Dementia: Diagnosis and
Treatment
Debra L. Bynum, MD
Division of Geriatric Medicine
University of North Carolina at Chapel Hill
Case
Mr. Jones is a 72-year-old gentleman brought to you by his
daughter for progressive memory loss. He denies any problems.
Previously an accountant, he is now unable to balance his check
book. He has had difficulty with getting lost while driving to the
store. He was diagnosed with depression two years ago after his
wife died. In addition, he has HTN and DM. His father was
diagnosed with Alzheimer’s disease at the age of 85. On exam,
his BP is 170/90; he is oriented, scores 26/30 on the MMSE (0/3
recall and difficulty with the intersecting pentagon); he is unable
to do the clockface.
A few months later, his MMSE is 24/30; on exam he has some
mild cogwheel rigidity and a slight shuffling gate, but no
tremor. His daughter reports that he has been having vivid visual
hallucinations and paranoid thought.
Questions:
1. What are some limitations to the
MMSE?
2. Is there any association between HTN
and dementia in the elderly?
3. What are the risk factors for dementia?
4. What type of dementia might Mr. Jones
have?
Outline
Risk factors and definition of dementia
Types of dementias
MMSE and testing
Treatment options
Question:
What are some risk factors for the
development of dementia?
Risk Factors for Dementia
Age
Family hx of AD or Parkinson’s (10-30%
risk of AD in patients with first degree
relative)
Head trauma
Depression (?early marker for dementia)
Low educational attainment?
?hyperlipidemia
?diabetes
HTN !!!
Risk Factors for AD
Gender (confounding in literature – women
more likely to live longer, be older….)
Down’s syndrome
?estrogen (probably not)
?NSAIDS (probably not)
Question:
What is the definition of a dementia?
What is the “line” between “normal”
memory loss with age and dementia…
Cognitive Decline with Aging
Mild changes in memory and rate of
information processing
Not progressive
Does not interfere with daily function or
independence
Mild Cognitive Impairment
12% of people over age 70
Usually memory affected
Does not significantly interfere with daily
function
3 times increased risk of developing AD
10–15% /year will develop dementia
DSM Criteria
1. Memory impairment
2. At least one of the following:
 Aphasia
 Apraxia
 Agnosia
 Disturbance in executive functioning
3. Disturbance in 1 and 2 interferes with daily
function or independence
4. Does not occur exclusively during delirium
Activities of Daily Living
ADLs: bathing, toileting, transfer,
dressing, eating
IADLs (executive functioning):
Maintaining household
 Shopping
 Transportation
 Finances

Diagnosis of Dementia
Delirium: acute, clouding of sensorium,
fluctuations in level of consciousness, difficulty
with attention and concentration
Depression: patient complains of memory loss
Delirium and depression: markers of
dementia?
5% people over age 65 and 35–50 % over 85
have dementia, therefore pretest probability of
dementia in older person with memory loss at
least 60%
Question:
What are some classic features of an
Alzheimer’s type dementia?
Alzheimer’s Disease
Role of the Hippocampus
Patient HM with surgery for seizures to
remove bilateral medial temporal lobes
resulting in severe anterograde amnesia
Formation of new memories
Spatial navigation
Early evidence for damage in this area
Alzheimer’s Disease
60–80% of cases of dementia in older patients
Early personality changes
Loss of short term memory
Functional impairment
Visual spatial disturbances (early finding)
Apraxia
Language disturbances
Delusions/hallucinations (usually later in
course)
Alzheimer’s Disease
Depression occurs in 1/3
Delusions and hallucinations in 1/3
Extracellular deposition of amyloid-beta
protein, intracellular neurofibrillary tangles,
and loss of neurons at autopsy
Clinical diagnosis: 87% of diagnosed AD
confirmed pathologically (but high pretest
probability increases predictive value of clinical
diagnosis!!!)
Alzheimer’s Disease
Onset usually near age 65; older age, more
likely diagnosis
Absence of focal neurological signs (but
significant overlap in the elderly with hx of
CVAs…)
Aphasia, apraxia, agnosia
Family hx (especially for early types)
Normal/nonspecific EEG
MRI: bilateral hippocampal atrophy
(suggestive)
Question:
What features would make you think
more about a vascular etiology to a
dementia?
Vascular Dementia
Onset of cognitive deficits associated with a
stroke (but often no clear hx of CVA but
multiple small, undiagnosed CVAs)
Abrupt onset of sxs with stepwise deterioration
Findings on neurological examination
Infarcts on cerebral imaging (but ct/mri
findings often have no clear relationship)
Overlap
Most patients previously categorized as either
Alzheimer’s type or vascular type dementias
probably have BOTH
Likelihood of AD and vascular disease
significantly increases with age, therefore
likelihood of both does as well
Vascular risk factors predispose to AD -- ?does
it allow the symptoms of AD to be unmasked
earlier??
Question:
What is the risk of dementia with
Parkinson’s disease?
Dementia with Parkinson’s
30% with PD may develop dementia;
Risk Factors:
Age over 70
 Depression
 Confusion/psychosis on levodopa
 Facial masking upon presentation

