Dementia
Diagnostic and Therapeutic Considerations
Summer 2010
Leon S. Kraybill, MD, CMD
Geriatric Specialists, Lancaster General Hospital
A population explosion
US population over 65 yo, in millions
80
71.5
70
60
54.6
50
40.2
40
31.2
30
25.7
20
16.7
10
0
35
3.1
4.9
1900
1920
9
1940
1960
1980
1990
2000
Source: Administration on Aging
2010
2020
2030
Coming to your office….
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In 2004, Americans > 65 were
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36.3 million
12.4% of population
1 in 8
In 2050, Americans > 65 are predicted:
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71.5 million
1 in 5 Americans
And older every year….
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The old old (>85 yo)
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2000 - 4.2 million (1.5%)
2010 – 5.5 million (2.0%)
2030 – 9.6 million (2.6%)
2050 – 19 million (5.0%)
In 2050 – 5% of the US population will be
over 85 years old
Source: Federal Interagency Forum on Aging Related Statistics
Dementia – disease of the 21st century?
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Dementia is most closely associated with
advancing years
More older patients = more dementia
During a 1 hour lecture – 50 new cases of
dementia in US (vs. 24 new breast cancers, 52
MI deaths, 4 MVA deaths)
Alzheimer’s dementia in US
Ubiquitous & rising
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2000: 4.5 million
2010: 5.3 million
2020: 5.7 million - 27% increase
2030 - 7.7 million - 70% increase
2050 – 13.2 million - 300% increase
Source: National Institute on Aging
Prevalence of dementia in 2002
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Dementia present in 37.4% of
individuals aged 90 and older
Alzheimers dementia is more prevalent
with advancing age. In age 90+ group,
AD accounted for 79.5% of all dementia
cases compared to 46.7% among those
aged 71–79 years.
Plassman, et al. Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study.
Neuroepidemiology 2007;29:125–132.
Why should we care?
In 2009 - Almost 11 million Americans provided unpaid
care for a persons with dementia. They provided
12.5 billion hours of unpaid care
Personal cost: In 2009, the economic value of the care
provided by family and other unpaid caregivers of
people with Alzheimer’s and other dementias was
$144 billion
2010 Alzheimer’s Disease: Facts and Figures www.alz.org/documents_custom/report_alzfactsfigures2010.pdf
Why should we care?
Dementia is under diagnosed and under treated
 Between 30-75% of cases of dementia or
probable dementia are not diagnosed by primary
care physicians 1
 Only 35% of individuals with mild to moderate
Alzheimer’s have ever been given a standard
memory support drug 2
1) Does This Patient Have Dementia? JAMA. 2007;297:2391-2404.
2) Undertreatment of patients with Alzheimer’s disease in an elderly United States population. Alzheimer's & Dementia: The Journal of the
Alzheimer's Association, Volume 1, Issue 2, Pages 93-168 (October 2005).
Nursing Home costs 2009
Home care -the average hourly rate for non-medical home care,
including personal care & homemaker services, was $19 or
$152 for an 8-hour day.
Adult day center services – average cost of adult day services
was $67/day
Assisted living facility -the average cost for basic services in an
assisted living facility was $105/day, or $37,572/year
Nursing home - the average cost for a private room in a nursing
home was $219/day, or $79,935/year. The average cost of a
semi-private room $198/day, or $72,270/year
2010 Alzheimer’s Disease: Facts and Figures
www.alz.org/documents_custom/report_alzfactsfigures2010.pdf
Isn’t dementia incurable?
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Yes, by current medical standards and treatments
But treatments can alter the disease trajectory,
manage the symptoms, relieve the fears, and allow
response
Most of your older patients will not expect you to
cure their diseases, prevent their death, or return
them to the health of their youth. But they do yearn
for explanation of disease, understanding of what is
to come, and the dignity of being known as a person.
Who will provide care?
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Family physicians/internists will be called
upon to provide care for older patients
whether we choose to or not
The family practice training uniquely
prepares us to see and treat these patients as
people and not as a conglomeration of organ
systems.
Geriatric physicians 2007
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7,128 - physicians certified in geriatric medicine
1,596 - physicians certified in geriatric psychiatry
36,000 – estimated need for geriatricians in 2030
Decrease to (+)700 - estimated actual change of
geriatricians by 2030
2010 Alzheimer’s Disease: Facts and Figures
www.alz.org/documents_custom/report_alzfactsfigures2010.pdf
You are the specialist!
The well trained and compassionate family
physician/internist is the best equipped
and most appropriate person to diagnose,
manage and treat dementia.
Plus, it’s rewarding and fun.
Lecture Objectives
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Describe why identification of dementia is
important and who should manage it
Outline an evaluation and assessment
approach to dementia – from presentation to
death
Identify the most common forms of dementia
Compare medications for dementia
To screen or not to screen?
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2003 US Preventive Services Task Force
(USPSTF) said no
Have our treatment options changed?
Does intervention prevent or delay the
consequences?
Does early diagnosis allow for better social
and emotional support?
Dementia criterion: DSM-IV
Requires multiple cognitive deficits
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Memory impairment
Plus 1 of following
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Agnosia – impaired ability to recognize and identify objects
Aphasia – impaired language
Apraxia – impaired motor activities despite intact ability
Executive function – impaired ability to organize, abstract, plan
Impairs function, and is a decline
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision ed. Washington, DC: American
Psychiatric Association; 2000.
2010
The diagnosis of dementia is a
clinical diagnosis, based on
the clinical course of the
disease, after other conditions
are ruled out.
When to suspect dementia
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Missed or late office visits
Poor recollection of past important medical treatments
Medication “noncompliance”
Family complaints of memory loss exceed the patient’s
recognition of a problem
Loss of engagement in the office visit
Tentativeness in a previously confident patient
Inattentive to appearance, hygiene or continence
Unexplained weight loss or failure to thrive
Unusually jovial or evasive responses
De novo depression
Know the 10 signs

