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Dementia Facts: Distinguishing the Differential Diagnosis

Article  in  Journal of the Mississippi State Medical Association · May 2019

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 S C I E N C E O F M E D I C I N E

Dementia Facts:
Distinguishing the Differential Diagnosis
NETRALI PATEL, MD; LILIAN E. MASSIHI, MD; ASHISHKUMAR PATEL, MD; ANDREW MAJESTE, BSN, RN

Introduction indicated. Careful evaluation to exclude reversible causes of cognitive

impairment is significant. Patients with early dementia may benefit
Dementia is characterized by chronic, global, irreversible deterioration from formal neuropsychological testing and further imaging for
in memory, executive function, and personality. Speech and motor uncertain diagnosis. This article is intended to be used as a guide to
function may also be impaired in persons with dementia. Over 5.8 help providers evaluate suspected dementia and differentiate between
million Americans are currently living with Alzheimer’s disease the various types. The dementia syndromes discussed in this paper are
(AD), and this number is expected to increase to nearly fourteen outlined in Table 1.
million by the year 2050. 1 More than 55,000 Mississippians aged
65 and older have Alzheimer’s disease.2 There is a growing need for What Are Common Risk Factors for AD? 3
early detection and diagnosis of AD and other types of dementia. When thinking about risk factors associated with the development
A dementia evaluation consists of cognitive evaluation, a complete of AD, the literature suggests that family history does play a role.
history, physical and neurological exam, neurocognitive testing, and Genetic testing is not indicated in the clinical workup, but research
depression screening. Diagnostic laboratory and imaging studies, as has found genetic correlations between the early and late onset of
well as pharmacological and behavioral therapies, are offered when AD. Early onset is defined as the development of AD prior to age
65 and is associated with genetic mutations of Amyloid Precursor
Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). Late onset
Table 1. Dementia Syndromes is defined as the development of AD after age 65 and is associated
Table 1. Dementia Syndromes with genetic mutations to the apolipoprotein E (APOE) gene
including APOE ε2, APOE ε3, and APOE ε4. Other risk factors are
Demen�a Syndromes:
associated with comorbidities including the history of head trauma,
Mild1.Cogni�ve
Table DementiaImpairment
Syndromes
hyperlipidemia, hypertension, and diabetes. Psychosocial risk factors
Alzheimer’s Disease
Dementia Syndromes: for the development of AD include low education level and depression.
Lewy Body Demen�a
MCI Table 2 outlines the differences between normal aging and early signs
Frontotemporal
Alzheimer’s Disease Demen�a of dementia.
Lewy Body Dementia
Pseudodemen�a
Frontotemporal DementiaDemen�a
Parkinson’s Disease The normal aging process is associated with declines in certain
Pseudodementia cognitive abilities. These changes are small and should not result in
Parkinson’s Disease Dementia
impairment in function. New learning is slower, yet still occurs. It
Table
Table 2. Signs
2. Early Earlyof Signs of Alzheimer’s
Alzheimer’s Dementia
Dementia vs Normal Aging 4,5 vs Normal Aging 4,5
is important to detect these changes early. Participation in certain
4,5
Table 2. Early Signs of Alzheimer’s Dementia vs Normal Aging activities, building cognitive reserve, and engaging in cognitive
Normal Aging Early Signs of ADretraining may all be approaches
Normal Aging Early Signs of AD to achieving successful cognitive
Forge�ng the names of people they
Forgetting the names of people they rarely see rarely see Forge�ng names of
Forgetting names of people close to them people close
aging.toMost
themadults over the age
of 65 will not develop dementia
Briefly
Briefly forge�ng
forgetting part of part of an experience Forgetting things
an experience Forge�ng things
more often than more o�en
they used to than
or they
Mild used to Impairment
Cognitive
(MCI), and more work is
Not putting things away properly Repeating phrases or stories needed to understand better
Not pu�ng things away properly Repea�ng phrases or stories
in the same conversation
in the same conversa�on how we can maximize cognitive
Mood changes in response to an appropriate cause Unpredictable mood changes function and quality of life for
Mood changes in response to an appropriate cause Unpredictable mood changes these individuals.6 Early signs of
Changes in their interests Decreased interest in activities AD are more pronounced and
and difficulty making choices persistent, worsening over time
Changes in their interests Decreased interest in ac�vi�es
and difficulty making choices

