Mild Cognitive Impairment:

Definition and Treatment

Donald L. Round, PhD

Neuropsychological and Psychodiagnostic Testing
Center
McLean Hospital
Ms. Joan B Visits Memory Clinic

She is a 71 year old woman,

widowed, retired teacher
living independently.
Family has become
concerned because of her
increasing forgetfulness,
lowered self-confidence,
and social withdrawal
during the past year.

*composite patient, details disguised

Is Ms. Bs STM Problem Normal?
 Cognitive Abilities Change
With Age
Cognition: means of acquiring and processing
information about our selves and our world
Includes memory and other functions
Cognitive abilities peak in 30s
Plateau through 50s, 60s
Slow decline typical for late 70s
 What Non-Memory Cognitive
Faculties Decline with Normal Aging?
Working memory span
Use of mental imagery (e.g. mental rotation)
Processing speed
Selective Attention
Naming
Executive function
Logical analysis
Cognitive flexibility

Adapted from Price & Goldstein 2001 and from Emilien 2004
 Is Ms. Bs Problem Abnormal?

MCI is diagnosed if she has:

Memory complaint (preferably corroborated by
informant) or other impaired cognitive domain
Normal activities of daily living (ADL)
Normal general cognitive function (may show
reduced flexibility, rapid processing)
Abnormal memory considering age and
education
Not demented
Petersen et al. 1999
 MCI Subtype Classification
MCI

Impaired memory?

YES NO

Memory only? More than one domain?

YES NO YES NO

Multidomain Multidomain Single

Amnestic MCI MCI Amnestic MCI Non-amnestic Nonamnestic MCI
4-8%/yr
12%/yr

Dementia
Adapted from Winblad et al: J Int Med 2004;256:243
When Evaluating Memory Impairment,
Rule Out Treatable Medical Conditions
 Treatable Conditions: Fatigue
Older people sleep less than young people
Older people sleep less soundly and wake
more easily
The amount of time spent in REM sleep
decreases
Sleep disorder may be present
Treatable Conditions: Alcohol Abuse
Many people begin to drink
problematically after
retirement

Older people are more

sensitive to the effects of
alcohol

Women may be especially

likely to hide their drinking
 Some Medical Disorders Are
Associated with Cognitive Symptoms
Neurodegenerative Cardiopulmonary
Disorders
Disorders
Normal Pressure Neoplasms
Hydrocephalus
Substance Intoxication
Head Injury/Subdural /Withdrawal
Hematoma
Medication-related effects
Nutritional/Metabolic/
Endocrine Disorders Hyperlipidemia
Autoimmune/Collagen Hypertension
Vascular Diseases Diabetes
Infectious Disorders

Modified from Price and Goldstein 2001

 Some Medications Are
Associated with Encephalopathy

Anticholinergic blockers
Benzodiazepines Sympathomimetics
(bronchodilators)
Barbiturates
Digoxin
Narcotics Dopamine antagonists
H2 antagonists (stomach (atypical antipsychotics)
upset) Dopamine agonists (restless
legs, PD, atypical antipsychotics)

Price and Goldstein 2001

 Routine Lab Studies
CBC LFTs
Electrolytes B12
BUN Folic acid
Creatinine Fasting lipids
TSH RPR
ESR

and Blood Pressure!

Modified from Price and Goldstein 2001

 Special Studies

CSF A42,
RBC folate Hyperphosphorylated Tau
HIV Urine C&S
Lyme serology Ceruloplasmin, Slit lamp
Urinary heavy metals examination
Toxicology screen EEG
ANA, Thyroid CXR (chicken xenobiotic receptor)
antibodies Brain biopsy
APOE genotype
 Imaging Studies
CT: Detects most of reversible conditions
MRI: Sensitive for vascular, inflammatory,
infectious, neoplastic findings
PET: recent research findings and new
Medicare coverage are promoting use
In 5% of demented patients, imaging detects
clinically unexpected structural lesions1