Alzheimer’s Association checklist - see
handout
www.alz.org/national/documents/checklist_10signs.pdf
Cognitive screening tests
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Every medical provider needs to be
comfortable with at least 2 cognitive
screening tests
…. And use them!
Each has strengths and weaknesses
Good review - Does This Patient Have Dementia? JAMA. 2007;297:2391-2404.
Cognitive screening test principles
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They do not diagnose, only provide
supportive evidence
They provide a numerical score (not
necessarily a functional assessment)
Not all patients with normal scores are
normal, nor abnormal = impaired
Better to follow over time, than define
dementia at any one point
Mini-Mental® State Examination
(MMSE™) by Folstein et. al.
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Widely used and available
Tests multiple cognitive domains
Influenced by educational level
May not detect mild cognitive impairment
Administration time 5-10 minutes
Protected by copyright, unauthorized reproduction is
forbidden
www.minimental.com
www.aafp.org/afp/20010215/703.html
Montreal Cognitive Assessment
(MOCA)
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Tests a broad range of cognitive domains
More sensitive to mild cognitive impairment
Administration time – 10 minutes
Free access to test, instructions, and multiple
languages at www.mocatest.org
Clock drawing test
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Ask patient to place the numbers on the face
of a clock, and then place hands for a specific
time (i.e. 11:10)
Many different instructions and scoring
approaches
Tests construction, visuospatial function,
conceptualization, executive function
Sensitivity (59-85%), specificity (85%)
Clock-drawing: is it the ideal cognitive screening test? Int J Geriatr Psychiatry 2000: 15, 548-561
Clock drawing test
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Benefits
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Simple, quick (1-2 minutes)
Easy to administer
Less affected by level of education, language, cultural
differences
Better for patient with poor concentration
Limitations
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Poor screening for mild dementia
Does not absolutely define different types of dementia
Animal naming test (verbal fluency)
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Timed test : Name as many animals as
possible in 1 minute
Scoring:
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> 18 Normal
13-17 Borderline
< 12 Abnormal
Blessed Orientation Memory
Concentration Test (Modified Blessed)
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Tests orientation, recall, attention
Requires 4-6 minutes
Does not require paper, pencil, use of hands
Scoring is weighted towards short term
memory loss
Comparison of screening tests
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Sens%
MMSE
80-90
MOCA
100
Mini cog
76
Clock drawing
59-85
Modified Blessed
69
Animal naming (ANT) 50-72
ANT + Memory phrase 79-87
Spec%
<80
87
89
90
90
90-98
90-98
Minutes
5-10
10
2-4
1-2
4-6
2
3
Initial dementia evaluation
Evidence supports (to rule out other conditions):
 CBC
 Glucose, electrolytes, BUN/creatinine, Liver
function tests
 Serum Vitamin B12
 Thyroid function tests
 Noncontrast CT or MRI (MRI improves specificity)
 Depression screening
Detection, Diagnosis and Management of Dementia, American Academy of Neurology Guideline summary,
www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf
Evidence does not support routine use of:
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Syphilis screening
EEG
Lumbar puncture (with some exceptions: mets, CNS
infection, hydrocephalus, <55 yo, unusual dementia)
Linear or volumetric MR or CT (for hippocampal
atrophy)
SPECT
APOE-e4 genotyping for AD
Detection, Diagnosis and Management of Dementia, American Academy of Neurology Guideline summary,
www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf
Insufficient evidence to support/refute:
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PET
Other genetic markers for AD
CSF or other biomarkers for AD
Detection, Diagnosis and Management of Dementia, American Academy of Neurology Guideline summary,
www.aan.com/professionals/practice/pdfs/dementia_guideline.pdf
Genetic testing - ApoE-e4
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ApoE gene on chromosome 19 determines a protein that
carries cholesterol
ApoE-e4 is one of 3 common forms of the ApoE gene, and is
more common in AD
One ApoE-e4 gene increases the risk of developing AD
Two ApoE-e4 genes further increase the AD, but does not
guarantee the development of Alzheimer’s
Conclusion - ApoE-e4 does not add substantially to diagnostic
confidence. Not recommended for routine screening
Genetic testing
Familial autosomal dominant early-onset AD
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Less than 1 percent, caused by rare genetic variations found in a small