MAY • JOURNAL MSMA 172

 Diagnosis

Figure 1. Algorithm to Determine What Steps Must Be Taken Next in Differentiating the Dementia Diagnosis

Suspected Cogni�ve Decline

↓
Evaluate ADLS and Mental Status

↓↓
Normal ADLS with Impaired Abnormal ADLS with Normal Abnormal ADLS with Impaired Normal ADLS and Normal Mental
Mental Status Mental Status Mental Status Status
↓ ↓ ↓ ↓
Mild Cognitive Impairment (MCI) Consider Depression or Dementia Cognitively Intact
Frontotemporal Dementia
↓
Evaluate for treatable causes with
laboratory tes�ng and neuroimaging

↓
← (Abnormal) (Normal) →
↓ ↓

Treat the underlying issue (Subdural Temporal link to stroke?

hematoma, normal pressure
hydrocephalus, brain tumor, metabolic NO↓
a�er encephali�s)
YES↓

YES↓ NO↓
Lewy Body Demen�a
Alzheimer’s Demen�a,
Frontotemporal
Demen�a, or Primary
Progressive Aphasia

and adversely affecting activities of daily living. from either MCI or AD. Image on left: PET scan showing normal level
of glucose metabolism (indicated in yellow and red; middle: MCI;
The Dementia Work-Up3 and right: Alzheimer’s disease. The levels of glucose metabolism in the
Figure 2. Brain Changes- Radiological imagining available can help providers distinguish between a
brain are decreased in patients with MCI and with Alzheimer’s dementia,
The American Geriatrics Society recommends several specificcontrol glucose
normal brain and one suffering from either MCI or AD. Left: PET scan showing normal level of
butmetabolism
there is (indicated
a greaterin yellow
decline andwith
red) MCI and Alzheimer’s
Alzheimer’s disease:(indicated
dementia The levels ofin
glucose
laboratory and radiologic tests in the evaluation of patients withmetabolism in the brain are decreased in patients with MCI and with Alzheimer’s dementia, but there is
yellow and red).
suspected dementia. Laboratory tests are directed at excluding reversiblea greater decline with Alzheimer’s dementia (indicated in yellow and red).
causes of dementia which include CBC, Folate, TSH, and Vitamin
B12. There are certain laboratory tests to consider when specific risk
factors are present including CSF analysis, HIV test, Lyme titers and
Rapid Plasma Reagin (RPR) test. A CT Brain or MRI Brain should be
considered if there is an abrupt or rapid decline in cognition, there are
focal deficits, or there are predisposing conditions. The clinician should
consider an Amyloid PET Scan (Figure 2) or Metabolic Brain PET
Scan if definitive diagnosis changes the management of patients.

