Differential Diagnosis of Dementias

George T. Grossberg, MD

Samuel W. Fordyce Distinguished Professor

Director, Geriatric Psychiatry

Department of Neurology & Psychiatry

St Louis University School of Medicine

2

Disclosures

• None for this presentation

3

Differential Diagnosis of Dementias

Presentation Overview

Clinical evaluation for dementia

Cognitive assessment tools

Profiles of common dementias

Imaging the different dementias

Neuropsychiatric symptoms in dementias

4

Common Types of Neurodegenerative

Dementia1

Alzheimer’s dementia (AD)

Parkinson’s disease dementia (PDD)

Dementia with Lewy bodies (DLB)

Vascular dementia (VaD)

Frontotemporal dementia (FTD)

Mixed (multiple pathologies/etiologies) dementia

Lewy Body

Dementia

Spectrum2

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision. (DSM-IV-TR®.) Washington, DC: American

Psychiatric Association; 2000.

2. Lewy Body Dementia Association, Inc. 2010. Caregiver Burden in Lewy Body Dementias: Challenges in Obtaining Diagnosis and Providing Daily Care. Atlanta, GA:

Lewy Body Dementia Association; 2010.

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The Typical Dementia Scenario

• Patients may not seek medical care for symptoms

• Lack of insight common

• Patient denies problem, family/friends express

concerns

• Caregivers may gradually compensate and cover

up symptoms for the patient, "masking" the true

magnitude of the deficits

• Delayed diagnosis until moderate stage

Agronin ME. Alzheimer disease and other dementias : a practical guide. 2nd ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008.

6

Core features of degenerative dementia

• Deficits in cognitive domains that may include

memory

• Usually progressive deterioration

• Cognitive impairment interferes with social or

occupational function

• Not attributable to another disorder

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision. (DSM-IV-TR®.) Washington, DC:

American Psychiatric Association; 2000.

7

Clinical Evaluation for Dementia1

History

Physical,

Neurologic,

Mental Status

Examinations

Laboratory,

Psychiatric, and

Neuropsych Tests

• Obtain medical and psychiatric history, along

with current symptoms

• Include collateral source such as family or

other informant

• Identify neurologic deficits

• Conduct general screen for cognitive

impairment

• Identify reversible causes of cognitive

impairment

• Build on mental status examination, and

provide clearer picture of pattern and degree

of cognitive impairment

Agronin ME. Alzheimer disease and other dementias : a practical guide. 2nd ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008.

8

The “Dementia Workup”

• Detailed history from patient & reliable informant

• Head to toe physical & neurological examination

• Bloodwork(if not done recently)-

CMP;CBC;TSH;B12/Folate; ?vit

D;?CRP;?Homocysteine

• RPR, HIV testing(if indicated)

• Plain CT/MRI(one time);?FDG-PET;?amyloid-

PET

• UA;CXRY(if indicated);EKG

• EEG,LP- not part of routine workup

9

Delirium is a Reversible Cause of Cognitive

Impairment

Dehydration

Electrolyte/Endocrine disorder

Lack of oxygen

Injury/Impaction

Rule out psychiatric disorder

Infection

Urinary retention/Unfamiliar environment

Medications

Desai AK, Grossberg GT. Psychiatric consultation in long-term care : a guide for health care professionals. Baltimore: Johns Hopkins University Press; 2010.

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Delirium, Dementia, and Depression1,2

Delirium Dementia Depression

Onset Sudden Insidious Recent or recurrent

Duration Minutes to

days Months to years Weeks to months

Progression

Reversible –

resolves with

treatment

Irreversible Reversible, relapses

common

Consciousness Fluctuating Generally alert Generally alert,

possibly withdrawn

History of

depression

Usually

negative Usually negative Usually positive

Visuospatial Preserved Often abnormal Preserved

Mood – Sadness/

Guilt/Worthlessness Absent Usually absent Usually Present

1. Cefalu C, Grossberg GT. Leawood, KS: American Academy of Family Physicians; 2001. 2. American Psychiatric Association. DSM-IV-TR®.

Washington, DC: American Psychiatric Association; 2000.

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Examples of Cognitive Assessment Tools

for the Office Setting

• Mini-Mental State Examination (MMSE)1

• AD8 informant interview2

• Mini-Cog assessment3

• Montreal Cognitive Assessment (MoCA)4

• St Louis University Mental Status (SLUMS)

Examination5

1. Folstein MF et al. J Psychiatr Res. 1975;12:189-198. 2. Galvin JE et al. Neurology. 2005;65:559-564. 3. Borson S et al. Int J Geriatr Psychiatry.