Hallucinations and delusions

May be exacerbated by treatment
Some Other Dementias
Dementia with Lewy Bodies
Cortical Lewy Bodies on path
10–20% of dementias
Compare to PD: Lewy Bodies in
substantia nigra
Overlap with AD and PD
40% patients with AD have LBs on path
Dementia with Lewy Bodies
Visual hallucinations (early)
Parkinsonism
Cognitive fluctuations
Dysautonomia
Sleep disorders
Neuroleptic sensitivity
Memory changes later in course
Dementia with Lewy Bodies
Visual hallucinations
2/3 of patients with DLB
 Rare in AD
 May precede other symptoms of DLB
 Psychosis, paranoia and other psychiatric
manifestations early in course

Dementia with Lewy Bodies
Cognitive Fluctuations
60–80%
 Episodic
 Loss of consciousness, staring spells, more
confused or delirious like behavior
 Days of long naps
 Significant impact on functional status

Dementia with Lewy Bodies
Parkinsonism
70–90%
 More bilateral and symmetric than with PD
 Tremor less common
 Bradykinesia, rigidity, gait changes

Dementia with Lewy Bodies
Sleep disorders
REM sleep behavior disorder/parasomnia
 Acting out of dreams: REM dreams without
usual muscle atonia
 85% of patients with DLB
 May precede other symptoms by years

DLB: Neuroleptic Hypersensitivity
30–50% of patients
May induce Parkinsonian symptoms or
cognitive changes that are not reversible,
leading to rapid decline in overall status
NOT dose related
Slightly less likely with newer atypical
antipsychotics, but can STILL happen
DLB: Treatment
More progressive course than AD or
Vascular dementia
Possibly better response to cholinergic
drugs than AD or vascular dementias
?response of psychiatric type symptoms
to cholinergic agents/cholinesterase
inhibitors
Progressive Supranuclear Palsy
Uncommon
Vertical supranuclear palsy with
downward gaze abnormalities
Postural instability
Falls (especially with stairs)
“Surprised look”
Difficulty with spilling food/drink
Frontotemporal Dementia
Impairment of executive function



Initiation
Goal setting
Planning
Disinhibited/inappropriate behavior (90%)
Cognitive testing may be normal; memory loss
NOT prominent early feature
5–10% cases of dementia
Onset usually 45–65 (rare after age 75)
Familial: 20–40%
Pick’s Disease
Subtype of frontal lobe dementia
Pick bodies (silver staining intracytoplasmic
inclusions in neocortex and hippocampus)
?Serotonergic deficit?
Language abnormalities and behavioral
disturbances