number of families worldwide
Disease tends to develop before age 65, sometimes in individuals as
young as 30.
Presenilin 1 (PSEN1) on chromosome 14, commercially available,
consider for families with AD onset < 50 yo
Presenilin 2 (PSEN2) on chromosome 1 – not commercially
available
Amyloid precursor protein (APP) on chromosome 21 – not
commercially available
Neuroimaging (CT or MRI)
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Usually recommended as part of the initial
evaluation
Especially important if:
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Onset less than 1 year
Symptoms before 65yo
Vascular risk factors suggesting cerebrovascular
involvement
Focal neurological finding, metastatic disease
Value in late-stage disease is not established
APA Practice Guidelines: Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias, Second Edition.
Published in October 2007. http://www.psychiatryonline.com/content.aspx?aid=152139.
Neuroimaging details
CT – used to rule out reversible causes of cognitive
impairment
MRI – maybe better at showing early signs of AD,
and differentiating from other forms of dementia
(ie silent cerebrovascular disease)
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In AD, MRI can show left sided atrophic changes in
entorhinal cortex, amygdala, and anterior hippocampus
several years before onset of clinical symptoms
Henry-Feugeas MC, MRI of the “Alzheimer syndrome”, J Neuroradiol. 2007 Oct;34(4);220-7.
Neuroimaging: White matter disease
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Terms: Leukoaraiosis, leukoencephalopathy,
small vessel ischemia, white matter disease
Scattered loss of white matter in the brain
due to subcortical vascular disease
Inconsistently associated with cognitive
function…does not equate with dementia
Ischemic burden
Poor prognosis for death, stroke, and MI
Other neuroimaging tests
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PET – assesses function via cerebral
metabolism. Since function may be disrupted
before structural changes occur, may show
changes of AD 3 years before clinical
diagnosis. Recently approved by Medicare to
differentiate between AD and FTD
SPECT – evaluates function via cerebral
blood flow. Conflicting results – not
appropriate for routine AD assessment
Do I have dementia or Alzheimer’s?
Mild Cognitive
Impairment
(MCI)
Dementia
Alzheimer’s
dementia
(AD)
Vascular
dementia
(VaD)
Lewy body
dementia
(LBD)
Frontotemporal
dementia
(FTD)
Dementia types
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Alzheimer’s 50-80% of dementing illness
Vascular 10-20%
Lewy body 5-10%
Frontotemporal 4-20%
Mixed 10-30%
Does This Patient Have Dementia? JAMA. 2007;297:2391-2404.
See addendum –spread sheet on different types
Mild cognitive impairment (MCI)
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Problems with memory, language, or other cognitive
domains severe enough to be noticeable to other people and
to show up on tests, but not serious enough to interfere with
daily life
Prevalence: About 12% (10-20%) of those > 70
About 15% per year progress to dementia - but some never
progress to overt dementia
Nearly half of all people who have visited a physician about
MCI symptoms will develop dementia in three or four years
MCI types
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Amnestic MCI
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Memory loss is predominant
Progress to Alzheimer’s disease at a rate of
approximately 10% to 15% per year
Non-amnestic MCI
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Impairments in other domains
At risk for progression to other dementias
MCI treatment
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There is no specific treatment for MCI
Meta-analysis of randomized controlled trials
shows that treatment of MCI with
cholinesterase inhibitors does not delay onset
of dementia or AD 1
Small study (15 patients) – calcium channel
blocker, nilvadipine, may delay cognitive
decline 2
1. Raschetti R, Cholinesterase inhibitors in mild cog imp, PLoS Med 2007; 4(11):e338.
2. Hanyu H, Nilvadipine prevents cognitive decline of patients with mild cognitive impairment, Intl J Geriatr Psychiatry 2007;22(12):1264-1233
Alzheimer’s disease – DSM-IV
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Impaired memory
At least one of the following cognitive
disturbances: aphasia, apraxia, agnosia, and
disturbed executive function.
The cognitive abnormalities must represent a
change from a previous higher level of function, be
progressive, & impair functioning
Gradual onset and continued decline
Not present exclusively during a period of delirium.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision ed. Washington, DC:
American Psychiatric Association; 2000.
Structural hallmarks of AD
1. Amyloid plaques – abnormal extracellular protein
deposits
2. Neurofibrillary tangles – intracellular tau proteins
3. Irreversible impairment and loss of neurons