2000;15:1021-1027. 4. Nasreddine ZS et al. J Am Geriatr Soc. 2005;53:695-699. 5. Tariq SH et al. Am J Geriatr Psychiatry. 2006;14:900-910.

Note. These are assessment tools, and are not fully diagnostic of dementia.

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Mini-Mental State Examination (MMSE)

• Brief, structured mental status

examination for global cognitive

function1

• Typical deterioration of 3–4 points

per year in a person with AD2

• Sensitivity and specificity vary in

different patient populations3

• May be necessary to account for

differences due to age, education,

and ethnicity/race3

• Does not specifically test episodic

memory1

• Copyright issues3

1. Folstein MF et al. J Psychiatr Res. 1975;12:189-198. 2. Doody RS et al. Arch Neurol. 2001;58:449-454. 3. Weiner MF, Garrett MD, Bret ME.

Neuropsychiatric Assessment and Diagnosis. In: Weiner MF, Lipton AM, eds. Textbook of Alzheimer disease and other dementias. Washington, DC:

American Psychiatric Pub.; 2009.

Score range, 0–301,3

≥28 Unimpaired*

20–27 Mild AD

10–19 Moderate AD

<10 Severe AD

These cognitive score may aid in identifying

progression of dementia

* In a high-functioning patient, a

MMSE score of ~28 could

indicate impairment3

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1. Problems with judgment (e.g., problems

making decisions, bad financial decisions,

problems with thinking)

2. Less interest in hobbies/activities

3. Repeats the same things over and over

(questions, stories, or statements)

4. Trouble learning how to use a tool, appliance,

or gadget (e.g., VCR, computer, microwave,

remote control)

5. Forgets correct month or year

6. Trouble handling complicated financial affairs

(e.g., balancing checkbook, income taxes,

paying bills)

7. Trouble remembering appointments

8. Daily problems with thinking and/or memory

The Informant Interview: The AD8

• Informant-based questionnaire

– Can be administered at home or

in waiting room

– Yes/No format

• Detects change in individuals compared

with previous level

of function

– No need for baseline assessment

– Patients serve as their own control

– Minimally affected by age, gender,

race, and education

• Brief (<3 min), yes/no format

– 2 or more “yes” answers highly correlated

with dementia

– Sensitivity, 85%

– Specificity, 86% Galvin JE et al. Neurology. 2005;65:559-564.

Adapted from Galvin JE et al. The AD8, a brief informant interview to detect dementia. Neurology

2005;65:559-564. Copyright 2005. the AD8 is a copyrighted instrument of the Alzheimer’s Disease Research

Center, Washington University, St. Louis, Missouri. All rights reserved.

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Rapid Screen for

Cognitive Impairment: Mini-Cog

• Rapid screen for cognitive

impairment

– 5 minutes to administer

• 3-word registration

• Simple clock-drawing test

• 3-item recall

• Not influenced by education

level or language

• Sensitivity, 99%

• Specificity, 93%

Borson S et al. Int J Geriatr Psychiatry. 2000;15:1021-1027.

Abnormal Clock Normal Clock

Demented

Nondemented Demented

Nondemented

Recall 0 Recall 1-2 Recall 3

Mini-Cog

Adapted from Borson S et al. Int J Geriatr Psychiatry. 2000;15:1021-1027; with permission.

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Montreal Cognitive Assessment (MoCA)

1. Nasreddine ZS et al. J Am Geriatr Soc. 2005;53:695-699. 2. Hoops S, Nazem S, Siderowf AD, et al. Nov 24 2009;73(21):1738-1745.

Image: The Montreal Cognitive Assessment. December 17, 2009. http://www.mocatest.org/. Accessed December 17, 2009; with permission.

• Brief (10-min) cognitive

screening test sensitive to

domains involved in AD1

• Demonstrated utility in PDD2

• Includes measures in

executive function1

• Established utility in a multiple

settings1,2

• Test free for nonprofit use:

http://www.mocatest.org/

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Saint Louis University Mental Status

Examination

• Designed to improve screening for mild neurocognitive disorder (MNCD)

• 11-item, clinician-scored scale

• Study of SLUMS vs MMSE (N = 705)

– DSM-IV-TR® criteria used to diagnose MNCD or dementia

– Patients assessed by MMSE and SLUMS

– Sensitivity and specificity

• Dementia: similar for MMSE and SLUMS

• MNCD: SLUMS appears superior to MMSE

Tariq SH et al. Am J Geriatr Psychiatry. 2006;14:900-910.

