence and

burden of this disease.

There are several risk factors that can increase

ones risk of developing Alzheimers disease

(Slide 2). Aging is the most powerful risk. In

addition, female gender remains a risk factor

for Alzheimers disease even after accounting

for the fact that women tend to live longer.Certain genotypes, such as the apolipoprotein

E4 (ApoE4) genotype, also contribute to risk.

Elevated cholesterol makes it more likely a per-

son will develop Alzheimers disease, as does the

protein homocysteine. Diabetes, serious head

injury, psychological stress, hypertension, and

smoking also increase the likelihood of devel-

oping Alzheimers disease.3-12 Although certain

risk factors such as age, gender, and genotype

cannot be modified, the remaining risk factors

can be controlled. For example, one can manage

their cholesterol, have a doctor check their homo-cysteine levels, and prevent or control diabetes.

SLIDE 2

Alzheimers Disease: Risk Factors

Age

Female gender

ApoE-4 genotype

Hypercholesterolemia

Hyper-homocysteinemia

DiabetesHead injury

Psychological stress

Hypertension

Smoking

Cannot be modified

Can be modified

SLIDE 1

Alzheimers Disease Doubles in Frequency Every 5 Years

After the Age of 602

45

40

35

30

25

20

15

10

5

060 65 70 75 80 >85

Age (Years)

Perce

ntage

ApoE-4=apolipoprotein E4.


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Head injuries can be avoided, as can psychologi-

cal stress, hypertension, and smoking.

There are also several factors that are associ-

ated with a lower risk of Alzheimers disease,

such as high levels of education. In addition,

active cognitive involvement in ones leisure

activities, exercise, and a diet with high antioxi-

dant content have also been epidemiologically

associated with a reduced risk of Alzheimers

disease. Antioxidants include the omega-3 fatty

acids found in fish, vitamin E, and vitamin C.

In addition, vitamin B6, vitamin B12, and folate

are also thought to reduce Alzheimers disease

risk.13,14 A study by Orgogozo and colleagues15

conducted in the Bordeaux region of France,

found that modest use of alcohol reduces the

likelihood of developing Alzheimers disease;

those findings were verified in subsequent

studies conducted in other countries as well.

Statins improve hypercholesterolemia, which inturn reduces Alzheimers disease risk, and some

data indicate that nonsteroidal anti-inflamma-

tory drugs, such as ibuprofen, when taken for

many years, are also helpful in reducing the risk

of Alzheimers disease.

Finally, a substantial relationship exists

between exercise and risk of dementia (Slide

3).16 High levels of exercise reduce the risk by

~50%. However, even low levels of exercise

reduce the risk of developing Alzheimers dis-

ease substantially. A high level of exercise is

defined as 30 minutes of exercise three times aweek, while anything less than that is considered

a low level of exercise.

Biological Basis of Alzheimers DiseaseThere is now a consensus that Alzheimers dis-

ease is caused by the production and accumula-

tion of toxic amyloid protein in the brain. Once

the amyloid is deposited, it affects the brain in a

variety of adverse ways. Neurofibrillary tangles

emerge in some of the nerve cells, killing them.

Discrepancies between the relative cognitive

integrity in some patients despite high burdens

of Alzheimers disease-type pathology suggest

that there is high individual variability to the

effects of amyloid protein. Oxidative injury is

induced by amyloid protein (which is why anti-

oxidants are believed to be an important pre-

ventative measure), and excitotoxicity follows

the release and reduced reuptake of excitatory

amino acids. All of these contribute to nerve cell

death. These findings are incredibly important,

as they suggest therapeutic targets. Researchers

are now exploring drugs that will reduce the pro-

duction or accumulation of amyloid in the brain.

Increasing attention is being paid to the ear-

liest stages of Alzheimers disease, as it may

prove easier to prevent the disease than to treat

it after onset. It appears the protein begins to

accumulate before the presentation of clinical

symptoms. When the protein exerts its delete-

rious effect on brain function, a person devel-

ops mild cognitive impairment (MCI) with mild

memory symptoms. This is the stage at which

researchers hope to be able to intervene and pre-

vent the disease. Currently, Alzheimers disease

is diagnosed after the MCI worsens into demen-

tia. At this stage, a great deal of deterioration has

already occurred, and it is often too late to slow

or stop the rapid rate of disease progression. Itis hoped that treatment during the emergence of

MCI will prove effective. Eventually, physicians

may be able to treat patients experiencing amy-

loid accumulation before they show any clinical

symptoms at all.

New Diagnostic Tools for AlzheimersDisease

A study by Small and colleagues17 dem-

onstrated the connection between -amyloid

protein accumulation, neurofibrillary tangles

(composed of hyperphosphorylated tau pro-tein) and Alzheimers disease (Slide 4). Positron

emission tomography scans of the brains of

subjects demonstrated that patients with no

signs of amyloid or tau deposits at baseline

did not develop amyloid or tau accumulations

after 2 years. However, patients with very mild

cognitive symptoms were shown to have some

protein (amyloid and tau) accumulation in the

brain. By 2-year follow up, these patients had

developed full-blown Alzheimers disease. This

knowledge will soon be applied in clinical prac-

SLIDE 3

Exercise and Risk of Dementia 16

High >30 min, 3x per week; Low


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tice; physicians will scan patients to determine

whether they have the beginning signs of amy-

loid and tau deposition in the brain. Anti-amy-

loid and anti-tau therapies are currently being

tested in clinical trials and are expected to be

available in the foreseeable future.

Amyloid imaging with Pittsburgh Compound-

B also shows differences between patients with

the Alzheimers disease-related brain abnormali-

ties and control patients.18 The metabolic scan

is nearly normal in older control patients, but

there is a tremendous amyloid signal coming

from deposits in the brain of the person with

Alzheimers disease. This scan is expected to

become widely available.

Future Therapies for AlzheimersDisease

There are a few therapeutic drugs that are

currently available for Alzheimers disease.

Donepezil, rivastigmine, and galantamine

enhance acetylcholine in the brain, while

memantine inhibits excitotoxic amino acid inju-

ry in the brain. Although these medications

are helpful, they do not alter the course of

Alzheimers disease. They improve the symp-

toms of the disease temporarily.

Future therapies will draw on the amyloid-

production-and-accumulation paradigm (Slide

5). Anti-amyloid agents that reduce the pro-

duction and accumulation of amyloid are the

ultimate goal. For example, a clinical trial of

curcumin, a curry spice, was recently completed.