1. Petersen et al. 2001

from Golomb et al. 2001
 Ms. Bs Medical Assessment

Hypertension
Hyperlipidemia
Osteoarthritis
Labs: Mild anemia, Normal B12 and folate
MRI: Cortical atrophy, mild WMD
 Psychiatric Assessment:
History and Mental Status Examination
History of Affect and mood
symptoms Thought process
Cognitive /Perceptions/Content
Behavioral
Cognitive
Mood
examination
Other
Screening Exams
Family History
Speech/Language

Price and Goldstein 2001

 Semistructured Interview Questions
Judgment and Problem Solving:
* Increased difficulty handling problems? Greater reliance on
others?
* Change in pattern of driving (increased cautiousness, trouble
with decisions) thats not visual?
* Change in judgment?
* Difficulty with finances, checkbook, bills?
* Difficulty handling emergencies?
Home and Hobbies:
* Increased difficulty with household tasks, new appliances?
* Change in participation/ability with hobbies, reading?
Personal Care:
* Need prompting to shave or shower?

Adapted from Daly et al. 2000

 Screening with MMSE for MCI1
Low Sensitivity (49% for CDR) means failure to
reveal deficits in about 50% of patients at early stage.
[Sensitivity is enhanced with extra delayed-recall
trials.2]
High Specificity (92%), that is, most patients who
score below 27 actually have early or later dementia
Adjust for age and education
Scoring:
- 26-30 may be wnl
- 20-26 mild deficit
- 10-20 moderate deficit
- <10 severe

1. from Petersen et al. 2001; 2. Feldman and Jacova 2005

 9MMSE
Cognitive area and scoring: Score Score
Maximum Actual
Orientation
*What is the (date, day, month, year, season)? 5
*Where are you (clinic, town, country)? 5

Memory
*Name three objects. Ask the patient to repeat 3
them

Attention
*Serial sevens or ask the patient to spell world 5
backwards (dlrow)

Folstein et al 1975
 9MMSE (2) Score Score
Maximum Actual
Recall
*Ask for the three objects mentioned above to be 3
repeated

Language
*Name a pencil and watch 2
*Repeat, 'No ifs, ands or buts 1
*A three stage command 3
*Read and obey - CLOSE YOUR EYES 1
*Write a sentence 1
*Copy a double pentagon 1

Folstein et al 1975 Total 30

 Montreal Cognitive Assessment (MOCA) - 1
Visuospatial/Executive

1 1 1 1 1

Nasreddine et al. JAGS 2005;53:695-9.

 Montreal Cognitive Assessment (MOCA) - 2

Naming

1 1 1

Nasreddine et al. JAGS 2005;53:695-9.

 Montreal Cognitive Assessment (MOCA) - 3

Memory / Delayed Recall

After 5 Minutes

1 1 1 1 1

Nasreddine et al. JAGS 2005;53:695-9.

 Montreal Cognitive Assessment (MOCA) - 4
Attention, Language, Abstraction, Orientation
2 Points

1 Point

3 Points

2 Points

1 Points

2 Points

5 Points
Nasreddine et al. JAGS 2005;53:695-9.
 Montreal Cognitive Assessment
Designed to Separate NC from MCI

Nasreddine et al. JAGS 2005;53:695-9.

 Montreal Cognitive Assessment (MOCA)
Designed to separate MCI subjects from those with Normal
Cognition with greater predictive value

MMSE MoCA

Sensitivity 29% 84%

(MCI vs NC)
Specificity 71% 83%
(MCI vs NC)

Data from Nasreddine et al. JAGS 2005;53:695-9.

 Rule Out Dementia:
DSM-IV-TR Diagnostic Criteria
Development of multiple cognitive deficits manifested
by both
Memory impairment
One (or more) of the following cognitive disturbances:
aphasia, apraxia, agnosia, disturbance in executive
functioning
Significant social or occupational impairment and
decline from previous level of functioning
Gradual onset and continuing cognitive decline
Not due to other CNS or systemic conditions or other
Axis I psychiatric disorders

adapted from American Psychiatric Association. 2000

 Depressive Symptoms/ Depressive Disorder:
Symptoms are Highly Prevalent in MCI
Eating
Sleep