High School

Education

Less Than High

School Education

Normal 27–30 25–30

MNCD 21–26 20–24

Dementia 1–20 1–19

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Rapid Brief Cognitive Screens:

Pros and Cons

Screening Test Pros Cons

MMSE1,2

Widely used, validated, reliable

Adjustments for age, education, and

race may be necessary

Copyright issues

AD8 informant

interview3 Reliable, sensitive, specific, rapidly administered Knowledgeable informants may not be

readily available

Mini-Cog

assessment4 Superior to MMSE in prediction of dementia

status, rapidly administered, produces a visible

performance indicator

Clock-drawing test scoring is vulnerable

to varying interpretations

MoCA5,6 Useful in patients with scores >25 on MMSE,

strong executive function component Conclusions regarding validity in PDD

restricted to specialty clinic setting

SLUMS

examination7 Potentially superior to MMSE for early detection of

cognitive impairment

Research needed to confirm applicability

beyond initial study group

Note: insufficient information is available to determine whether any one screening tool is superior to another. Positive

screening results should be followed by complete neurologic and medical examinations.

1. Folstein MF et al. J Psychiatr Res. 1975;12:189-198. 2. Weiner MF, Garrett MD, Bret ME. Neuropsychiatric Assessment and Diagnosis. In: Weiner

MF, Lipton AM, eds. Textbook of Alzheimer disease and other dementias. Washington, DC: American Psychiatric Pub.; 2009. 3. Galvin JE et al.

Neurology. 2005;65:559-564. 4. Borson S et al. Int J Geriatr Psychiatry. 2000;15:1021-1027. 5. Nasreddine ZS et al. J Am Geriatr Soc. 2005;53:695-

699. 6. Zadikoff C et al. Mov Disord. 2008;23:297-299. 7. Tariq SH et al. Am J Geriatr Psychiatry. 2006;14:900-910.

Profiles of Dementias

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Alzheimer’s Dementia

• Multiple cognitive deficits, consisting of

memory impairment and ≥11

– Aphasia

– Apraxia

– Agnosia

– Executive function

• Each deficit causes significant impairment

in social or occupational functioning1

• Difficulty learning and remembering

new information2

• Repetitiveness, anomia2

• Poor orientation to time2

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision. (DSM-IV-TR®.) Washington, DC: American

Psychiatric Association; 2000. 2. Geldmacher D. Alzheimer’s Disease. In: Weiner MF, Lipton AM, eds. Textbook of Alzheimer disease and other dementias. 1st ed.

Washington, DC: American Psychiatric Pub.; 2009. 3. Tarawneh R, Galvin JE. Dementia with Lewy Bodies and other Synucleinopathies. In: Weiner MF, Lipton AM,

eds. Textbook of Alzheimer disease and other dementias. 1st ed. Washington, DC: American Psychiatric Pub.; 2009.

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AD largely

involves

temporal-

parietal deficits3

Praxis

Language

Gnosis

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Parkinson’s Disease Dementia

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision. (DSM-IV-TR®.) Washington, DC: American Psychiatric

Association; 2000. Emre M, Aarsland D, Brown R, et al. Mov Disord. Sep 15 2007;22(12):1689-1707; quiz 1837. 3. Tarawneh R, Galvin JE. Dementia with Lewy Bodies and

other Synucleinopathies. In: Weiner MF, Lipton AM, eds. Textbook of Alzheimer disease and other dementias. 1st ed. Washington, DC: American Psychiatric Pub.; 2009.