Figure 2. Radiological imaging can help providers evaluate brain

changes and distinguish between a normal brain and one suffering
Figure 3. Normal vs. Alzheimer’s Brain Radiological imagining available that can help providers
distinguish between a control normal brain and one suffering from AD. Alzheimer’s: Marked dilation of
173 VOL. 60 • NO. 5 • 2019 the sulci and fissures, diffuse atrophy with volume loss, ventricular enlargement.
An Algorithm for Diagnosis
The dementia workup is vital in differentiating the type of dementia and
the plan of care needed for patient treatment. When there is suspected
cognitive decline, the clinician should evaluate both mental status
and activities of daily living (ADLs). Depending on what deficits are
present, the clinician can utilize the algorithm in Figure 1 to determine
what next steps must be taken in differentiating the dementia diagnosis.
Mild Cognitive Impairment (MCI)3
The clinical course of MCI is usually gradual and is primarily caused byFigure 3. Normal vs. Alzheimer’s Brain Radiological imagining available that can help p
an abnormal amyloid deposition. The cognitive symptom associateddistinguishFigure between
with MCI is memory impairment; however, symptoms do not preventthe distinguish
sulci and fissures,
patients from performing daily activities and are not as severe as those The
of AD. Clinically a patient will score 24-26 on the Mini-Mental Status atrophy with volume loss, ventricular enlargement.
Exam (MMSE) with functional status intact.7 The progression of MCI
is unknown, but approximately 12% of MCI cases progress to AD
within one year. There are currently no medications approved by the
FDA to treat MCI. Treatment is focused on reduction in risk factors
associated with MCI including increased physical activity, controlling
cardiovascular risk factors and participating in mentally stimulating
and socially engaging activities to help sustain brain activity.7
Presently Recognized Forms of Dementia
Alzheimer’s Dementia
Alzheimer’s dementia has a gradual onset with a progressive decline
in cognitive functioning. The etiology behind AD is currently debated
across the literature. The primary hypothesis is that AD is caused by
amyloid plaques and oligomers or tau neurofibrillary tangles (or both).
The accumulation of these proteins or protein aggregates within the
brain affect neuronal function and ultimately cell death.3 AD is the
most common type of dementia, accounting for approximately two-
thirds of all cases and affecting 6%–8% of those ≥65 years old. The
disease prevalence doubles every 5 years after age 60; an estimated 45%
or more of those who are ≥85 years old have AD.3
Memory impairment is often a core symptom of any dementia, but in AD
it is typically the core feature present in the earliest stages. Typically, AD
patients demonstrate difficulty learning and retaining new information.
In later disease stages, their ability to learn and retrieve information is
compromised even more, and patients are unable to access older, more
distant memories.3 MMSE score is <24 accompanied by impaired
functional status. The primary neurological symptoms associated
with AD are aphasia, apraxia, disorientation, visuospatial dysfunction,
impaired judgment, and executive dysfunction.
In AD there may be structural and functional imaging findings on an
MRI, CT, and FDG-PET scan. On an MRI there is possible global
atrophy, small hippocampal volumes, hippocampal atrophy, and
volume loss. On a CT there may be diffuse cortical atrophy with
disproportionate volume loss in the medial temporal lobe structures.3
A FDG-PET scan may be useful, but not required for diagnosis of AD.
This scan will show hypo-metabolism in bilateral parietal and temporal
lobes.3
174 VOL. 60 • NO. 5 • 2019
Treatment for AD is often focused on symptoms management and
behavioral modifications. Behavioral methods should be attempted
first before considering antipsychotic medication. Reassurance,
referral to adult day care, caregiver support groups, psychoeducation,
distraction, redirection, and a structured environment can be
beneficial.3 The use of cholinesterase inhibitors, particularly Donepezil
is indicated for all stages of AD. When patients advance to the mild to
moderate stages of AD, Galantamine (Razadyne) and Rivastigmine
(Exelon) are indicated. As the disease progresses to the moderate-to-
severe stage the addition of Memantine (Namenda) is indicated.
3. Radiological
a controlimagining is available
normal brain to help
and one suffering fromproviders
AD. Alzheimer’s: M
betweendiffuse atrophy
a control withbrain
normal volumeandloss,
oneventricular enlargement.
suffering from AD.
AD brains shows marked dilation of the sulci and fissures, diffuse
Lewy Body Dementia
The clinical course of Lewy body dementia (LBD) is gradual. Etiology
of LBD is characterized by Parkinson dementia and the abnormal
buildup of alpha-synuclein inclusion bodies. The clinical presentation
and features include deficits in memory, visuospatial, hallucinations