Irritability
Disinhibition

Apathy
Euphoria
Dementia
Anxiety
MCI
Depression
Agitation

Hallucinations
Delusions

0 0.1 0.2 0.3 0.4 0.5

Lyketsos et al. 2002
 Depression and Cognitive Impairment
Twenty per cent of depressed elderly show significant
cognitive symptoms
the most common condition in which the
erroneous diagnosis of dementia is made,
is in endogenous depression1
Misdiagnosis may result in:
Continued suffering
Enhanced risk of suicide
Missed opportunity for effective treatment
Inappropriate confinement to LTCF

1. Kiloh LG. Acta Psychiatr Scand 37:336-51, 1961

 Late-Life Depression Can
Present in Confusing Ways
Depressed mood may not be prominent.
Anger, irritability, anxiety, cognitive complaints
Prior history and family history may be absent.
Picture may be confused by comorbid:
Situational factors
Medical illness
Somatization
Psychotic features
Cognitive impairment
Ms. Bs Psychiatric Assessment

MMSE score is 27/30, MoCA 20/30

No difficulty with ADLs
Not dementia
Evidence of mild depressive mood,
mild anxiety
Low score on GDS
No personal or family history of
depression
What Does Neuropsychological Assessment
Add to Assessment of Normal and Abnormal
Effects of Aging?

Characterize deficits
Diagnostic confirmation
Differential diagnosis
Quantify deficits
Baseline
Prognosis
Repeat testing can assess progression
 Integrated Cognition

From Cummings, 2003

 Stages of Memory
Example: Example: Example:
Keeping phone What did you have for lunch? What was your first
number in mind grade teachers name?

Immediate
Encoding Short Long
Memory/
Term Consolidation Term
Working
Memory Memory
Memory

Retrieval
Retrieval
 Types of Long-Term Memory
...knowing and understanding
what objects are, how to use
words: this is a butterfly
Semantic

Long ... memory of specific

Term event: I saw this
Memory/ butterfly at my home
yesterday
Storage Episodic

... memory of how to

do things: ride a
bicycle, tie shoes, use a
mouse on the computer
Procedural
 Two common categories
of memory deficits:

Storage versus Retrieval Deficits

 Types of Memory Disorders

RETRIEVAL DEFICITS

STORAGE DEFICITS

Cummings, 2003
 Neuropsychological Batteries
For most types of dementia
Better sensitivity and specificity than clinical
interview
Better sensitivity and specificity than a single
test
Better Differential Diagnostic Capacity
Usually normed on the basis of age, gender and
education
No current gold standard battery
Time consuming, expensive, and requires doctoral
level examiner
 Most Valuable Tests

Orientation Time, place, person

Attention Digit Span (forward and backward)
Visual Processing Copying (Modified Rey Figure)
Naming Boston Naming
Verbal Memory CVLT-SF
Visual Memory Modified Rey Figure
Set Shifting Trails A&B
Graphomotor Loops/Alternating Patterns
 Mental Flexibility

Example: Trails A & B of patient with early stage AD

 Mental Flexibility

Cummings, 2003
 Executive Function
Draw A Clock: 10 after 11

79 year old right handed male 79 year old right handed male
Mild Vascular Dementia Mild Vascular Dementia
 An Example:
Executive Functioning and Driving
Average Completion Time
As we age, it takes considerably
Ages 20-29: 25 seconds
Ages 75-79: 53 seconds longer to process information,
formulate responses, and
execute our plans
Ms. Bs Neuropsychological Assessment

Good effort on testing

No fluctuation of alertness or concentration
Difficulty encoding and storing new memory
Minimal symptoms of executive dysfunction
DX: AMNESTIC MCI / POSSIBLE MIXED
ETIOLOGY
What Does MCI Predict?
 MCI Predicts Greater Risk
for Conversion to AD
7.0%
6.0%
General Population:
5.0% Annual incidence of AD1
4.0%
3.0%
2.0%
1.0%
0.0%
60-64 65-69 70-74 75-79 80-84 85-89 90-94 95+

MCI Population1:
6 - 25% per year dementia
80% of 1 MCI cohort AD in 6 yr
1. Petersen et al. Arch Neurol 2001
 MCI Neuropathology is Intermediate
Between Normal and AD
80%
Percentage of Biopsies
with Neuritic Plaques