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• Develops in the context of established PD (>2

years)1

• Cognitive and motor slowing with significant

impairments in:1,2

– Executive function

– Memory retrieval

• A decline from premorbid levels, with deficits

sufficient to impair function1,2

• Slowing of cognitive processes/processing

speed2

• Fluctuating attention deficits2

• Difficulties with abstraction and visuospatial

skills2

PDD affects the

basal ganglia

first, and

disrupts

ascending

subcortical

circuits3

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Dementia with Lewy Bodies C

ore

C

linic

al

• Fluctuating cognition with pronounced variations in attention and alertness1

• Recurrent detailed visual hallucinations,

• Spontaneous features of parkinsonism1

• Suggestive features1

• REM sleep behavior disorder

• Severe neuroleptic sensitivity

• Impairment in attention, visual perception and visual construction1

• Memory is relatively spared early on, but deficit evident with progression1

• Cognitive and motor symptoms often co-present

1. McKeith IG, et al. Neurology. 2005;65:1863-1872. 2. Tarawneh R, Galvin JE. Dementia with Lewy Bodies and other Synucleinopathies. In: Weiner MF,

Lipton AM, eds. Textbook of Alzheimer disease and other dementias. 1st ed. Washington, DC: American Psychiatric Pub.; 2009.

DLB has basal

ganglia,

transitional,

cortical forms2

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Vascular Dementia

• Decline in cognitive function from a

prior baseline and a deficit in

performance in ≥21

– Executive/attention

– Memory (may not always be impaired)2

– Language

– Visuospatial function

• Evidence of cerebrovascular

disease via neuroimaing1,3,4

• Focal neurological signs that

may relate to vascular lesion

location1,3,4

• Cognitive deficits may occur in

a stepwise fashion1,3,4

1. Gorelick PB, Scuteri A, Black SE, et al. Stroke. Sep 2011;42(9):2672-2713. 2. Szoeke CE, Campbell S, Chiu E. Vascular Cognitive Disorder. In: Weiner MF,

Lipton AM, eds. Textbook of Alzheimer disease and other dementias. Washington, DC: American Psychiatric Pub.; 2009. 3. American Psychiatric Association.

Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text Revision. (DSM-IV-TR®.) Washington, DC: American Psychiatric Association; 2000.

4. Roman GC, Tatemichi TK, Erkinjuntti T, et al. Neurology. Feb 1993;43(2):250-260.

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Frontotemporal Dementia

• FTD may be classified into various subtypes1,2

– Primary progressive aphasia (PPA)

• Progressive nonfluent aphasia

• Logopenic variant

• Semantic dementia (SD)

– Behavioral Variant (bvFTD)

• PPA primarily affects language early, whereas

bvFTD may be classified as an early behavioral

disorder1

• FTD variants may overlap later in the disease

course1,2 1. Lipton AM, Boxer A. Frontotemporal Dementia. In: Weiner MF, Lipton AM, eds. Textbook of Alzheimer disease and other dementias. Washington, DC:

American Psychiatric Pub.; 2009.2. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Neurology. Mar 15 2011;76(11):1006-1014.

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Behavioral Variant of Frontal Temporal

Dementia

• Progressive deterioration of behavior

and/or cognition with ≥ 3 early:1

– Behavioral disinhibition

– Apathy

– Loss of sympathy/empathy

– Perseverative, stereotyped or

compulsive behavior

– Hyperorality

– Executive deficits with relative

sparing of memory and visuospatial

function

• Frontal and/or anterior temporal

atrophy on MRI or CT1

• Tactless and impulsive behavior2,3 1. Rascovsky K, Hodges JR, Knopman D, et al. Brain. Sep 2011;134(Pt 9):2456-2477. 2. Neary D, Snowden JS, Gustafson L, et al. Neurology. Dec 1998;51(6):1546-1554. 3.

McKhann GM, Albert MS, Grossman M, et al. Arch Neurol. Nov 2001;58(11):1803-1809.

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Imaging in the Diagnosis

• Left - AD shows prominent sulci in tempo-parietal areas, typically

accompanied by ventricle enlargement

• Middle- VaD most often shows cerebrovascular lesions on T2-weighted MRI

• Right - FTD shows prominent sulci in frontotemporal areas with relative

parietal and occipital sparing

26

Imaging: AD vs DLB

• AD can show marked hippocampal atrophy

• In DLB, the hippocampus may be relatively spared

Hippocampal

atrophy

AD

DLB

Tarawneh R, Galvin JE. Dementia with Lewy Bodies and other Synucleinopathies. In: Weiner MF, Lipton AM, eds. Textbook of Alzheimer disease and other

dementias. 1st ed. Washington, DC: American Psychiatric Pub.; 2009.