This agent has approximately five times the

antioxidant power of Vitamin E and reduces

amyloid plaques.19 Researchers are also looking

at a variety of neuroprotective agents, which

can decrease nerve cell death. Hopefully, in the

distant future, regenerative medicines and stem

cell therapies will become available to treat

nerve cell death after it has occurred.

References1. Alzheimer A. ber eine eigenartige Erkrankung der Hirnrinde.

Allgemeine Zeitschrift fr Psychiatrie und Psychisch-GerichtlicheMedizin. 1907;64:146-148.

2. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quan-titative integration of the literature. Neurology. 1987;43:465-479.

3. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apoli-poprotein E type 4 allele and the risk of Alzheimers disease. Science.1993;261(5123):921-923.

4. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. DiabetesMellitus and risk of Alzheimers disease and decline in cognitive function.Arch Neurol. 2004;61(5):661-666.

5. Luchsinger JA, Tang MX, Shea S, Mayeux R. Hyperinsulinemia and rish ofAlzheimer disease. Neurology. 2004;63(7):1187-1192.

6. Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and demen-tia: the Honolulu-Asia Aging Study. Neurobiol Aging. 2000;21(1):49-55.

7. Verghese J, Lipton RB, Hall CB, Kuslansky G, Katz MJ. Low blood

pressure and the risk of dementia in very old individuals. Neurology.2003;61(12):1667-1672.8. Qiu C, von Strauss E, Fastbom J, Winblad B, Fratiglioni L. Low blood pres-

sure and risk of dementia in the Kungsholmen project: a 6-year follow-upstudy. Arch Neurol. 2003;60(2):223-228.

9. Van Osch LA, Hogervorst E, Combrinck M, Smith AD. Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease.Neurology. 2004;62(11):1967-1971.

10. Ott A, Andersen K, Dewey ME, et al. Effect of smoking on global cognitivefunction in nondemented elderly. Neurology. 2004;62(6):920-924.

11. Honig LS, Tang MX, Albert S, et al. Stroke and the risk of Alzheimerdisease. Arch Neurology. 2003;60(12):1707-1712.

12. Graves AB, Mortimer JA, Bowen JD, et al. Head circumference and inci-dent Alzheimers disease. Neurology. 2001;57:1453-1460.

13. McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP. Moderatelyelevated plasma homocysteine, methylenetetrahydrofolate reductasegenotype, and risk for stroke, vascular dementia, and Alzheimer diseasein Northern Ireland. Stroke. 2002;33(10):2351-2356.

14. Pappolla MA, Bryant-Thomas TK, Herbert D, et al. Mild hypercholesterol-emia is an early risk factor for the development of Alzheimer and amyloidpathology. Neurology. 2003;61(2):199-205.

15. Orgogozo JM, Dartigues JF, Lafont S, et al. Wine consumption anddementia in the elderly: A prospective community study in the Bordeauxarea. Rev Neurol (Paris). 1997;153(3):185-192.

16. Lytle ME, Vander Bilt J, Pandav RS, Dodge HH, Ganguli M. Exercise leveland cognitive decline: the MoVIES project. Alzheimer Dis Assoc Disord.2004;18(2):57-64.

17. Small GW, Kepe V, Ercoli LM, et al. PET of brain amyloid and tau in mildcognitive impairment. N Engl J Med. 2006;355(25):2652-2663.

18. Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimersdisease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306-319.

19. Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ. Curcuminlabels amyloid pathology in vivo, disrupts existing plaques, and partiallyrestores distorted neurites in an Alzheimer mouse model. J Neurochem.2007;102(4):1095-1104.

SLIDE 5

Future Alzheimers Disease Treatments

Tx=Treatment.

Amyloid Production

and Accumulation

Neurofibrillary

Tangles, Oxidation,Excitotoxicity

Nerve Cell Death

Anti-Amyloid Agents

Neuroprotective

Agents

Cell Death Tx,

Regeneration, Stem

Cell Tx

SLIDE 4

FDDNP is a Scan that Labels Brain Amyloid

Small GW, Kepe V, Ercoli LM, et al. PET of brain amyloid and tau in mildcognitive impairment. N Engl J Med. 2006 Dec 21;355(25):2652-2663.Reprinted with permission from the New England Journal of Medicine,(Copyright 2006), Massachusetts Medical Society. All rights reserved.

Baseline Follow-up Baseline Follow-up

Control Control Impairment DiseaseMild Cognitive Alzheimers


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CREATIVITY IN THE CONTEXT OFNEUROLOGIC ILLNESS

By Bruce L. Miller, MD

Dr. Miller is professor of neurology, A.W. & Mary Margaret Clausen distinguished chair, and clinical director of the Memory and Aging Center at

the University of California, San Francisco, School of Medicine.

Disclosures: Dr. Miller has served on the speakers bureaus of Novartis and Pfizer.

IntroductionCreativity in the context of neurologic illness

is extremely complicated, but fascinating and

inspiring to those who study it. Artistic people

with degenerative diseases often are still com-

pelled to engage in their creative talents after

developing a neurologic illness. In some cases,

people with these disorders even develop new

abilities that did not exist prior to onset of ill-

ness. Those who study creativity and dementiamust first address a fundamental neurologic

question: Where in this elegant structure does

the ability to produce art come from?

Art and the BrainThe brain is incredibly elegant, but remains

very mysterious. There are several areas of the

brain that have been associated with the abil-

ity to produce art. Because the frontal lobes

are highly developed in humans compared to

nonhuman primates who cannot produce art,it might be reasonable to deduce that art arises

from these structures. However, it seems more

likely that the posterior parietal lobes, in particu-

lar on the right of the brain, are central to the

ability to produce art.

The left hemisphere, which is responsible for

language, is often considered the dominant elo-

quent hemisphere. However, when one studies

artists it becomes apparent that the right brain is

very eloquent in a different way. The right brain

allows people to copy images, pull up internal

imagery, and replicate it on paper. It also allows

people to perform an activity that is probably

unique to humans: cross-associating sounds,

motions, feelings, and visions. The left brain

plays an important but smaller role in art pro-

duction, largely centering on the development of

symbolic, abstract, linguistic-based concepts.