70%
60%
50%
40%
30%
20%
10%
0%
3 4 5 6-7
GDS Score

Golomb et al. J Neurol Neurosurg Psych 2000;68:778-81

 Amnestic MCI May Be
Especially Predictive of AD
MCI-amnestic: Isolated amnestic disorder
with CDR 0.5 and Petersen definition
MCI-other: Deficits in two or more areas
of cognition significant in comparison to
age-appropriate and education-matched
controls
Preliminary Data Support
Therapeutic Interventions
 Recognition of MCI
Allows Early Intervention

Therapy
preventative
modifying
symptomatic
MCI
Age 0 20 40 60 80
Autopsy

Pathology
Clinical Diagnosis
Inflammatory response
Cell damage
Amyloid deposition
Gene
 An Ounce of Prevention:
Preserving Brain Health
Healthy diet/Vitamins
Physical exercise
Mental activity/Memory training
Minimize stress
Screening in primary care and other settings
Control elevated blood pressure, cholesterol,
homocysteine, hypothyroidism, folate/B12
deficiency, diabetes, depression
Medications (some to take, some to avoid)
Small: BMJ. 2002; 324:1502-5 and other sources
 Midlife Vascular Risk Factors
and Late-Life MCI
1,449 subjects aged 65-79 y.o. were
followed an average of 21 years
MCI (Mayo Clinic criteria) was found in
6.1% of follow-up subjects, dementia in
4.0%
Midlife elevated serum cholesterol (OR
1.9), midlife systolic BP (a NS trend) were
correlated with MCI in late life*.
*higher age and fewer years of education were also strong correlates of MCI.
Note that cholesterol lowering drugs were not in use at time of subjects midlife visits.
Kivipelto et al: Neurology 2001;56:1683-9.
Behavioral strategies to Maintain Memory (1):
Lifestyle factors

Regular physical activity

Improved sleep
Mental activity
Increased novelty
Social support network
 Behavioral strategies to Maintain Memory (2):
Enhance Memory by Facilitating Concentration

New learning takes

intention and focus
Slow down
Minimize distractions
One thing at a time
Rehearse and reinforce
Behavioral strategies to Maintain Memory (3):
Enhance Memory by Making Associations

Making associations maximizes the

connections in the brain.

Connect new
information with
prior experience
Behavioral strategies to Maintain Memory (4):
Enhance Memory by Using Mental Pictures

Make mental pictures

Examples:
Parking
Remembering a name
Phone-call
Medicine
Behavioral strategies to Maintain Memory (5):
Enhance Memory by Organizing New Information

Chunking

Categorizing
Behavioral strategies to Maintain Memory (6):
Enhance Memory with Use of Aids

Write it down
Notes
Lists
Calendars
Make it visible
 Do Cognitive Exercises
Improve Memory?
2832 adults (age 65 94) randomized to:
Memory training
Problem solving training
Training processing speed
No training (control group)
Relative to control group, improvement seen in
26% of memory group
74% of problem solving group
87% in speed group
Memory gains not maintained at 2 years
Speed/Problem solving gains were maintained at 2 years

Ball et al: Effects of cognitive training interventions with older adults. JAMA 2002;288:2271-81.
 For Partners: Learning to Speak MCI

Find a quiet environment for conversation

Speak at an unhurried pace
Reorient to time/situation as needed
Allow extra time for discussion and explanation
Avoid information overload
Respond gently, patiently to repetitive questions
Check for understanding: Have listener repeat
information back to be sure they understand
Stimulate cognitively with enjoyed activities but
avoid testing or correcting
 MCI & Environmental Modifications

Increase structure/consistency
Simplify needs:
Hire out for home maintenance activities as needed
Help with bill-paying
Evaluate/Supervise complex, potentially dangerous
activities (driving, cooking, use of power tools)
Assess adequacy of residential support
Consider need for alternate living situation
Consider need for guardianship/HCP
Balance dignity vs. safety
 Patient Safety: Driving
Management Options

MCI increases driving risk

Consider referral for private
driving evaluation
Physician reporting is
voluntary in MA; advise
patient to self-report serious impairment to DMV
Pharmacologic Interventions
 What Should an MCI Medication Do?