and Parkinsonian features.8 The diagnostic criteria include progressive
cognitive decline, dementia (required) plus core features (2 required
for probable LBD) including recurrent, detailed, fluctuations (change
in alertness, attention), visual hallucinations, and early parkinsonism.
Suggestive features include REM Sleep Disorder (acting out
dreams), severe neuroleptic sensitivity (motor, consciousness, NMS,
autonomic dysfuntion) and low dopamine transporter uptake in
BG. Supportive features include repeated falls, syncope, transient
loss of consciousness and low uptake with reduced occipital activity
PET/SPEC. MRI reveals less atrophy of the hippocampus and other
medial temporal lobe structures relative to patients with AD; more
atrophy seen in cortical and subcortical structures such as striatum,
substantia innominata, hypothalamus and dorsal midbrain.9 FDG-
PET reveals hypometabolism in parietal and occipital regions with
relatively preserved metabolism in temporal lobes. Treatment consists
of cholinesterase inhibitors +/- carbidopa/levodopa for movement.8
Vascular Dementia
The clinical course of vascular dementia (VD) is sudden and thought
to cause an estimated 15%–20% of cases. It often coexists with AD
pathology, i.e., so-called “mixed dementia.” The etiology is related to
reduced blood flow to the brain, damaging and killing brain cells. Motor
and cognitive symptoms depend on the location of ischemia. There is
a gradual or stepwise progression of the disease as ischemia worsens.
Cortical or subcortical changes, however, may be seen. Cholinesterase
inhibitors are used for memory deficit only. Widespread use in VD is
not recommended.3
Frontotemporal Dementia
The course of symptoms in patients who have frontotemporal
dementia begins at >50 years of age with a younger age of onset than
seen in other dementias. It is the most common cause of young-onset
dementia (i.e., dementia developing in midlife or earlier). The estimated
point prevalence is 15–22/100,000, and incidence 2.7–4.1/100,000.
Twenty-five percent are late-life onset cases.10 The etiology reveals the
accumulation of tau or ubiquitin proteins. Patients experience primarily
cognitive symptoms, such as problems with executive function,
hyperorality, personality changes, preservation of visual-spatial skills.3
The progression is gradual but faster than that of Alzheimer’s disease.
FDG-PET scan reveals hypometabolism in frontal and temporal
regions. Currently there is no treatment approved by the FDA.11
Pseudodementia
The course of symptoms is short and abrupt in onset with depression
being the etiology. Cognitive symptoms are temporary and dementia-
like. Motor symptoms include delayed motor response. Lab tests,
imaging (i.e., MRI & CT) and the neurological exam are normal.
PHQ-2, PHQ-9 and GDS results, however, may likely be abnormal.
Treatment is based on treating underlying depression (SSRIs/SNRIs/
MAOIs/Psychotherapy).
Parkinson’s Disease Dementia
Parkinson’s Disease Dementia develops in the setting of established
Parkinson’s disease (PD).12 PD can be caused by mutations in the SNCA
gene. Alpha-synuclein is the protein that is the main component of
Lewy bodies which accumulate in the brain in PD patients.1 Prevalence
and incidence increase with age and is slightly higher in men than in
women.14 Executive dysfunction is present early in the disease and
manifests in deficiencies in set shifting, attention and planning. Tests of
face recognition, a measure of visuospatial function, are impaired early.15
Motor symptoms include tremor, rigidity, bradykinesia, and postural
instability.16 The neurocognitive exam is congruent with parkinsonian
symptoms. MRI reveals global atrophy and enlarged ventricles (AD
findings). White matter hyperintensities are found in PDD.17 Treatment
includes Levodopa, dopamine agonists, anticholinergic inhibitors.18
Slowing Progression of Memory Loss 3
While dementia is never 100% preventable, there are changes that can
be incorporated in the everyday routine to slow down memory loss
and improve overall cognitive functioning. For example, stimulating
one’s senses (i.e. involving as many senses as possible such as, vision,
sound, touch, smell and taste), writing things down i.e. making lists,
keeping calendars, following a routine, maintaining associations,
repeating names, running through the alphabet, and and keeping one’s
175 VOL. 60 • NO. 5 • 2019
body and brain active (trying new activities, working crossword puzzles
or word finding and math puzzles, exercising 30-45 minutes/day, playing
a musical instrument and enjoying leisure activities) are some ways
of slowing down memory loss. Also, following good health strategies
including controlling blood pressure and cholesterol, preventing or
managing diabetes, maintaining a healthy weight, drinking alcohol in
moderation, avoiding smoking and eating a well-balanced, heart-healthy
diet can be effective ways to better manage these diseases. n
About the MIND Center
A visit to The Memory Impairment and Neurodegenerative Dementia
(MIND) Center Clinic includes a comprehensive 90-minute evaluation