It has been known for over a century that

injuries to the right posterior parietal lobe cause

loss of artistic ability. This decline in ability is

detailed in a patient who suffered a series of

strokes. Prior to the stroke, one patient showed

the ability to capture vivid, realistic detail and a

sense of motion in drawing a bicycle and rider.

Following the first stroke, the patient drew the

same image, but it no longer contained a sense

of movement and was dramatically simplified.

Following the second stroke, the patients abil-

ity was further devastated. It seems that one

need not injure much of the right hemisphere

to lose the ability to produce art.

The Effect of Neurologic Illness on ArtAlzheimers disease attacks the area of the brain

that allows people to retrieve internal images

and to copy pictures. Patients with Alzheimers

disease may lose their ability to copy entirely.

There is an anatomic reason for this loss: The

right posterior part of the brain shows profound

decreases in blood flow. In spite of this anatomic

reality, people with Alzheimers disease do man-

age to produce art. These patients work with

their remaining strengths. For example, a paint-

ing by an artist with Alzheimers disease may

lack shapes and realism, but may have interest-

ing composition and use of color.

Frontotemporal dementia (FTD) refers to a

group of disorders that affect the frontal and

temporal lobes of the brain. Patients with FTD

were observed to develop new artistic abili-

ties in spite of their neurologic degeneration.1

The phenomenon at first seemed coincidental,

but the experience proved a common theme

among many FTD patients. Patients who tend

to develop these skills are those in whom the

anterior temporal lobes, especially the left tem-


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poral lobe, have degenerated. This is seman-

tic dementia, which often diminishes aspects

of language ability. A remarkable number of

semantic dementia patients develop visual cre-

ativity in the setting of the il lness.2

FTD differs from Alzheimers disease in sever-

al important ways. Alzheimers disease causesdamage to the posterior region of the brain,

which may explain why many Alzheimers dis-

ease patients experience difficulty producing

art. FTD causes selective degeneration of the

anterior temporal lobes, but tends to spare the

posterior region of the brain for many years. It

is not yet comprehensively understood what

the anterior temporal lobes do, but damage

to those lobes appears to cause tremendous

difficulty with language. For example, patients

with anterior lobe degeneration lose the ability

to name objects and lose information about

them. Unlike patients with Alzheimers dis-

ease, who might not be able to name an object

such as a microphone, patients with FTD have

difficulty both naming a microphone and rec-

ognizing what it does, but would like to know

for what it is used.3

Remarkably, 20 years before semantic demen-

tia was ever described in neurology, Gabriel

Garcia Mrquez captured the phenomenon in

his novel One Hundred Years of Solitude.4 He

described patients getting sick with an illness

that causes them to lose knowledge about things

in their world:

He discovered he had trouble remembering almost

every object in the laboratory. Then he marked them

with their respective names so that all he had to do

was read the inscription in order to identify them...

This is the cow. She must be milked every morning

so that she will produce milk, and the milk must be

boiled in order to be mixed with coffee to make cof-

fee and milk. Thus they went on living in a reality thatwas slipping away, momentarily captured by words,

but which would escape irremediably when they

forgot the values of the written letters.4

His description is in all likelihood a case

of semantic dementia, described in literature

before it was described in neurology.

If asked to color an image of a frog, an FTD

patient might select a color other than green

because he or she lacks knowledge of what frogs

are and look like. The entire visual system in the

right posterior part of the brain is totally intact,

however. This disparity allowed one patient,

who did not recognize the concept of a camel, to

copy it perfectly. Ultimately, however, the draw-

ings lose specificity because they lack semantic

meaning. Animals become prototypical. A dog

begins to resemble a cat; a fish resembles an

insect or a penguin; a bird resembles a gnat.

Pursuance of Art ThroughoutNeurodegenerative Disease:Case Examples

In studying creativity and dementia, an extraor-

dinary story emerges about human beings who,

in spite of incredibly debilitating diseases, do

not stop creating art, show incredible courage,

and inspire those who encounter them. Many

people with neurologic disease are compelled

to draw even as semantic knowledge about

the world slips away. They continue to express

themselves through art as the degenerative

illness progresses. Following are case studies

depicting this phenomenon. The first example

describes effects of a dementing illness on cre-

ativity, while the latter two describe creativity in

the context of progressive neurologic disorder.

These case studies are meant to illustrate the

diversity within creativity and neurologic illness

as a genre of study.

Case APatient A was an artist who experienced progres-

sive loss of language in her left hemisphere. Patient

A, who was trained as a molecular biologist, began

to paint in adulthood and quickly showed a lot of

ability. Before her disease became evident, she

produced a remarkable piece titled Unraveling

Bolero, depicting a meticulous visual rendering of

Maurice Ravels orchestral piece Bolero. Her favor-

ite notes in each meter are depicted with different

colors and sizes to represent the volume and qual-ity of the music. It is her attempt to visually capture

the rhythm ofBolero. At the time Patient A painted

Unraveling Bolero, she still had use of language.

She was able to describe her process thoroughly:

The color treble parts are embellished with geomet-

ric shapes in black, and also engraved into the paper

to represent the quality of tone of each note. When

the modulation finally occurs, I use gaudy fluores-

cent colors to make the few notes in the piece. The

music soon collapses and dies in the final two bars.4




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An image of Patient As brain from around the

time she painted Unraveling Bolero was com-

pared to brain images of 30 healthy controls.

She was preclinical, but starting to get ill. She

showed left inferior frontal atrophy. However,

the right posterior part of her brain, which is

critical for artistic creativity, is actually larger

than in the 30 healthy control subjects. Thispart of the brain is believed to allow the asso-

ciation between music, sound, and vision. Many

questions arise from these findings. Does the

degeneration of the anterior portion of the brain

somehow stimulate an increased sprouting of

neurons in the posterior parts of the brain? What

is the relationship between Patient As enlarged

posterior brain region and her remarkable artis-

tic flourishing?

As her disease progressed, Patient As art con-

sisted of less complex depictions of nature, such as

pebbles and leaves. She continued to create vividpaintings, even after she became completely mute.

