Differential Diagnosis of Dementias - Alzheimer's Association

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

Disclosures
• None for this presentation
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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
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Common Types of Neurodegenerative
Dementia 1
• Alzheimer’s dementia (AD)
• Parkinson’s disease dementia (PDD)
• Dementia with Lewy bodies (DLB)
• Vascular dementia (VaD)
• Frontotemporal dementia (FTD)
Lewy Body
Dementia
Spectrum 2
• Mixed (multiple pathologies/etiologies) 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.
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.
5

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.
6

Clinical Evaluation for Dementia 1
History
Physical,
Neurologic,
Mental Status
Examinations
• 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
Laboratory,
Psychiatric, and
Neuropsych Tests
• 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.
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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
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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 Depression 1,2
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 interview 2
• Mini-Cog assessment 3
• Montreal Cognitive Assessment (MoCA) 4
• St Louis University Mental Status (SLUMS)
Examination 5
Note. These are assessment tools, and are not fully diagnostic of dementia.
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.
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Mini-Mental State Examination (MMSE)
• Brief, structured mental status
examination for global cognitive
function 1
• Typical deterioration of 3–4 points
per year in a person with AD 2
• Sensitivity and specificity vary in
different patient populations 3
• May be necessary to account for
differences due to age, education,
and ethnicity/race 3
• Does not specifically test episodic
memory 1
• Copyright issues 3
Score range, 0–30 1,3
≥28
Unimpaired*
20–27 Mild AD
10–19 Moderate AD

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 (

Rapid Screen for
Cognitive Impairment: Mini-Cog
• Rapid screen for cognitive
impairment
Mini-Cog
– 5 minutes to administer
• 3-word registration
• Simple clock-drawing test
• 3-item recall
• Not influenced by education
level or language
Recall 0 Recall 1-2 Recall 3
Demented
Nondemented
• Sensitivity, 99%
• Specificity, 93%
Abnormal Clock
Demented
Normal Clock
Nondemented
Adapted from Borson S et al. Int J Geriatr Psychiatry. 2000;15:1021-1027; with permission.
Borson S et al. Int J Geriatr Psychiatry. 2000;15:1021-1027.
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Montreal Cognitive Assessment (MoCA)
• Brief (10-min) cognitive
screening test sensitive to
domains involved in AD 1
• Demonstrated utility in PDD 2
• Includes measures in
executive function 1
• Established utility in a multiple
settings 1,2
• Test free for nonprofit use:
http://www.mocatest.org/
Image: The Montreal Cognitive Assessment. December 17, 2009. http://www.mocatest.org/. Accessed December 17, 2009; with permission.
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.
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Saint Louis University Mental Status
Examination
• Designed to improve screening for mild
neurocognitive disorder (MNCD)
• 11-item, clinician-scored scale
High School
Education
Less Than High
School Education
Normal 27–30 25–30
MNCD 21–26 20–24
Dementia 1–20 1–19
• 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.
16

Rapid Brief Cognitive Screens:
Pros and Cons
Screening Test Pros Cons
MMSE 1,2
Widely used, validated, reliable
Adjustments for age, education, and
race may be necessary
Copyright issues
AD8 informant
interview 3
Mini-Cog
assessment 4
MoCA 5,6
SLUMS
examination 7
Reliable, sensitive, specific, rapidly administered
Superior to MMSE in prediction of dementia
status, rapidly administered, produces a visible
performance indicator
Useful in patients with scores >25 on MMSE,
strong executive function component
Potentially superior to MMSE for early detection of
cognitive impairment
Knowledgeable informants may not be
readily available
Clock-drawing test scoring is vulnerable
to varying interpretations
Conclusions regarding validity in PDD
restricted to specialty clinic setting
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.
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Profiles of Dementias

Core
Clinical
Alzheimer’s Dementia
• Multiple cognitive deficits, consisting of
memory impairment and ≥1 1
– Aphasia
– Apraxia
– Agnosia
– Executive function
• Each deficit causes significant impairment
in social or occupational functioning 1
Language
Praxis
Gnosis
• Difficulty learning and remembering
new information 2
• Repetitiveness, anomia 2
• Poor orientation to time 2
AD largely
involves
temporalparietal
deficits 3
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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Core
Clinical
Parkinson’s Disease Dementia
• 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 function 1,2
• Slowing of cognitive processes/processing
speed 2
• Fluctuating attention deficits 2
PDD affects the
basal ganglia
first, and
disrupts
ascending
subcortical
circuits 3
• Difficulties with abstraction and visuospatial
skills 2
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 20
other Synucleinopathies. In: Weiner MF, Lipton AM, eds. Textbook of Alzheimer disease and other dementias. 1st ed. Washington, DC: American Psychiatric Pub.; 2009.

Core
Clinical
Dementia with Lewy Bodies
• Fluctuating cognition with pronounced
variations in attention and alertness 1
• Recurrent detailed visual hallucinations,
• Spontaneous features of parkinsonism 1
• Suggestive features 1
• REM sleep behavior disorder
• Severe neuroleptic sensitivity
• Impairment in attention, visual perception
and visual construction 1
• Memory is relatively spared early on, but
deficit evident with progression 1
• Cognitive and motor symptoms often copresent
DLB has basal
ganglia,
transitional,
cortical forms 2
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.
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Core
Clinical
Vascular Dementia
• Decline in cognitive function from a
prior baseline and a deficit in
performance in ≥2 1
– Executive/attention
– Memory (may not always be impaired) 2
– Language
– Visuospatial function
• Evidence of cerebrovascular
disease via neuroimaing 1,3,4
• Focal neurological signs that
may relate to vascular lesion
location 1,3,4
• Cognitive deficits may occur in
a stepwise fashion 1,3,4
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.
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4. Roman GC, Tatemichi TK, Erkinjuntti T, et al. Neurology. Feb 1993;43(2):250-260.

Frontotemporal Dementia
• FTD may be classified into various subtypes 1,2
– 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
disorder 1
• FTD variants may overlap later in the disease
course 1,2
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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Core
Clinical
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 CT 1
• Tactless and impulsive behavior 2,3
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
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Imaging: AD vs DLB
AD
Hippocampal
atrophy
DLB
• AD can show marked hippocampal atrophy
• In DLB, the hippocampus may be relatively spared
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.
26

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. 28
Arch Neurol. 2003;60:1745-1748.

Current FDA-Approved Therapies
AD
PDD
Number of Acetylcholinesterase Inhibitors 1 4 1
Number of NMDA Antagonists 1
1 0
• AD symptoms correlate with disruption of cholinergic circuits 2
• PDD is characterized by a larger cholinergic deficit than AD 3
• There are no FDA-approved medications of any class to treat
DLB, VaD, or FTD
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.
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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.
30

Caregiver Challenges in Different Types of Dementias
• AD – typically older onset, with frequent comorbidities
• 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
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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
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