These changes are especially evident in the
hippocampus and cerebral cortex where memory,
language, reasoning, perception, and judgment
occur
AD characteristics:
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A progressive disorder affecting cognition,
personality, behavior, and activities of daily
living (ADLs)
Memory impairment, especially short term,
rapid forgetting of new material
Gradual and steady inexorable decline
Anosognosia – lack of recognition of disease
Early changes of AD
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Early impaired psychological reasoning –
impaired understanding of the intention of
others
Become oblivious to the emotions of others,
before memory loss is evident
Likely why family members become so
frustrated & feel the patient is manipulative
*****Family education is imperative*****
Diagnosis of AD
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Listen to your patients and families, listen to your
intuition, suspect, screen
Look for red flags (ADLs, depression, change in
appearance, change in dress, change in personality,
change in engagement)
An experienced clinician can make a diagnosis of
AD with 90% reliability based on medical,
neurological and psychiatric evaluations
Staging of dementia
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See Addendum – seven stages in FAST scale
See Addendum – Mild/Moderate/Severe
Evolving science
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First updates in the Alzheimer’s diagnosis in 25
years
Proposed three stages of the disease process
 Preclinical (new)
 Mild cognitive impairment (MCI)
 Alzheimer’s dementia
http://www.alz.org/research/diagnostic_criteria/
Preclinical disease
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Like carcinoma in situ, or cholesterol and CAD
Three diagnostic criteria
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Asymptomatic amyloidosis – abnormal levels of amyloid
but no cognitive or functional symptoms
Amyloidosis + one other marker of disease – atrophy on
imaging, abnormal PET, abnormal levels of
phosphorylated tau protein
Amyloidosis + a biomarker + slight cognitive symptoms
Mild cognitive impairment
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Three proposed criteria
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Patient aware, measurable deficits, preserved
cognitive and functional skills
Change in brain topography – hippocampal
atrophy or hypo-metabolic brain regions
Confirmed amyloid abnormality – reduced in
CSF (and thus increased in brain), or positive
amyloid brain imaging
Vascular dementia
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Second most common in US, especially in old
old patients
Memory loss, plus loss in one other cognitive
domain, in setting of cerebrovascular disease
Stepwise progression with periods of stability
Frequently combined with other dementias,
pure vascular dementia is likely uncommon
Concurrent depression is common
Vascular dementia treatment
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Insufficient data to support cholinesterase
inhibitors and memantine in vascular
dementia 1
Insufficient evidence to support use of
aspirin, gingko biloba, calcium blockers or
pentoxifylline 2
1. Kavirajan H, Schneider LS: Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: A
meta-analysis of randomized controlled trials. Lancet Neurol 2007; 6(9):782-792.
2. Waldemar G, Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with
dementia: EFNS guideline. Eur J Neurol - 01-JAN-2007; 14(1): e1-26
Lewy body dementia (see handout)
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Required: progressive cognitive decline, occurring
before or with the parkinsonism
Core: Delirium-like fluctuation, visual
hallucinations, parkinsonism
Suggestive: REM sleep behavior disorder,
neuroleptic sensitivity
Dementia onset within 12 months of motor features
of parkinsonism
McKeith IG, Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology - 27-DEC-2005; 65(12): 1863-72.
Treatment of Lewy body dementia
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14 small studies of ChEI showed benefit in
cognition and neuropsychiatric symptoms
Possible greater ChEI benefit than in AD
Insufficient data to evaluate memantine
Avoid neuroleptics, if required – quetiapine
Low dose parkinson’s meds, only if
necessary
Waldemar G, Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline.
Eur J Neurol - 01-JAN-2007; 14(1): e1-26
Frontotemporal dementia (FTD)
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Deficits in frontal system tasks: verbal fluency,
executive function (attention, abstraction, planning,
problem solving)
Behavior: early personal and social disinhibition,
emotional blunting, loss of insight, hyperorality,
perseverative behavior
Mean age of onset is 53-56
No evidence that current antidementia meds are
effective in FTD
Cholinergic theory of AD
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Acetylcholine
Acetylcholinesterase breaks
down the acetylcholine for
repeat use
Alzheimers dementia is
associated with decreased
cholinergic activity
Cholinesterase inhibitors
slow the breakdown process,
thus increasing the amount
of acetylcholine present in
the synapse
Cholinesterase inhibitors (ChEIs)
Evidence suggests that early treatment of mild-tomoderate AD with ChEIs can:
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Prolong Functioning
Preserve Cognitive abilities
Improve behavioral & psychological symptoms
Postpone transfer to skilled nursing
Ease Caregiver burden
Reduce costs for residents and caregivers
Institutionalized severe dementia residents – less decline,