It is intriguing to note that Unraveling Bolerowas

her most complex work, marrying sound, music,

vision, and feeling, and that it was produced in the

earliest stages of her aphasia. Anecdotally, 6 years

after Ravel produced Bolero, the composer devel-

oped progressive nonfluent aphasia. In an extraor-

dinary constellation of events, 6 years after Patient

A painted Unraveling Bolero, she developed the

same progressive aphasia that Ravel had.5

Case BPatient Bs twin sister, who was an artist, died

from amyotrophic lateral sclerosis (ALS), a relent-

less and currently incurable disease. Because the

disorder was familial, it was apparent Patient B

would also develop ALS. She began painting

whimsical depictions of life in Hawaii in dedication

to her sister, and became rather well known. She

developed ALS, and began to experience trouble

in her right hand so pronounced that she could no

longer use it to paint. Instead, she began to paint

with her non-dominant left hand. After losing use

of both hands, she continued to paint by holding

a brush with her mouth. Patient B became quite

impaired, and eventually retained movement only

in her eyes. She was able to communicate and

continue painting through a computer system that

followed her eye movements. She spent many

hours per day using the computer system to move

colors into compositions. Patient Bs paintings

express her experience while suffering with her

illness and her feelings for her supporters.

Case CPatient C was a young autistic boy who began

to compulsively draw horses around 2 years

of age. At 2.53 years of age, he produced

very realistic, extraordinary images, exhibiting

savant syndrome. At around 5 years of age, his

drawings demonstrated a sense of vanishing

point. Patient C lacked language, and his social

skills were severely impaired. It seems likely

that loss of function in one area of the brain is

associated with tremendous abilities in other

areas. Patient C was unable to express emo-

tion verbally or physically, even while taking

an electroencephalogram or having his blood

drawn. However, he was able to express emo-

tion through his paintings. Unlike many chil-

dren with savant syndrome, he has continued

to paint, and is currently a very successful artist

in Southern California.It gives the author pause to realize that

Patient Cs early works are strikingly similar

to cave paintings that were produced ~20,000

years ago. It is worth considering the possibili-

ty that the first cave painters were compelled to

produce art because of brain asymmetry. Such

a disorder may have played a role in bringing

humankind one step forward.

ConclusionArt reflects the emotional, perceptual, concep-

tual, and motor systems of the artist. It offers

insights into the workings of the brain, and it

is healing. Art is possible in spite of neurologic

disease, and may even be enhanced by it. Most

importantly, studying art and dementia is a model

for recognizing the strengths, not just weaknesses,

of psychiatric patients. As powerful therapies are

developed, physicians must begin to recognize

their patients strengths and work with them to

conquer disability and degeneration.

References1. Miller BL, Cummings J, Mishkin F, et al. Emergence of artistic talent infrontotemporal dementia. Neurology. 1998;51(4):978-982.

2. Miller BL, Boone K, Cummings JL, Read SL, Mishkin F. Functional cor-relates of musical and visual ability in frontotemporal dementia. Br JPsychiatry. 2000;176:458-463.

3. Rosen HJ, Perry RJ, Murphy J, et al. Emotion comprehension in thetemporal variant of frontotemporal dementia. Brain. 2002;125(Pt10):2286-2295.

4. Garcia Marquez G. One Hundred Years of Solitude. 1st perennial clas-sics ed. HarperCollins: New York, NY: 2004:51-52.

5. Seeley WW, Matthews BR, Crawford RK, et al. Unravelling Bolro:progressive aphasia, transmodal creativity and the right posteriorneocortex. Brain. 2008;131(Pt 1):39-49.




10/24

IntroductionThe diagnosis of dementia has always repre-

sented both a challenging and hastened end to

life. William, born in 1924, grew up on a farm,

served in World War II, and became a successful

restaurateur. His dementia began at 57 years of

age and lasted 9 years. By year 3 he could no

longer be managed at home and was placed in a

nursing home. By year 5, he no longer knew his

children, and at year 6, he could no longer speak.

Williams family described his eventual passing

as a blessing, saying that he had been released

from a terrible prison. Although the painful real-

ity of this disorder continues, there has been

significant progress in Alzheimers disease treat-

ment and now, optimism about the future of

Alzheimers disease management.

Several risk factors for developing Alzheimers

disease have been identified. The most influ-

entialage and geneticscannot be changed.Modifying risk factors that can be changed

such as diet and hypertensionlikely provides

some protection if applied over years of time.

Unfortunately, the population that stands to ben-

efit most from risk factor changeyoung people

who can alter risks over decadesare those least

likely to take the threat of eventual Alzheimers

disease seriously and do so.

Symptomatic Versus Disease-Modifying

TreatmentThe current Alzheimers disease treatmentsare generally classified as symptomatic,

meaning that they benefit disease symptoms

but do not appreciably alter the basic disease

process. Treatment may initially result in an

improvement over baseline or delay to decline,

but inevitable deterioration resumes its down-

ward trajectory after only a 69 month respite

(Slide 1). The many medications currently used to

control behavioral symptoms, such as selective

serotonin reuptake inhibitors and antipsychotics,

are also considered symptomatic since their

benefit only spans the time of administration and

none change basic pathology.

It is expected that the new generation of

Alzheimers disease medications will invoke a

new paradigmthat of disease modification.

Rather than a temporary reprieve, disease-modi-

fying treatments are expected to change basic

pathology, thereby stopping or slowing the dis-ease process (Slide 2). A disease-modifying treat-

ment might permanently reduce the slope of

decline or stabilize a patients condition entirely.

Patients on a disease-modifying treatment would



ALZHEIMERS DISEASE RESEARCH:PROGRESS AND PROMISES

By Daniel D. Christensen, MD

Dr. Christensen is clinical professor of psychiatry and neurology and adjunct professor of pharmacology at the University of Utah School of

Medicine in Salt Lake City.

Disclosures: Dr. Christensen has served as a consultant for Bayer, Bristol-Myers Squibb, Designer Genes, Eisai, Eli Lilly, GlaxoSmithKline, Janssen,

Myriad Genetics, Novartis, NPS, Pfizer, RiboMed, Solvay, and Wyeth; has served on the advisory boards of Eisai, GlaxoSmithKline, Myriad, and

Pfizer; has served on the speakers bureaus of Abbott, Bayer, Bristol-Myers Squibb, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Pfizer,

Solvay, Upjohn, and Wyeth; and has received grant or research support from Abbott, Bristol-Myers Squibb, Designer Genes, Eccles Institute of

Human Genetics, GlaxoSmithKline, Janssen, Myriad Genetics, Novartis, NPS, Organon, Pfizer, RiboMed, Solvay, and Wyeth.