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Neuropsychiatric Symptoms in Dementias

NPI Item AD PDD DLB VaD FTD

Delusions ● ● ●● ● -

Hallucinations - ●●● ●● ● -

Agitation ●● ●● ●●● ●●● ●●●

Depression ●● ●●● ●●● ●● ●●●

Anxiety ●● ●●● ●●● ●● ●

Apathy ●●● ●●● ●●●● ●●● ●●●●

Disinhibition - - ● ● ●●●●

Irritability ●● ● ●●● ●● ●●●

Sleep ● ● ●●● ●● ●●

- 0-14% ● 15-29% ●● 30-44% ●●● 45-59% ●●●●

≥ 60%

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Pathologic Profiles of Dementias

Pathologic Signs AD PDD DLB VaD bvFTD

Neuritic plaques ●●● ● ●● - -

NFTs ●●● ● ●● - -

Cortical Lewy bodies ● ● ●● - -

Subcortical Lewy bodies ● ●●● ●●● - -

Ischemic damage ●● - - ●●● -

Tau or TDP-43 inclusions - - - - ●●●

Biochemical Deficit AD PDD DLB VD FTD

Cholinergic ●●● ●●●● ●●● -/● -

Dopaminergic ● ●●● ●●● - -

- Generally absent ● Infrequent ●● Typical ●●● Hallmark Feature ●●●● Severe Deficit 1. Stahl SM. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed, Fully rev. and expanded. ed. Cambridge ; New York: Cambridge

University Press; 2008. 2. Geldmacher D. Alzheimer’s Disease. Textbook of Alzheimer disease and other dementias. 1st ed. Weiner MF, Lipton AM, eds. Washington, DC:

American Psychiatric Pub.; 2009. 3. Tarawneh R, Galvin JE. Dementia with Lewy Bodies and other Synucleinopathies. Textbook of Alzheimer disease and other dementias. 1st

ed. Weiner MF, Lipton AM, eds. Washington, DC: American Psychiatric Pub.; 2009. 4. Bird TD, Miller BL. Alzheimer’s disease and other dementias. Harrison’s Principles of

Internal Medicine. 16th ed. Kasper DL, Braunwald E, Fauci, AS, et al., eds. New York, NY: McGraw-Hill; 2005. 5. Szoeke CE, Campbell S, Chiu E et al, Vascular Cognitive

Disorder. Textbook of Alzheimer disease and other dementias. 1st ed. Weiner MF, Lipton AM, eds. Washington, DC: American Psychiatric Pub.; 2009. 6. Rascovsky K, Hodges

JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. Sep 2011;134(Pt 9):2456-2477. 7. Bohnen NI, Kaufer

DI, Ivanco LS, et al. Cortical cholinergic function is more severely affected in Parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study.

Arch Neurol. 2003;60:1745-1748.

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Current FDA-Approved Therapies

1. Fortinash KM, Holoday-Worret PA. Psychiatric Mental Health Nursing. 3rd ed. St. Louis, MO: Mosby; 2004. 2. Boyd M Psychiatric Nursing: Contemporary

Practice. 4th ed. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008. 3. Reisberg B et al. N Engl J Med. 2003;348(14):1333-1341.

AD PDD

Number of Acetylcholinesterase Inhibitors1 4 1

Number of NMDA Antagonists1 1 0

• AD symptoms correlate with disruption of cholinergic circuits2

• PDD is characterized by a larger cholinergic deficit than AD3

• There are no FDA-approved medications of any class to treat

DLB, VaD, or FTD

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The Importance of Making an Early

Diagnosis

• Identify and treat reversible causes

• Help explain presence of troublesome behaviors

• Allow the patient to make critical life decisions

• Identify and treat psychiatric symptoms

• Maximize patient safety

• To provide treatment

• Allow caregiver early access to support and

community resources

Agronin ME. Alzheimer disease and other dementias : a practical guide. 2nd ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008.

31

Caregiver Challenges in Different Types of Dementias

• AD – typically older onset, with frequent co-

morbidities

• PDD – prominent motor symptoms leading to

falls

• DLB – frequent and sometimes severe

neuropsychiatric symptoms

• VaD – depression and continuing risk factors for

stroke

• FTD - younger onset, predominant behavioral

and language symptoms

32

Summary

• Diagnosis of dementia begins with recognizing

cognitive impairment (CI) in the patient

– Cognitive assessment tools can be valuable

• Reversible causes of CI should be ruled out via

the dementia workup

– Delirium must be ruled out, or if present, treated

accordingly

• Key clinical features of each dementia can aid

the clinician in arriving at the specific diagnosis

• Making the specific diagnosis early is critical for

the patient and caregiver