Dementia: So Far, So Near, Majid Barekatain, M.D., Associate Professor of Psychiatry Neuropsychiatrist Isfahan University of Medical Sciences 27-28 Ordibehesht

Dementia:So Far,

So Near,

Majid Barekatain, M.D.,Associate Professor of Psychiatry

NeuropsychiatristIsfahan University of Medical Sciences

27-28 Ordibehesht 1392April 16-17, 2013

حرف های ما هنوز ناتمام ....

تا نگاه می کنی :وقت رفتن است

باز هم همان حکایت همیشگی!

پیش از آن که با خبر شویلحظه ی عزیمت تو ناگزیر می شود

آی .....ای دریغ و حسرت همیشگی

ناگهانچقدر زود

قيصر امين دیر می شود!پور

Lancet 1997; 349: 1546-49

Lancet 1997; 349: 1546-49

Prevalence of Dementia Increases with Age

3%

19%

47.20%

0%5%

10%15%20%25%30%35%40%45%50%

65 - 74 75 - 84 85 +

Age Group

Projected Prevalence of AD

16

14

12

0

2

4

6

8

10

2000 2010 2020 2030 2040 2050

4

5.86.8

8.7

11.3

14.3

Mill

ions

4.5 Million AD Cases Today—Over 14 Million Projected Within a Generation

Year

Evans DA et al. Milbank Quarterly. 1990;68:267-289.

Global Aging

Definitions

Normal

Mild Cognitive Impairment

Dementia

Dementia

• An acquired disorder of intellectual impairment produced by a dysfunctional brain

Dementia Definition

• Syndrome of acquired persistent intellectual impairment

• Persistent deficits in at least three of the following cognitive domains:

– memory– Language– Visuospatial– personality or emotional state – Higher cognition

• Resulting in impairment in Activities of Daily Living (ADL)

Mild Cognitive Impairment (MCI) Definition

• Memory complaint usually corroborated by an informant

• Objective memory impairment for age - that represents a change in function for the person

• Essentially preserved general cognitive function• Largely intact functional activities• Not demented• Alzheimer’s disease may start like this but many non-

AD conditions present like this also

Petersen J Int Med 2004;256;183-194

Rates of MCI Conversion to Dementia

• Vary from 1% - 25% per year to AD depending on the definition used and measurement instruments

• 10% - 12% per year to AD is typical• 57% conversion to dementia after 3 years

in one study• 25% do not convert to dementia even

with long term follow-upChertkow et al. Neurology 2001;56:B46

Symptoms of AD

• Cognitive symptoms include:– Memory loss and impaired temporal orientation– Impaired praxis and spatial ability– Language and executive disturbance

• Functional symptoms include:– Reduced ability to carry out IADL/ADLs, e.g.,

dressing, handling money, personal hygiene

Henderson & Jorm. In: Maj M, Sartorius N, eds. © 2000 John Wiley & Sons Ltd, Chichester, UK

• Behavioural/psychological symptoms include:• Mood swings• Agitation• Aggression• Wandering

• The type and timing of symptom expression is highly variable between patients

Henderson & Jorm. In: Maj M, Sartorius N, eds. © 2000 John Wiley & Sons Ltd, Chichester, UK

Symptoms of AD

Cognitive deficits in AD

• Memory impairment – difficulty in learning new information, and/or forgetting previously learned material

• Aphasia: impaired language function• Apraxia: the inability to perform previously learned skills in

the absence of defects in motor or sensory function• Agnosia: a failure to recognise objects, eventually

progressing to not recognising family members, or their own reflection

• Decline in executive functioning• Spatial and temporal orientation may also be affected

Mendez MF, Cummings J. Dementia. A clinical approach. 3rd ed. Philadelphia: 2003

Short Term Memory

• Short-term memory (STM)– Ability to register information– Ability to recall the registered information

• Free recall (MCI, Mild AD)• Cued recall (Mild to Moderate AD)• Recognition (Moderate AD)


Long term memory

• Declarative (Moderate AD)– Concepts (semantic)

• Frontal lobe

– Events (episodic)• Cortical sensory association areas (auditory and visual)

– Words (lexical)• temporal lobe (hippocampus)

• Procedural (Severe AD)– Memory for motor tasks

• basal ganglia & motor cortex


Language

• Language is the encoding/decoding of a message to communicate thoughts with words or symbols

• Language can be:– Spoken / Comprehended– Written / Read– Pictured– Gestured

Domenico RA. Adv Exp Med Biol 1990; 282:79-88

Language deficitsMild AD

• Difficulties with:– word finding/naming– abstract or complex

concepts– pronouns– storytelling– humour / sarcasm– initiating conversation– maintaining topic

• Use of:– semantic paraphasias

(substituted words)– circumlocution– empty words (it, stuff,

thing)– gesture

• Relatively intact– comprehension and

repetition


Language deficitsModerate AD

• Decreased word fluency / vocabulary, confrontation naming

• Few ideas and frequent repeating• Poor use of pronouns• Poor pragmatics – e.g.- poor topic maintenance,

little sensitivity to conversational partners• Circumlocution increased• More difficulty with complex language

comprehension and production


Language deficitsSevere AD

• Severely diminished naming• Exhibits more paraphasias (word and sound

substitution), echolalia (repetition of other’s speech), palilalia (rep. of own speech)