some cognitive change
Tracey Holsinger, MD; Janie Deveau, MD; Malaz Boustani, MD, MPH; John W. Williams, Jr, MD, MHS. Does This
Patient Have Dementia? JAMA. 2007;297:2391-2404.
Symposium Reporter 2007: Opportunities to Improve the Prognosis of Severe Alzheimers Disease, released Nov 2007,
from American Medical Director Association annual symposium.
Metanalysis of studies 1986 - 2006
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96 publications, 59 unique studies
Both cholinesterase inhibitors and memantine had consistent
effects in the domains of cognition and global assessment, but
summary estimates showed small effect sizes.
CONCLUSIONS: Treatment of dementia with cholinesterase
inhibitors and memantine can result in statistically significant
but clinically marginal improvement in measures of cognition
and global assessment of dementia.
Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. AURaina P; Santaguida P;
Ismaila A; Patterson C; Cowan D; Levine M; Booker L; Oremus M SOAnn Intern Med. 2008 Mar 4;148(5):379-97.
APA guidelines 2007
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ChEIs should be offered to patients with mild to
moderate AD, after a thorough discussion of their
potential risks and benefits
ChEIs may be helpful for severe AD
ChEIs should be considered for mild to moderate
dementia with Parkinson’s (only rivastigmine approved,
but others likely similar)
ChEIs can be considered for Lewy Body dementia
Memantine may provide modest benefits and few
adverse reactions in moderate to severe AD (very limited
evidence in vascular dementia)
APA Practice Guidelines: Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias,
Second Edition. Published in October 2007. http://www.psychiatryonline.com/content.aspx?aid=152139.
Up to DateR conclusions
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Suggest treatment trial of ChEI in mild to moderate dementia (Grade 2A).
Do not routinely use tacrine (Grade 1A).
Suggest trial of ChEI in vascular dementia (VaD), mixed dementia,
dementia with Lewy bodies (DLB), and dementia in Parkinson's disease
(PD). (Grade 2B).
In severe dementia, ChEIs can be discontinued, but they should be
restarted if the patient worsens without the medication (Grade 2C).
Do not routinely recommend ChEI in mild cognitive impairment (MCI),
but if memory problems are particularly troubling, then a trial for
symptomatic benefit may be warranted (Grade 2C).
©2008 UpToDate® accessed 8/8/08
Recommendation grades
1. Strong recommendation: Benefits clearly outweigh the risks and burdens (or vice versa) for most, if not all, patients
2. Weak recommendation: Benefits and risks closely balanced and/or uncertain
Evidence grades
A. High-quality evidence: Consistent evidence from randomized trials, or overwhelming evidence of some other form
B. Moderate-quality evidence: Evidence from randomized trials with important limitations, or very strong evidence of some other form
C. Low-quality evidence: Evidence from observational studies, unsystematic clinical observations, or from randomized trials with serious flaws
AAFP & Am College of Physicians
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Review of 24 high quality studies of ChEIs
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Statistical improvement, not clinical difference
Subgroups may show clinical difference, but not defined
who that is
Recommendation: Base the decision to initiate
therapy on the individualized assessment of benefit
and risk (weak rec, moderate quality evidence)
Rec: Insufficent evidence to suggest that one agent
is superior (weak rec, low quality data)
Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of
Family Physicians. Ann Intern Med. 2008 Mar 4;148(5):370-8.
Alzheimer’s Association 2010 summary:
“No treatment is available to slow or stop the
deterioration of brain cells in Alzheimer’s
disease. The U.S. FDA has approved 5 drugs
that temporarily slow worsening of symptoms
for 6-12 months, on average, for about half of
the individuals who take them.”
2010 Alzheimer’s Disease: Facts and Figures www.alz.org/documents_custom/report_alzfactsfigures2010.pdf
Dr. Kraybill’s recommendations
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Don’t be afraid to try a ChEI
Be realistic with patient and family about the disease
and current treatments
Discuss adverse reactions
Establish the goals of therapy, and be willing to stop
treatment if unsuccessful
Followup regularly - the care of the caregiver
(education, understanding, praise) may give more
benefit than medication
What is success?
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Average untreated patient with dementia will
lose 2-4 points per year on MMSE, and have
functional decline
Is stability sufficient reason to justify use?
Symptoms progress more slowly than
anticipated
Clinical benefit is rarely sustained longer than
12-18 months, when clinical decline again
resumes
BUT…..
Clinical benefit is small, not permanent, and not
without potential adverse reactions
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Study: 2 point cognitive benefit on ADAS-cog
score (70 point scale) 1
Study: 3 point gain on SIB score (100 point
scale) at 24 weeks 2
Study in severe AD: 6 point gain on SIB score
(100 point scale) at 6 months
1) Burns, Alistair, Efficacy and safety of donepezil over 3 years: an open-label, multicentre study in patients with
Alzheimer’s disease, Int J Geriatr Psychiatry 2007: 22(8):806-812
2) Tariot PN, Memantine treatment in patients with moderate to severe Alzheimer Disease. JAMA. 2004;291:317-324.
Individual response is variable