SLIDE 1

Symptomatic Therapy in Alzheimers Disease

GlobalFunction

Time

Untreated Course

A. Improved from Baseline

B. Delayed Decline

C. Improved from Expected

Treated Course


11/24


have a dramatically different course of illness

than those on no treatment or on symptomatic

therapy alone. Symptomatic and disease-modi-

fying concepts are sometimes envisioned on

a continuum (Slide 3). In this model, effects

on early pathological mechanisms are disease

modifying and those on late pathological mecha-nisms are symptomatic with actual medications

manifesting one or more mechanisms, each

potentially falling anywhere along the spectrum.

Theoretically, by halting the earliest changes in a

pathological cascade, the disease process could

be halted and further deterioration avoided.

The Amyloid HypothesisMany theories have been put forth to explain

the underlying pathology of Alzheimers dis-

ease. Of these, the amyloid hypothesis is themost widely acknowledged and has largely

determined the next generation of Alzheimers

disease drugs. - and -secretase enzymes

cleave the amyloid precursor protein into sev-

eral products, among them the toxic amyloid-

42 (A42). A42 fragments aggregate, forming

insoluble plaques that are believed to underlie

brain cell damage and cognitive loss. Although

this theory now has prominence, future find-

ings will likely determine it to be imperfect. For

now, however, it is informing efforts to design

Alzheimers disease treatments that will hope-

fully target early pathological changes, thereby

slowing or stopping the disease.

The amyloid hypothesis suggests four pos-

sible points of intervention (Slide 4)1: increasing

the clearance of A42; inhibiting the secretaseenzymes to prevent A42 formation; modifying

the -secretase enzyme to shift production away

from toxic A42; and interfering with the process

of A42 aggregation. These four approaches rep-

resent potential disease-modifying strategies,

each of which is currently being employed in the

development of candidate drugs.

Increasing A42

ClearanceAn Alzheimers vaccine (AN-1792), devel-

oped several years ago, was meant to prime thebodys immune system to detect and reduce A42

plaque. In animal trials, genetically programmed

mice with A42 plaques were administered the

vaccine and showed both prevention and reduc-

tion of plaque formation.2 Trials in elderly human

Alzheimers disease patients were halted due

to the incidence of aseptic meningoencephalitis

in 6% of study subjects.3 Subsequent follow-

up indicated that subjects who developed high

antibody titers declined more slowly. And a few

autopsy reports suggested that high titer sub-jects showed areas of the cortex where amyloid

plaque had apparently been cleared.4 Several

immunotherapy modifications are currently under

development in hopes of producing a treatment

that is both safe and effective. Active (inducing

the patient to produce antibodies) as well as pas-

sive immunotherapies (infusing a patient with

antibodies) are in late-stage development.

Blocking A42

Production

Blocking -secretase and/or -secretase wouldprevent the production of A42. However, inhibit-

ing either of these enzymes has proven problem-

atic. -secretase inhibitors have been universally

large molecules, which are difficult to get past

the blood-brain barrier into the brain, and -

secretase inhibitors have shown troublesome

side effects. Even so, candidate molecules for

both are currently in trials. The secretase inhibi-

tor furthest along in development is LY-450139,

which is now preparing for a phase III trial.


SLIDE 2

Disease-modifying Treatment in Alzheimers disease(Theoretical)

GlobalFunction

Time

Improvement

Stabilization

More benign course

Expected decline

SLIDE 3

Disease-modifying Treatment in Alzheimers Disease(Theoretical)

Disease Modifying Symptomatic

Affect more basic/early

pathological mechanisms

Affect more late

pathological abnormalities


12/24

Modifying -secretase to lowerA

42production

Agents that shift production away from A42 are

also in development. Rather than blocking -secre-

tase entirely, these drugs attach to the -secretase

enzyme, changing the nature of its interaction with

the amyloid precursor protein. The amyloid protein

is thereby cut to shorter lengths that do not appear

to seed plaques or cause toxicity.Preclinical experiments of tarenflurbil attempt-

ed to establish memory preservation in geneti-

cally altered Alzheimers mice. Trials involved

placing a mouse in a pool of water to assess its

ability to recall the location of an escape plat-

form (Slide 5).5 Over 39 trials, the mouse learns

the location of a transparent platform upon

which it can escape the water. The platforms

location is fixed and generally remembered by

reference to visual markers at the perimeter of

the pool. When the platform is removed, these

Alzheimers disease mice swim in circles, show-

ing no apparent memory of where the escape

platform was located. Genetically identical mice,

treated for 5 months with tarenflurbil, center

their search swim at the former location of the

platform, suggesting some memory of where

they learned the platform should be. These data

are underscored by histological studies demon-

strating that the treated mice showed a greatly

reduced amyloid load (T. Golde, MD, written

communication, 2007).

In a 12-month, phase II human trial with an

additional 12 months of follow-on, Alzheimers

disease patients treated with 1,600 mg/day of

tarenflurbil, showed less decline than place-

bo patients on cognitive (Alzheimers Disease

Assessment Scale-cognitive subscale), func-

tional (Alzheimers Disease Cooperative Study-

Activities of Daily Living Inventory) and global

(Clinical Dementia Rating-Sum of Boxes) mea-

sures.6Tarenflurbil will complete phase III studies

by September 2008 and, if shown to be safe and

effective, could be available as early as 2009.

Decreasing A42

aggregationThe theory behind the aggregation-inhibitor

strategy is that soluble A42 molecules may

not be particularly harmful until they aggregate

into fibrils and plaques. Tramiprosate has been

the most prominent A42-aggregation inhibitor,

though recent phase III human trials appear tohave failed. Many others are in both preclinical

and clinical development.

Neural Regeneration: Future HopeThe current generation of Alzheimers disease

medications acts through temporary symptom

improvement. The next generation will focus

on decreasing the slope of deterioration and

possibly stabilizing the disease process entirely.

Future treatments will hopefully lead to neural



SLIDE 4

Amyloid Hypothesis: Points of Intervention1

Outside the Cell

APP

Inside the Cell

1. -SecretaseInhibitors

-Secretase

Cell Membrane -Secretase

2. -SecretaseInhibitors

3. SelectiveA-LoweringAgent (SALA)

A

Plaque Formation

Aggregation5. Anti-aggregation

Agents

4. Immunotherapies

A42

Lower production

of toxic A

fragments

Block A

production

Decrease Aaggregation

Increase

Clearance

APP=amyloid precursor protein; A=amyloid -peptide


13/24

regeneration and restoration of normal cognitive

function. Nearly 100 years ago, prominent neu-

ropathologist Santiago Ramn y Cajal said, In

the adult brain, nerve paths are fixed, ended, and

immutable. Everything may die, nothing may be

regenerated.7 This belief has been a fixture of

medical education for ~80 years. Fortunately, this

aspect of Cajals neuron doctrine is not true.