• Poor comprehension• Use of jargon and rambling speech, incoherence• Decreased eye contact• Diminished output or may be meaningless or

bizarre; may become mute


Communication

• Broad term encompassing all the ways we send and receive messages

• Includes speaking, listening, reading, writing, gesturing, miming

• Requires a sender and a receiver

Communication

• Verbal– Words

• Non verbal– Facial expression– Eye contact– Body language– Gesture– Paralinguistics

• Intonation, loudness, pitch, rithm

Functional communication

• The ability to receive or to convey a message, regardless of the mode, to communicate effectively and independently in a given environment

• Functional communication involves also functional abilities that enable patients to make themselves understood by relatives and carers.

American Speech-Language-Hearing Association (ASHA). Functional Communication Measures Project. Rockville,MD 1990; ASHA., Domenico RA. Adv Exp Med Biol 1990; 282:79-88.

Executive Function

• Planning, (Mild to Moderate AD)• Working memory, (MCI, Mild AD)• Attention, (MCI, Mild AD)• Problem solving, (Mild to Moderate AD)• Verbal reasoning, (Moderate to Severe AD)• Inhibition, (Moderate to Severe AD)• Mental flexibility, (Mild to Moderate AD)• Task switching, (Mild to Moderate AD)• Initiation and monitoring of actions, (Moderate to

Severe AD)

Symptom progression pattern in patients with Alzheimer’s disease

Stage of Global Deterioration Scale (GDS)

Adapted from:Reisberg et al. Am J Psychiatry 1982; 139: 1136–1139

MMSE stages

• Anxiety• Misplacing objects• Forgetting names

• Unable to recall names of close family members

• Disoriented to time and place• Unable to perform complex tasks

• Basic psychomotor skills are lost• Delusional behaviour• Incontinence

Forgetting names one formerly knew well

Word and name finding deficit becomes evident

Flattening of affect and withdrawal fromchallenging situations

Difficulties dressing properly

Can no longer care for oneself

Ca

reg

ive

r bu

rde

n

6

7

Loss of speech, locomotion, consciousness; full-time care needed

2

3

4

5

Se

ve

re

<1

0M

od

era

te1

0–

19

Mil

d2

0–

26

1

0 5 10 15 20Years after onset

Progression and symptoms of AD

Pattern of symptoms over time in patients with AD

Gauthier. (Ed) Clinical Diagnosis and Management of Alzheimer’s Disease. Third Edition, Informa Healthcare

Progression of Alzheimer’s diseaseMild Severe

Det

erio

rati

on

Mood

Cognitive function

Functional autonomy

Behaviour

Motorfunction

Difficulties prompting the seeking of help: overview

Difficulties listed in order of decreasing importance

Area of difficulty:

92%87%

79%

64%

Cognition Activities of daily living

Behaviour Communication

Memory/confusion

Concentration/attention

Orientation/getting lost

Recognising people

Finding belongings

Financial activities

Shopping

Using telephone

Cooking

Personality changes

Depression

Irritability

Social withdrawal

Wandering

Following conversation

Writing/reading

Speaking

Comprehension of language

Georges et al, Int J Geriatr Psychiatry 2008; 23 (5): 546–551

Methods of Screening

Screening with Biomarkers

Biomarkers in AD• Cerebrospinal fluid (CSF) biomarkers

– Tau ( in CSF in AD)

– A42 ( in CSF in AD)

– Neural thread protein (NTP)– Homocysteine ( level, risk of AD)

– Isoprostanes (oxidative/nitrative damage - levels in blood and CSF in AD)

– Sulfatide (in CSF in AD)

• Blood and urine biomarkers– Genetic blood tests and genotyping– Plasma A42, Homocysteine, isoprostanes, sulfatide– Urine neural thread protein (NTP)

Screening with Neuroimaging

Early Diagnosis: Structural Neuroimaging

• Volumetric measurement of hippocampus and entorhinal cortex atrophy with MRI is sensitive (95%) but not specific (40%) for AD

• Change in MRI hippocampal volume may be predictive over time in both MCI and individuals at genetic risk for AD

• 7-Tesla and 8-Tesla MRI being used in AD research

Laakso et al. Neurology 1996;46:678-81Golomb et al. Neurology 1996;47:810-3

Whitaker et al. Society for Neuroscience 2001

Gray Matter Reductions in AD Using Voxel Based Morphometry

Alexander GE et al., ADNI MRI Core Team, 2007

Functional Neuroimaging: PET

• PET shows hypometabolism in bilateral parietal, temporal, and posterior cingulate cortex in AD subjects and those who are asymptomatic but at increased risk for AD (those with Apo E 4)

• PET predicted 94% of mild cognitive impairment (MCI) subjects whose disease progressed to dementia during a 3 year period

Minoshima et al. J Nucl Med 1995;36:1238-48

Minoshima et al. Ann Neurol 1997;42:85-94Small et al. JAMA 1995;273:942-47

Typical AD PET Scan

Provided courtesy of M. Mega, MD, PhD, Department of

Neurology, UCLA School of Medicine.