Maximal benefit should be seen by 3 months
30 – 50% of patients will show no benefit
Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Am J Geriatr Psychiatry 2003 Mar-Apr;11(2):131-45.
Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies. Ann Intern Med 2003 Mar 4;138(5):400-10.

A smaller proportion (up to 20%) will show a
greater than average response
Mixed dementia: emerging concepts and therapeutic implications. JAMA 2004 Dec 15;292(23):2901-8.
Management of Alzheimer's disease. J Gerontol A Biol Sci Med Sci 2003 Apr;58(4):331-53
ChEI’s
NNT (number needed to treat to benefit 1)
 Improved cognition
6-12
 Global decline
12
 Nursing home placement
6
 Versus:
Statin to prevent MI = 28
BP meds for MI/CVA/death = 29-86
Recommendations for best practices in the treatment of Alzheimer’s disease in managed care. Am J Geriatr Pharmacother. 2006;4 Suppl A:S9-S24.
ChEIs adverse reactions




Secondary to cholinergic increase
Most frequent: nausea, vomiting, diarrhea
Also flushing, rhinorrhea, insomnia,
nightmares, agitation
Treating 12 patients results in one additional
patient having a treatment-related adverse
event (mostly gastrointestinal side effects)
Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. SOCMAJ 2003 Sep 16;169(6):557-64.
Cholinesterase Inhibitor class