consisting of a cognitive evaluation, a complete history, physical and
neurological exam, neurocognitive testing, and depression screening. Patients
are encouraged to bring a family caregiver who can report on memory and
cognitive changes they may have observed. Diagnostic labs and imaging
studies, as well as pharmacological and behavioral therapies, are ordered when
indicated. Ongoing care includes continued monitoring of disease progression,
medication management, and communication with primary care providers to
determine the best treatment options for each patient.
The MIND Center Clinic offers counseling, education, and support for
caregivers to better manage disease symptoms as well as caregiver burden. In
addition, MIND providers offer guidance on difficult issues such as assisted
living, skilled nursing or home health placement, as well as legal considerations.
Once a treatment plan is established, the patient is seen in the MIND Center
Clinic every six months for dementia management and instructed to follow-
up with their local physician for all other medical needs. Visits to the MIND
Center Clinic are reimbursed by Medicare and other payers in the same
manner as other outpatient or ambulatory visits. The patient is responsible for
paying a standard copay.
References
1. L
 atest Alzheimer’s Facts and Figures. Alzheimer’s Association website. https://
www.alz.org/alzheimers-dementia/facts-figures. Accessed April 26, 2019.
2.  Mississippi Alzheimer’s State Fact Sheet. Alzheimer’s Association website. https://
www.alz.org/getmedia/0fd6858b-fae4-489c-95ed-e63dc6743861/mississippi-
alzheimers-facts-figures-2019. Accessed April 26, 2019.
3. A
 merican Geriatrics Society. A guide to dementia diagnosis and treatment.
http://unmfm.pbworks.com/f/American+Geriatric+Society+Dementia+Diagnosis+
03-09-11.pdf/Accessed May 8, 2019.
4. K
nopman DS, DeKosky ST, Cummings JL, et al. Practice parameter:
diagnosis of dementia (an evidence-based review). Report of the Quality
Standards Subcommittee of the American Academy of Neurology. Neurology.
2001;56(9):1143–1153.
5.   Dementia and Memory Loss. http://www.psychiatry24x7.com/bgdisplay.
jhtml?itemname=dementia_memoryloss. Accessed on April 02, 2018.
6. Harada, CN, Love, MC, Triebel, K. Normal cognitive aging. Clin Geriatr Med.
2013;29(4):737-752.
7. Russ TC, Morling, JR. Cholinesterase inhibitors for mild cognitive impairment.
Cochrane Database Syst Rev. 2012;(9):CD009132.
8. Zupancic, M, Mahajan, A, Handa, K. Dementia with Lewy bodies: diagnosis and
management for primary care providers. Prim Care Companion CNS Disord. 2011;13(5)
doi: 10.4088/PCC.11r01190.
9.  B onifacio G, Zamboni G. Brain imaging in dementia. Postgrad Med J.
2016;92(1088):333-340.
10. Onyike, C. Diehl-Schmid, J. The epidemiology of frontotemporal dementia. Int Rev
Psychiatry. 2013;25(2):130-137.
11. B
oxer, Adam L, Boeve, B. Frontotemporal dementia treatment: current
symptomatic therapies and implications of recent genetic, biochemical and
neuroimaging slides. Alzheimer Dis Assoc Disord. 2007;21(4):S79-87.
12. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson's disease
dementia: recommendations from the Movement Disorder Society Task Force.
Helping you build
13. L
Mov Disord. 2007;22(16):2314-2324.
esage S, Brice A. Parkinson’s disease: from monogenic forms to genetic
a more secure future.
susceptibility factors. Hum. Mol. Genet.. 2009;18(R1):R48-59
14. de Lau, LM, Breteler, MM. Epidemiology of Parkinson’s disease. Lancet Neurol. We invest our own money
2006;5:525- 535.
15. R
 askin SA, Borod JC, Tweedy J. Neuropsychological aspects of Parkinson's disease. alongside yours,
Neuropsychol Rev. 1990;1(3):185. so we are invested
16.  Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol.
2006;5(1):75. in your success.
17. Lee SJ, Kim JS, Yoo JY, et al. Influence of white matter hyperintensities on
the cognition of patients with Parkinson disease. Alzheimer Dis Assoc Disord.
2010;24(3):227–233.
18. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review.
JAMA. 2014;311(16):1670-1683.
Author Information
Author Information: Prior Clinical Director of the MIND Center;
Assistant Professor, Departments of Medicine and Family Medicine at
the University of Mississippi Medical Center (UMMC), Jackson, MS
(N Patel.). Family medicine resident, UMMC (Massihi). Third-year MEDLEY & BROWN
pediatric cardiology Fellow in the Department of Pediatrics, UMMC F I N A N C I A L A D V I S O R S

(A Patel). Clinical research nurse, MIND Center and Department of

Neurology, UMMC (Majeste). Conflicts of interest: None.
601-982-4123 medleybrown.com
Corresponding Author: Andrew
Johns A2Z Ad 4.25x5.5.pdf 1
Majeste,
6/28/18
BSN, RN, MIND Center,
10:25 AM
2500 North State Street, Jackson, MS 39216. Ph: (601) 984-5490
(acmajeste@umc.edu).
M&B MSMA 4'17'17.indd 1 4/17/17 2:21 PM

“If you can think it,

we can print it.”
John Mathews
601-540-2864
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2125 TV Road • Jackson, MS 39204
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