Mild
Impairment

Cure
Disease process modifying
Symptomatic
Placebo
Severe

Baseline End
Time
Modified from Small G: Dementia. ACNP Curriculum
MCI: Pharmacologic Possibilities
Cholinesterase inhibitors*
Glutamate receptor modulators
NMDA antagonists*, AMPA modulators
Metabolic/Antiinflammatory approaches
(statins, estrogen, NSAIDS)*
Antioxidants (Vitamin E, Ginkgo biloba)*
Amyloid immunization techniques
Vaccine, IgG
A production/deposition reducers
or secretase inhibitors
Tau hyperphosphorylation inhibitors
Alzhemed, Flurizan
GABA receptor antagonists
Nicotinic receptor agonists
 Treatment Study Issues
Limited data available at present
Most treatment studies address AD, not MCI
Definition of MCI is still evolving
Potential treatment goals:
Reverse cognitive and/or memory deficit
Delay progression of deficit
Delay loss of independence
Caregiver and societal benefits
Studies underway
Cholinesterase Inhibitor Adverse Effects
Generally well tolerated
Side effects usually transient
Slower titration helps reduce side effects
Common: nausea, vomiting, diarrhea, insomnia,
fatigue, increased urination, cramps
Uncommon: syncope, bradycardia, confusion,
depression, extrapyramidal
Caution with liver/ gastric disease, COPD,
bradycardia, inadequate supervision
Glutamatergic Hypothesis of AD

Long Term Potentiation

Glutamate
AD

Neuronal Death
Danysz et al: Neurotoxicity Res 2000;285-87; Zajaczkowski W et al:
Neuropharmacology 1997;36:961-971; Harris et al: Neuroreport 1995:6.1875-1879
 Oxidative Mechanisms in AD:
Preventive Intervention for MCI?
Amyloid beta associated with generation of free
radicals
Free radicals can damage proteins, DNA, lipids
Epidemiologic data support neuroprotective effect of
antioxidant vitamins (A,E,C)
One prospective RCT shows functional outcome
benefits with antioxidant treatment (Vit E, selegiline,
placebo) in AD (entry MMSE mean score 12)
MCI trial of Vit E vs donepezil showed disappointing
results for Vit E
 Statins
Cholesterol increases -amyloid production
Elevated cholesterol levels associated with increased AD
risk
Three epidemiologic studies associate statin treatment with
reduced dementia risk:
60-73% lower prevalence of AD associated with
lovastatin or pravastatin treatment1
Users of 5 statins showed RR of 0.29 for onset of
dementia2
CSHA (Canadian Study of Health and Aging) found
OR 0.37 for onset of CIND , chiefly in individuals with
CMI (circumscribed memory impairment), associated
with statins3

1. Wolozin et al. 2000; 2. Jick et al. 2000; 3. Rockwood et al, 2004

 Statins (2)
RCT: Simvastatin trial1 in AD
44 subjects, 26 weeks
Simvastatin slowed MMSE but not ADAS-cog decline
Small decrease in CSF amyloid

1. Simons et al: Ann Neurol 2002;52:346-50

 Estrogen/Progesterone
Womens Health Initiative Memory Study
Prempro showed:
No protection against MCI
No protection against dementia
Increased risk for dementia
RR 2.05
AR: 23 excess cases/10,000 >65 years age

Shumaker S et al: JAMA 2003;289:2651-2662

 Inflammatory Mechanisms in AD
AD brains show elevated levels of:
acute phase proteins
inflammatory cytokines
complement proteins
activated microglial cells
Amyloid beta interacts with inflammatory process
Inflammatory process appears to play direct role in
neuronal loss
Use of NSAIDs associated with decreased AD risk
in multiple studies
Rofecoxib not effective in delaying AD onset1
Thal et al. Neuropsychopharmacology 2005
 Ginkgo Biloba Extract
and Memory
EGb increases processing speed, working
memory, executive processing in non-impaired
subjects 1,2
Preliminary data suggest modest improvements in
processing speed and working memory of AD
patients3
EGb 761 under evaluation in GEM study
Large, multicenter study
Standardized agent