Logorrhea (abundant unfocused speech)
Echolalia (spontaneous repetition of words/phrases)
Palilalia (compulsive repetition of phrases)
Fluent or non-fluent forms
Primary Progressive Aphasia
Patients slowly develop non-fluent, anomic
aphasia with hesitant, effortful speech
Repetition, reading, writing also impaired;
comprehension initially preserved
Slow progression, initially memory preserved
but 75% eventually develop non-language
deficits; most patients eventually become mute
Average age of onset = 60
Subset of FTD
“Reversible” Causes of Dementia
?10% of all patients with dementia; in
reality, only 2–3% at most will truly have
a reversible cause of dementia
“Modifiable” Causes of Dementia
Medications
Alcohol
Metabolic (b12, thyroid, hyponatremia,
hypercalcemia, hepatic and renal
dysfunction)
Depression? (likely marker though…)
CNS neoplasms, chronic subdural
NPH
Question:
An elderly patient with ataxia,
incontinence, memory loss and “large
ventricles” scan should raise suspicion
for …?
Normal Pressure Hydrocephalus
Triad:
Gait disturbance
 Urinary incontinence
 Cognitive dysfunction

NPH: Clinical Features
Gait



Early Feature
Most responsive to shunting
Magnetic/gait apraxia/frontal “ataxia”
Cognitive

Psychomotor slowing, apathy, decreased attention
Urinary

Urgency or incontinence
NPH
Hydrocephalus in absence of papilledema, with
normal CSF pressure
Begins as transient/intermittent increased CSF
pressure, leading to ventricular enlargement;
ventricular enlargement leads to normalization
of CSF pressure
Thought to be due to decreased CSF absorption
at arachnoid villi
Causes: SAH, tumors, CVA
NPH
Diagnosis: initially on neuroimaging
 Ventricular enlargement our of proportion to
sulcal atrophy
Miller Fisher test: objective gait assessment
before and after removal of 30 cc CSF
Radioisotope diffusion studies of CSF
MRI: turbulent flow in posterior third ventricle
and within aqueduct of sylvius
MRI flow imaging
SPECT (Single Photon emission CT): decreased
blood flow in frontal and periventricular areas
NPH: ?Shunting?
Limited data
Gait may be most responsive
Predictors of better outcome:
Lack of significant dementia
 Known etiology (prior SAH)
 New (< 6 months) symptoms
 Prominence of gait abnormality

Creutzfeldt-Jacob Disease
Rapid onset and deterioration
Motor deficits
Seizures
Slowing and periodic complexes on EEG
Myotonic activity
Other Infections and Dementia
Syphilis
HIV
Question:
What are some tools available to assess for
the presence and severity of cognitive
impairment?
MMSE
24/30 suggestive of dementia (sens 87%,
spec 82%)
Not sensitive for MCI
Spuriously low in people with low
educational level, low SES, poor language
skills, illiteracy, impaired vision
Not sensitive in people with higher
educational background
MMSE Tips
No on serial sevens (months backwards, name
backwards… assessment of attention)
Assess literacy prior
Assess for dominant hand prior to handing
paper over
Do not over lead
3-item repetition, repeat all 3 then have
patients repeat; 3-stage command, repeat all 3
parts of command and then have patient do…
Other Evaluation Tools
Trails B test
 Numbers 1–25 and letters scattered across page;
patient must connect, 1-A, 2-B, 3-C, etc; normally
able to do in <10 minutes
 Good for patients with high function/education
Verbal Fluency Test
 Name all within category in 30 seconds – 1 minute
 Letters FAS, animals, vegetables
 Tests executive function and language, semantic
memory
 Normally should name 20–30 in 60 seconds
 Highly associated with educational level
 Insight with grouping, rhyming, categories
Additional Evaluation
Clockface
Short assessments with good validity: 3-item recall and
clockface
Neurological exam (focality, frontal release signs such
as grasp, jawjerk; apraxia, cogwheeling, eye
movements)
Lab testing and neuroimaging
Treatment of AD
Tacrine
Cholinesterase inhibitor
1 systematic review with 5 RCTs, 1434 people,
1–39 weeks
No difference in overall clinical improvement
Some clinically insignificant improvement in
cognition
Significant risk of LFT abnormalities: NOT
USED
Donepezil
Aricept
Cholinesterse inhibitor
Easy titration (start 5/day, then 10)
Side effects: GI (nausea, diarrhea)
Can be associated with bradycardia
Main effect seems to be lessening of rate
of decline, delayed time to needing
nursing home/more intensive care
Other Agents
Rivastigmine
Galantamine
Cholinesterase inhibitors
?more side effects, more titration required
Future directions:




Prevention of delirium in at-risk patients
(cholinergic theory of delirium)
Behavioral effects in those with severe dementia?
Treatment of Lewy Body dementia
Treatment of mixed Vascular/AD dementia
Comments about Cholinesterase
Inhibitor Studies
Highly selected patients (mild – moderate
dementia)
?QOL improvements
Not known: severe dementia and mild CI
Memantine
NEJM April 2003
Moderate to severe AD (MMSE 3–14)
N-methyl D aspartate (NMDA) receptor
antagonist; theory that overstimulation of
NMDA receptor by glutamate leads to
progressive neurodegenerative damage
28-week, double blinded, placebo controlled
study; 126 in each group; 67% female, mean
age 76, mean MMSE 7.9
Memantine
Found less decline in ADL scores, less
decline in MMSE (-.5 instead of –1.2)
Problem: significant drop outs (overall
28% dropout rate) in both groups; data
analyzed did not account for drop outs,
followed those “at risk”
Selegiline
Unclear benefit
Less than 10mg day, selective MAO B
inhibitor
Small studies, not very conclusive
Vitamin E (Alpha Tocopherol)
NEJM 1997: selegiline, Vit E, both , placebo for tx
of AD
Double blind, placebo controlled, RCT with mod
AD; 341 patients
Primary outcome: time to death,
institutionalization, loss of ADLS, severe
dementia
Baseline MMSE higher in placebo group
No difference in Primary outcomes; adjusted for
MMSE differences at baseline and found delay in
time to NH from 670 days with Vit E to 440 days
with placebo
Ginkgo Biloba
1 systematic review of 9 double blind
RCTs with AD, vascular, or mixed
dementia
Heterogeneity, short durations
High withdrawal rates; best studies have
shown no significant change in clinician’s
global impression scores
Other Treatments
NO good evidence to support estrogens
or NSAIDS
Other Treatments
Behavioral/agitation:
Nonpharmacologic strategies
 Reasons for NH placement:

Agitation
 Incontinence
 Falls
 Caregiver stress

?Antipsychotics
NO data to support any significant
benefit for treating behavioral symptoms
of dementia with antipsychotic agents
Small group of patients with active
psychoses, disturbing hallucinations, or
aggressive behaviors who may have some
benefit
Antipsychotics
Side Effects:







Sedation
Anticholinergic effects
Prolonged QT
Edema
Orthostasis
Weight gain
Confusion
Warnings:

FDA black box warning for increased mortality (OR
1.5–1.7), and increased ?increased stroke risk
Antipsychotics
NO if you suspect
DLB
Antipsychotics
Risperidone (0.5 BID)
Olanzepine (zyprexa): 2.5–5 mg/day
Quetiapine (seroquel)


Rapid titration, use in PD
12.5–200 mg/day
Clozapine


Use in PD (least risk of tremor)
Agranulocytosis and limited use
Ziprasidone (geodon)

QT prolongation
Prevention?
HTN and DM linked to ALL types dementia
Studies of treating systolic hypertension in the
elderly (SHEPS and others): decreased risk of
development of cognitive impairment in
patients in treatment group
Decreased risk included vascular AND
Alzheimer type dementias
Cholinesterase inhibitors seem to work as well
(or as poorly) for both vascular and Alzheimer
type of dementias
What is the link? Both common, ?unmasking?
?Link with Hyperlipidemia
Conflicting data
Retrospective studies suggest decreased
risk in those patients who are treated
with statins
PROSPER study
6000 patients age 70–80 with vascular risk
factors given pravastatin or placebo
 3 year: no effect on cognitive function
 ?Long enough follow up?

Future
Treating vascular risk factors to decrease
development/unmasking of dementia?
Actively seeking to differentiate different types
of dementia, while also
Recognizing significant OVERLAP of dementia
etiologies in older patients
Move toward agents other than cholinesterase
inhibitors?
Move away from broad use of antipsychotic
agents