In the 1980s, Nottebohm and colleagues8 deter-

mined that the volume and weight of the brains

of canaries varied predictably with the seasons.

Brain mass increased9 in the spring as canaries

grew new neurons to store new songs and mat-

ing calls. This creation of new brain cells, known

as neurogenesis, was then demonstrated in mice,

rats, rabbits, dogs, and monkeys. Then in 1998,

Eriksson and colleagues10 found evidence of

neurogenesis in humans. Cameron and McKay11

have since estimated that people make ~250,000new brain cells each month. If this process could

be understood, controlled and promoted, neural

regeneration therapies would become a possibil-

ity. Tuszynski and colleagues12 have implanted

Nerve Growth Factor (NGF) secreting cells into

cholinergic areas of the brain lost to Alzheimers

disease. Results from the first eight patients

indicate a decreasing rate of degeneration in

NGF treated patients. While it seems unlikely

that neural implantation therapy will become

commonplace, we are sure to learn from these

efforts, and a simpler, more accessible approach

may be forthcoming. A number of molecules are

currently under investigation as candidate drugs

to promote neurogenesis.

New Directions in Alzheimers DiagnosisIn order for disease-modifying and preventive

treatments to be fully effective, earlier and more

precise diagnosis will be necessary. Researchers

have begun to explore the idea of pre-symp-

tomatic diagnosis, ie, determining the presence

of Alzheimers disease pathology long before it

progresses to a symptomatic state.

Specialized positron emission tomography scans

are currently being developed to detect amyloid

plaque in the living brain.13

Laser eye scans arebeing utilized in an attempt to detect early amy-

loid deposition through the lens of the eye. Skin

assays are being evaluated as a means to detect

early enzyme changes that may precede amyloid

accumulation. Blood and cerebrospinal fluid analy-

sis as well as gene expression arrays are under

development as possible biomarker indicators of

presymptomatic Alzheimers disease.



SLIDE 5

Effect of MPC-7869 Treatment on Learning and Memory in Alzheimers Mice5

Search Path

Untreated Control MPC-7869 Treatment5 months


14/24


Future Alzheimers Disease ManagementAlzheimers disease management in the future

may follow the model of current cardiovascular

disease management. Not long ago, very little

was known about cardiovascular disease. In the

1950s, the average age at which patients with

cardiovascular disease experienced symptomonset was only 57.3 years of age.14The field iden-

tified risk factors as well as physical and labora-

tory assessments which permitted an accurate

determination of an individuals cardiovascular

risk. High-risk patients could be managed with

the control or elimination of modifiable risk

factors along with procedures and new classes

of medications that intervene at various levels

of cardiovascular pathology. This approach has

been tremendously successful. By the mid-1980s,

average age of cardiovascular disease onset hadbeen delayed to 76.4 years of age.14

This may serve as the model for future

Alzheimers disease management, ie, identifica-

tion of risk and protective factors; new tests, and

assessments that allow an accurate determina-

tion of Alzheimers disease risk; the control or

elimination of modifiable risk factors in high-risk

individuals; followed by the use of new genera-

tion medications to decrease or even stop under-

lying pathology, arresting the disease process

before cognitive symptoms have begun.

Alzheimers Disease Research:Progress and Promises

Current research progress appears to be lead-

ing to a new era where Alzheimers disease

pathology is detected prior to symptom onset and

new medications and management approaches

significantly delay or even avert disease onset.

Then, hopefully, we will be a little closer to the

promise of President John Kennedys 1962 man-

date, It is not enough for a great nation to have

added new years to life. Our objective must be to

add new life to those years.15

References1. Golde TE. Alzheimer disease therapy: Can the amyloid cascade be halted?

J Clin Invest. 2003;111(1):11-18.2. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-

beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.Nature. 1999;400(6740):173-177.

3. Hock C, Konietzko U, Streffer JR, et al. Antibodies against beta-amyloidslow cognitive decline in Alzheimers disease. Neuron. 2003;38(4):547-554.

4. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO.Neuropathology of human Alzheimer disease after immunization withamyloid-beta peptide: a case report. Nat Med. 2003;9(4):448-452.

5. Kukar T, Prescott S, Eriksen J, et al. Chronic administration of R-flurbi-profen attenuates learning impairments in transgenic amyloid precursorprotein mice. BMC Neurosci. 2007;8 (1):54.

6. Christensen DD. Changing the course of Alzheimers disease: anti-amyloiddisease-modifying treatments on the horizon. Prim Care Companion J ClinPsychiatry. 2007;9(1):32-41.

7. Cajal SR. Degeneration and Regeneration of the Nervous System. NewYork, NY: Hafner; 1928.

8. Nottebohm F. A brain for all seasons: cyclical anatomical changes in songcontrol nuclei of the canary brain. Science. 1981;214(4527):1368-1370.

9. Paton JA, OLoughlin BE, Nottebohm F. Cells born in adult canary forebrainare local interneurons. J Neurosci. 1985;5(11):3088-3093.

10. Eriksson PS, Perfilieva E, Bjrk-Eriksson T, et al. Neurogenesis in theadult human hippocampus. Nat Med. 1998;4(11):1313-1317.

11. Cameron HA, McKay RD. Adult neurogenesis produces a largepool of new granule cells in the dentate gyrus. J Comp Neurol.2001;435(4):406-417.

12. Tuszynsik M, Thal L, Pay M, et al. A phase I trial of nerve growthfactor ex vivo gene therapy for Alzheimers disease. Neurology.2004;62(suppl5):A174-175.

13. Buckner RL, Snyder AZ, Shannon BJ, et al. Molecular, structural, andfunctional characterization of Alzheimers disease: evidence for arelationship between default activity, amyloid, and memory. J Neurosci.2005;25(34):7709-7717.

14. Ho KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival afterthe onset of congestive heart failure in Framingham Heart Study sub-jects. Circulation. 1993;88(1):107-115.

15. Kennedy JF. Special message to the Congress on the needs of thenations senior citizens. Public Papers of the Presidents of the UnitedStates: January 1 to November 22, 1963. US Government Printing Office:Washington, DC; 1964:189.