1. Mix and Crews 2000; 2. Stough et al. 2001;3. Oken et al. 1998
 MCI Conclusions
MCI is a clinically meaningful concept
Not normal
Not demented
Reliable criteria for diagnosis exist
Heterogeneous causes, variety of interventions
require differential diagnosis
Treatment may retard progression in some cases
Further investigation is needed
 Practical Recommendations
Increase detection efforts
Informant history
Formal screening, testing, imaging
Work up and follow up
Control contributing medical factors
Modify lifestyle
Nonpharmacologic interventions
Consider medications
 Suggestions for Ms. B

Psychoeducation
Control vascular risk factors
Hypertension, hyperlipidemia, homocysteine
Cognitive exercises / nonpharm strategies
Appropriate planning for the future
Cognitive enhancing meds? An
individualized risk/benefit decision
 Counseling Dementia Patients
Patients should not be considered as simply
passive recipients of care
Most patients - at all stages of dementing
process - can take active roles in their care
Given opportunity for coming to terms with
disability, some patients may be able to
decide upon subsequent care
 Communicating Dementia
Diagnosis
Some care providers feel patients should not
be told of dx
Frank discussion may have adverse
consequences
Others feel patients questions should be
truthfully addressed
If suicidal feelings arise, hospitalization
may be necessary
 Couple Therapy
Alternating between conjoint and individual sessions allows
short sessions with patient, time with caregiver for venting &
building relationship
Conjoint sessions give evidence of how couple is doing,
evaluate and guide changes in relative power shift so as to
avoid patient feeling powerless while other takes on growing
responsibility for care
Clarify what tasks/activities are problematic, what patient
would like assistance with
 Group Counseling
Social interaction to counter sense of being
alone, gain support, learn improved coping
skills
Information on possible treatments
Discuss impact of illness on selves &
families, concerns for future, attitude
toward death
 Reminiscing
Review life accomplishments and events to build esteem in
face of impending catastrophic loss
Goals are to help communicate, socialize, provide pleasure
& entertainment in relaxed, positive way
Not same as life review therapy which tries to work
through painful memories/experiences and is generally not
appropriate for people with dementia
Caveats: avoid invasion of privacy, unintended re-
traumatization (be aware of problematic life histories)
 Temporal Gradient
AD in early and mid stages
disproportionately affects STM
more

RECALL

less

recent remote
TIME
 Memory in Dementia
Generally, better recall of older, more
remote autobiographical events, possibly
b/c over-learned, frequently rehearsed
Typically less recall of middle years, worst
recall for recent events
 Ego Integrity vs. Despair
(Eriksons 8th Stage)
Ego integrity is the ego's accumulated assurance
of its capacity for order and meaning
Despair is signified by a fear of one's own death,
as well as the loss of self-sufficiency, and of loved
partners and friends
Healthy children, Erikson tells us, won't fear life if
their elders have integrity enough not to fear death
 Group Here-and-now
Approach
Assist with coping: if a member loses track of topic, leader
asks others if this happens to them
Need to be prepared for denial, a common adaptive
response
Consider whether addressing denial worthwhile or not
Some information can be handled gently and indirectly,
taking focus off individual
Summaries by leader at start and end of sessions can help
with orientation, recall of prior discussions
 Optimal Group Characteristics
Reduce cognitive load by keeping groups
smaller (helps with who said what, avoids
leader monologues)
Retain same seating (spatial location as cue)
Only one person speaks at a time
Eliminate/reduce distractions (e.g., noise,
tv)
 Mnemonic Aids
Non-specific aids (alarm clock) can lead to
frustration b/c dont help with recall of what
needs to be done
Diaries can help with prompting recall of
what important
Studies have shown that training in use of
aids, such as watch and diary, can help with
general orientation, sense of efficacy
 Mnemonic Aids (cont)
Photos and pictures in wallet, folder, or book can help facilitate
conversation
Assist task performance (preparing drinks, snacks) with signs on
drawers/cupboards, demonstration & rehearsal of physical movements,
use of verbal prompts/cues
Procedural memory usually better preserved than episodic or semantic
memory
New research suggests cooperative communication of particular
benefit
Combining rhythmic movement (dance), music, and information
 The End

Questions / Discussion