All three (donepezil, rivastigmine,
galantamine) are approved for mild to
moderate AD, and are equally efficacious
Donepezil is approved for severe AD
Each drug has a unique pharmacologic
profile, thus reasonable to try a different drug
if not responding to the first (no efficacy
evidence for choosing one over another)
ChEI dosages
Donepezil
Tabs, ODT
5-10 mg
(Aricept)
Rivastigmine
Capsules, Liquid, 6-12 mg
(Exelon) Patch
Galantamine
Tabs, Liquid
(Razadyne)
16-32 mg
Monthly cost at maximum dose

Cholinesterase Inhibitors






Donepezil (Aricept) 10 mg
Rivastigmine (Exelon) 6 mg tab
Rivastigmine (Exelon) 9.5 Patch
Galantamine ER (Razadyne) 24 mg
Memantine (Namenda) 10 mg
Combined: ChEI + Memantine
Source: Epocrates 8/10
$260
$257
$231
$212
$191
$403+
Rivastigmine Patch
Similar efficacy to capsule
Transdermal route provides continuous delivery of
the drug over 24 hours
Superior tolerability profile







Nausea:
Vomiting:
Decreased appetite:
Dizziness:
Capsule
Patch
23%
17%
4%
8%
7%
6%
1%
2%
A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer’s disease – rivastigmine patch versus capsule,
Int J Geriatric Psychiatry 2007; 22: 456-467
Rivastigmine Patch







Initial dose: 4.6 mg/24 hour patch x 4 weeks
Maintenance dose: 9.5 mg/24 patch
If on oral preparation and receiving < 6 mg, start
with 4.6 mg/24 hour patch
If on oral preparation and receiving 6-12 mg/day,
start with 9.5 mg/24 hour patch
First patch is applied on the day following the last
oral dose
No dosage adjustments for renal or hepatic
impairment
Rotate sites, not repeating site within 14 days
Starting ChEIs





Warn about adverse reactions: nausea,
vomiting, nightmares, agitation
Most cholinergic side effects wane in 2-4
days
Caution if: urinary obstruction, COPD,
conduction delay, or seizure history
Start at low dose, titrate up q4 weeks
Seek to get to maximal dose
ChEIs and acute illness



Interruption of treatment (2-6 weeks?) may
result in irretrievable loss of cognition and
function
Continue antidementia therapy during acute
illness and hospitalization, unless
contraindicated
If stopped, resume as quickly as possible
Recommendations for best practices in the treatment of Alzheimer’s disease in managed care. Am J Geriatr Pharmacother. 2006;4 Suppl A:S9-S24.
When to stop ChEIs?
No clear guidelines
Consider discontinuing if:

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
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MMSE <9 and dependent in all basic ADLs
No longer possible to have meaningful social
interactions or quality of life (in opinion of family and
physician)
Weight loss (even without cognitive decline)
Consider reintroduction if there is any deterioration
Reconsidering medication appropriateness for patients late in life. Arch Intern Med 2006;166:605–609.
Glutamate Hypothesis