15/24



Current Alzheimers LandscapeMany efforts are being made to medically man-

age or eliminate Alzheimers disease. Millions of

family members, friends, and professionals are

serving as caregivers for those with the disorder.

These two efforts are important, but they are not

enough. The public must also be educated in order

to reduce the risk for Alzheimers disease and

related dementias in younger generations. These

various goals can be accomplished through many

different community-focused activities, including

care and support for families; public awareness;

community, patient, and professional education;

research; and advocacy.

There are an estimated 5 million Americans

with Alzheimers disease. This includes 4.9 million

people >65 years of age, and 200,000 people 65 of

age with Alzheimers disease or another demen-

tia.1 One American develops the disease every 72

seconds, and the rates of occurrence will increase

as the baby boomer generation ages (Slide 1).2

While mortality rates from many other diseases

have declined, Alzheimers disease mortality has

increased. Heart disease deaths have declined by

8%, breast cancer deaths by 2.6%, prostate can-

cer deaths by 6.3%, and stroke deaths by 10.4%.

Alzheimers disease mortality, on the other hand,

has increased by ~33%. Today, 411,000 new cases

of Alzheimers disease are diagnosed each year

in the United States. At the current rate, nearly 1

million new cases will be diagnosed by 2050.

Human and Economic ImpactApproximately 10 million Americans are involved

in the care of a person with Alzheimers disease,

and there are ~1 to 3 care providers for each

Alzheimers disease patient. Families providing at-

home care comprise 80% of Alzheimers disease

care. Those family members pay a price, as does the

US economy. In 2005, it was estimated that unpaid

caregivers of people with Alzheimers disease and

other dementias provided 8.5 billion hours of care,

valued at almost $83 billion.1 In addition, the cost

of caring for someone with Alzheimers disease is

three times higher than the cost of an age-matched

person without the disease (Slide 2).3 If the increas-

ing rate of Alzheimers disease occurrence is not

addressed, Medicare will assuredly suffer.

ADVOCATING FOR PEOPLE WITH ALZHEIMERSDISEASE AND THEIR CAREGIVERS

By Debra Cherry, PhD

Dr. Cherry is the executive vice president of the California Southland Chapter of the Alzheimers Association in Los Angeles.

Dr. Cherry reports no financial, academic, or other support that may pose a conflict of interest.

SLIDE 2

Average Medicare Costs for Beneficiaries with Alzheimers

Disease vs. Other Beneficiaries, 20003

$14,000

$12,000

$10,000

$8,000

$6,000

$4,000

$2,000Without AD With AD

$4,454

$13,207

SLIDE 1

Estimated Number of New Alzheimers Disease Cases2

1200

1000

800

600

400

200

01995 2 000 2010 2020 2030 2040 20 50

Year

NewC

asesinThousands

377411

454491

615

820

959


16/24



Unfortunately, in spite of the strong economic

motivation to increase funding for Alzheimers

disease research, funding levels remains essen-

tially flat (after adjusting for inflation). Congress

has proposed funding the Alzheimers Disease

Demonstration Grants to States program, the

Alzheimers Association 24/7 Helpline, and theAlzheimers Association Safe Return Program

at 2007 levels. Congress also proposed a 2%

increase in Alzheimers disease research at the

National Institutes of Health, bringing the fund-

ing level for 2008 to $661 million. These federal

initiatives are promising, but much more remains

to be done.

Goals for the Near FutureIf medical and public health efforts can suc-

ceed in delaying the onset of Alzheimers diseaseand slowing its progression by 2010, a dramatic

drop in the number of Alzheimers disease cases

would be apparent almost immediately. Within

10 years, the number of Alzheimers disease

cases would drop by 2.3 million.4 Over the next

40 years, 5.3 million fewer people would develop

this disorder. Delaying the onset of Alzheimers

disease or slowing its progress by only 35 years

would save Medicare $51 billion in 2015. By2050, savings to Medicare would amount to $444

billion (Slide 3).4 With the active participation

of the medical community and society at large,

these are achievable goals.

References1. Alzheimers Association. Alzheimers Disease Facts and Figures.

Washington, DC: Alzheimers Association; 2007.2. Hebert LE, Beckett LA, Scherr PA, Evans DA. Annual incidence of

Alzheimer disease in the United States projected to the years 2000through 2050. Alzheimer Dis Assoc Disord. 2001;15(4):169-173.

3. Alzheimers Association. Alzheimers Disease and Chronic Health: TheReal Challenges for 21st Century Medicine. Chicago, Ill: Alzheimers

Association; 2003.4. The Lewin Group to the Alzheimers Association. Saving Lives, SavingMoney: Dividends for Americans Investing in Alzheimers Research.Washington, DC: Alzheimers Association; 2004.

SLIDE 3

Medicare Spending for People with Alzheimers Disease Using Current Projections vs. Projections with Delayed Onset

and Slowed Progression4

1,200

1,000

800

600

400

200

0 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050Savings $0 $0 $0 $51 $88 $126 $177 $238 $310 $385 $444(in billions)

$62 $62$91 $91

$160 $160$189

$138

$229

$141

$294

$168

$394

$217

$529

$291

$696

$386

$879

$494

$1049

$605

Medicare Spending for People with Alzheimers

Baseline estimatesDelayed onset and slowed progression


17/24



Q. What are the primary differences between

Alzheimers disease and dementia?

Dr. Cummings: There are three common-

ly confused concepts: senility, dementia, and

Alzheimers disease. Senility is a concept that we

have abandoned. It implies that impaired mental

function is normal. However, this is not normal.

It is normal to be mentally healthy until ones

life ends, so senility is no longer a viable con-

cept. Dementia refers to cognitive impairment.

Alzheimers disease is the most common cause

of dementia. Dementia is the general concept;

Alzheimers disease is the specific concept.

Q: Even in the later stage of senile dementia,

some people can still remember the lyrics and

melodies of songs. Why is that?

Dr. Miller: I was taught that degenerative dis-

eases hit the brain diffusely. However, the more

we study degenerative diseases, the more we

realize they attack very specific circuits in the

brain. Alzheimers disease attacks a memory

circuit first, and then spreads elsewhere. The

parts of the brain involved with listening tomusic and even producing music are not as

badly affected. For example, many people with

Alzheimers disease can continue to play the

piano beautifully in spite of the diseases sever-

ity. This means that there are many systems in

the brain that remain intact. It is important to

tap into those systems that are still working. I

do not think physicians do that enough. They

may underestimate how much mental aware-

ness or ability still exists in their patients.