Normal Brain AD Brain

Cognitive Screening

Examples of Brief Cognitive Assessment/Screening Tests

• MMSE• Clock Drawing Test• Mini-Cog• AD8• 7-minute Screen• Montreal Cognitive Assessment (MoCA)• Neuropsychiatry Cognitive Assessment Tool

(NUCOG)• Self-Administered Gerocognitive Examination

(SAGE)

MMSE

• Score: 0 (worst) - 30 (best)• Tests orientation, attention, mental control,

calculations, delayed memory (no clueing), language, and constructional praxis

• Easy to use, well known• Not great for frontal or executive functions• Sensitivity 78% and specificity 84% for dementia with

a cutoff of 26/30• Takes 7 to 10 minutes; needs examiner• PAR bought rights - costs about $1 per use

Folstein et al. J Psychiat Res 1975;12:189-98Feher et al. Arch Neurol 1992;49:87-92

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Folstein et al. J Psychiat Res

1975;12: 189-98

MMSE

Mini-Mental State Examination:Typical change over time

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9 10 11 12

Years since diagnosis

MMSE Score

Average change is 3 points/year without treatment between MMSE of 23 to 5

Mild Cognitive Impairment (MCI)

Clock Drawing Test

• Various scoring methods• Tests constructional praxis, visuospatial

skills, and executive functioning• Easy to use, well known• Limited in evaluating other cognitive

domains• Sensitivity 83% and specificity 72% for AD• Takes 1 minute; needs no examiner

Shulman et al. Int Geriatr Psychiatry 1986;1:135-40Cahn et al. Arch Clin Neuropsych 1996;11:529-39

Early Diagnis: Cognitive Screening

Mini-Cog

• 3-item recall and clock drawing• Easy to use• Limited in evaluating other cognitive

domains• Sensitivity 76% and specificity of 89% for

dementia• Score not influenced by language or

education• Takes 3 minutes; needs examiner

Borson S et al. Int J Geriatr Psychiatry 2000;15:1021-1027Borson S et al. JAGS 2003;51:1451-1454

Mini-Cog

AD8• Score: 0 (best) - 8 (worst)• Informant rates changes in the patient’s

judgment, interests, memory, functioning, and orientation

• Easy to use• Does not measure patient cognition• Sensitivity 84% and specificity 80% for dementia

with a cutoff of 2 or greater• Takes 3 minutes; needs examiner and informant

Folstein et al. J Psychiat Res 1975;12:189-98Feher et al. Arch Neurol 1992;49:87-92

AD8

Galvin et al. Neurology

2006;67:1942-1948

7 Minute Screen• Special scoring calculator required• Tests orientation, memory, clock drawing, verbal

fluency• Not easy to use in primary care office• Low scores very specific for AD• Sensitivity 92% and specificity 96% for AD vs normal

controls• Takes 7 - 12 minutes; needs examiner

Solomon et al. Arch Neurol 1998;55:349-55

7 Minute Screen

Montreal Cognitive Assessment (MOCA)

• Score: 0 (worst) - 30 (best)• Tests orientation, memory, clock drawing,

constructions, verbal fluency, naming, repetition, attention, abstraction, calculations, executive (trails B)

• Not easy to give in primary care office• Sensitivity 100% and specificity 87% for AD

vs normal controls with a cutoff of 26/30• Takes 10-13 minutes; needs examiner

Nasreddine et al. J Am Geriatr Soc 2005;53:695-699

MOCA

Nasreddine et al. J Am Geriatr Soc 2005;53:695-699

Self-Administered Gerocognitive Exam (SAGE)

• Score: 0 (worst) - 22 (best) • Tests orientation, memory, language, fluency,

naming, visuospatial, abstraction, calculations, executive functioning, and problem solving

• Self-administered, easy to use• Limited memory evaluation; excellent

executive measures• Takes 10 to 15 minutes; needs no examiner

Scharre et al. Alzheimer Dis Assoc Disord 2009 at sagetest.osu.edu

SAGEPage 1

Scharre et al. Alzheimer Dis Assoc

Disord 2009 at sagetest.osu.edu

SAGEPage 2





SAGEPage 3



SAGEPage 4

Staged Screening: Impact of Diagnosis

Screening for Cognitive Impairment

• No cognitive screening test is diagnostic• If normal, serious conditions are less likely• The “worried well” can be relieved that

they were “tested” and they did fine• Serial screening could be suggested over

time• If abnormal, further evaluation may be

considered

Staged Screening Approach for Cognitive Impairment

• One single test or score should not be the only criteria to embark on an expensive dementia evaluation

• Doing a screening process in stages may provide better evidence for diagnosis of MCI or dementia

• A staged screening process is recommended

و ....ناگهان

چقدر زود دير مي شود!

Documents

Dementia: So Far, So Near, Majid Barekatain, M.D., Associate Professor of Psychiatry Neuropsychiatrist Isfahan University of Medical Sciences 27-28 Ordibehesht