Main excitatory neurotransmitter in the CNS,
released normally in a phasic manner
Released in large amounts in injured or dying
glutamate-producing neurons
Increased tonic extracellular glutamate
increases NMDA-receptor activation,
triggering a series of events leading to toxicity
and death in downstream neurons
Memantine




N-methyl-D-aspartate antagonist (NMDA
inhibitor)
Approved by FDA October 2003 for use in
moderate to severe dementia
Prevents glutamate excitotoxicity
Side effects; dizziness, confusion, headache,
constipation…but similar to placebo
Does Memantine work?




Meta-analysis of all published studies – small
improvement in patients with agitation and
other behavioral sx
Improvement of about 2 points in NPI (score
range is 0-120)
Studies too small and effect too small for
conclusive recommendations
Large scale controlled clinical trial is being
conducted world wide on effects of
memantine on agitation.
Efficacy of Memantine on Behavioral and Psychological Symptoms Related to Dementia: A Systematic MetaAnalysis,
Ann Pharmacother 2008; 32-38.
Combination tx: Memantine + ChEI


Theoretically: two classes have different
mechanisms of action, thus expect additive
benefit
Study - Donepezil gave improvement of 3
points on SIB score (0-100). Donepezil plus
Memantine gave 4 points
Tariot PN, Memantine treatment in patients with moderate to severe Alzheimer Disease. JAMA. 2004;291:317-324.

Tolerated well – increased headache and
mild confusion
AD: Conflicting data for:

Vitamin E – no longer recommended due to
limited efficacy and safety concerns. Do not
use greater than 400 IU.
APA Practice Guidelines: Practice Guideline for the Treatment of Patients With Alzheimer's Disease, Second Edition. Published in October 2007.

Gingko biloba – benefit is disproved, not
recommended in AD
AD:No supportive data, or limited data








Vitamin C
Hormone replacement therapy (i.e. estrogen) Women’s Health Initiative study showed 2 fold
increase in dementia
Non-steroidal anti-inflammatory drugs
Lecithin
Acetyl-I-carnitine
Melatonin
Vitamin B12
Vitamin B6
When does Dad need to go to a nursing
home?
ADL tool is used extensively as a flag signaling
functional capabilities of older adults in clinical and
home environments (see addendum for ADLs)
Common reasons for transfer







Exhaustion of family
Wandering/safety/falls
Incontinence/hygiene/skin care
Agitation/anxiety/fearfulness
Should we transfer sooner? Many residents thrive,
eat better, have better hygiene and better
medication management in a structured
environment.
How long will Mom live?

Study in AD - duration from incident dementia to
death = 4.6 years (female), 4.1 years (male)
Larson, Survival after initial diagnosis of Alzheimer disease, Annals of Internal Medicince 2004;140:501-509.

Study in dementia


Median survival time in years from dementia onset to
death = 4.6 (female), 4.1 (male), overall 4.5 years
Age based:




65-69 yo
70-79 yo
80-89 yo
>89 yo
10.7 years
5.4 years
4.3 years
3.8 years
Xie J, Survival times in people with dementia: analysis from population based cohort study with 14 year follow-up, BMJ. 2008 Feb 2;336(7638):225-6.
How will Grandma die?



Anticipatory guidance is key
Dysphagia and aspiration are common in
final stages. Altered food consistency can
limit symptoms (quality of life issue?) PEG
tubes do NOT prevent aspiration, and may
prolong the dying process.
Most common cause of death – infection
originating in the respiratory tract, skin, or
urinary tract.
Protective against dementia






Viewing the brain as a highly vascular organ,
and taking vascular protection measures are
probably the best prevention
Exercise (walk >2 miles/day)
High fish/DHA, low sat. fat
Green tea
Red wine, modest alcohol
Mediterranean diet
Dementia care….




The opportunities are many
The ability to help is great
The rewards are unlimited
The personal and professional satisfaction is
high
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Dementia: An Update, 2007