Q: What are the current and future treatments

for aggressive behaviors in patients with

Alzheimers disease?

Dr. Christensen: There are a number of ways

that physicians currently approach aggressive

behaviors. If an Alzheimers disease patient is

not on medication, doctors should first try to

build a solid basis of a treatment. Patients

with Alzheimers disease often become con-

fused and agitated, and this is to be expected.

Anxiety, fearfulness, and suspicion are all nor-

mal reactions to confusing situations like the

ones Alzheimers disease patients experience. A

solid foundation of treatment should help miti-

gate this confusion. There are also a number of

medications physicians can use beyond the basic

treatment. However, behavioral therapies should

be attempted first. It is best to avoid resorting to

agitation medicines wherever possible. There are

also medicines physicians should try to avoid,

such as benzodiazepines and tricyclic antidepres-

sants. Too often, physicians respond to agitation

by pulling out the big elephant guns: atypical

antipsychotics. Of course, if one is shootingan elephant, this strategy is useful. However,

agitation is usually a very small problem that

could be easily handled by more benign agents

or strategies. Hopefully, the new generation of

Alzheimers disease medications will prevent

people from experiencing the stages of the ill-

ness where agitation is a problem.

Q: Alzheimers patients may become aggressive.

When should a family consider placing an aggres-

sive loved one in a nursing home? Do you havesuggestions on how to find a good facility?

Dr. Cherry: Every family is different. Before

considering a nursing home, caregivers should

consider whether something concrete has

caused the increase in agitation. Families could

join a support group or speak to an Alzheimer s

Association care consultant to explore what

in the patients environment or health might

be stimulating this change in behavior. A uri-

nary tract infection, for example, might cause

agitation. When nursing home care is consid-ered, web based reports on homes, such as

the one available through www.medicare.gov,

can be helpful. The Alzheimers Associations

Carefinder program available through

www.alz.org or a call to a local chapter for a

care consultation can also help by providing the

caregiver with a checklist and ideas of what to

ask. Ultimately, visiting the sites is necessary

but the more preparatory work done before-

hand, the more productive the visit will be.

QUESTION-AND-ANSWER SESSION


18/24

CNS Spectr13:2 (Suppl 2) MBLCommunications Februar y 200818


Q: Is there a link between cases of early onset

Alzheimers disease? Are these familial, environ-

mental, or genetic?

Dr. Cummings: There are two kinds of genetic

influences. One is a rare genetic mutation thatcauses direct inheritance of Alzheimers disease.

In these families, half of each generation is

affected. People born with the gene will inevita-

bly develop Alzheimers disease, usually around

4050 years of age. Onset at 40 or 50 years of age

is usually caused by this mutation. Much more

common is the inheritance of a risk factor. With

genetically increased risk, the onset of the disor-

der is not assured. One can have the gene with-

out getting dementia, and one can get dementia

without having the gene. Though it is possible

to test for the latter case, this is discouraged for

people who are mentally normal because, at this

point, we do not have therapies to offer them.

Q: Given the current drugs available, can treat-

ments help at every stage of the disease?

Dr. Miller: It looks like the recent compounds

have been primarily beneficial in mild to moder-

ate Alzheimers disease progression, and have

mild effects throughout the course of the illness.The current set of drugs, cholinesterase inhibi-

tors and the modulators, work in many patients

in the moderate-to-severe stages, but there is

almost always a point where the family and

physician agree that it is time to pull away. Every

family and every patient must decide when qual-

ity of life has deteriorated such that the drugs are

no longer desirable, and when prolongation of

life is not what the patient would have wanted.

The goal should be maximum quality of life for

as long as possible, and the current medications

do not always further that goal.

Q: If a person


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William Utermohlen was born in 1933.

Upon completing his Bachelors degree at the

Pennsylvania Academy of Fine Arts, he joined

the Army and then moved to England to study at

the University of Oxford. This is where he met his

wife, Patricia. Bill painted scenes from his child-

hood in Philadelphia, images of Vietnam War vet-

erans, and pictures inspired by Dantes Inferno.

Later, many of his paintings depicted family life,

conversations with friends, and his homethey

were happy pictures.

Snow, from the 1990s, shows the flat he shared

with his wife (Slide 1). In it, Bill had withdrawn

himself from the group, and the mirror over the

mantelpiece features a dead friend. Psychiatrists

say this painting presages Bills development

of Alzheimers disease. Blue Skies, from 1995,

shows Bill receiving his Alzheimers diagnosis(Slide 2). He hangs onto the table for grim death,

and the future, shown in the window, is just

empty space. Bill was put on donepezil and had

to be monitored every month. A very sympa-

thetic male nurse encouraged him to continue

painting and drawing. Every visit, he would say,

Do me another one.

Bills paint application became very different

as his illness progressed. All of his previous pic-

tures had been very carefully constructed with

smaller drawings and photographs, but after his

disease progressed, he could not wait to get the

pictures out. His self-portraits placed emphasis

on his head and skull. In 1997, when asked to

donate his brain to science after he died, Bill was

terribly brave and said, Of course, of course.

But he came home terrified, and painted Self-

By Patricia Utermohlen, MA

Testimonial:

Patricia Utermohlen, MA, is professor of Art History at the Syracuse University London Program. She and William Utermohlen were married

for 42 years.

SLIDE 1

Snow

SLIDE 2

Blue Skies

IMPACT OF ALZHEIMERS DISEASE ON ONE

ARTISTS BODY OF WORK


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Portrait with Saw (Slide 3). The skull is visible

beneath his skin; the mouth is bitter. Another

painting from 1997 shows his wife with bright

red hair (Slide 4). She had red hair when they

first met, and he may have been remembering

that period of time.

By 1998, Bills self-portraits did not featurebodies anymore. In 1999, he painted Erased Self-

Portrait, which was an erased head (Slide 5). At

the end, he drew empty ovals. For Bill, drawing

was like breathing. Through his pictures, he tried

desperately, until the last moment, to convey

what his illness felt like.

SLIDE 3

Self-Portrait with Saw

SLIDE 4

Portrait of the Artists Wife Pat

SLIDE 5

Erased Self-Portrait


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