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 Alzheimers 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:
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?
1.

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 Parkinsons (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.)
Downs 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
1015% /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 3550 % 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
Alzheimers type dementia?

Alzheimers 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

Alzheimers Disease
6080% 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)

Alzheimers 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!!!)

Alzheimers 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
Alzheimers 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
Parkinsons disease?

Dementia with Parkinsons

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
1020% 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
6080%
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
7090%
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

3050% 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
510% cases of dementia
Onset usually 4565 (rare after age 75)
Familial: 2040%

Picks 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 23% 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 125 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 2030 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,
139 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 314)
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 clinicians
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

1.51.7), and increased ?increased stroke risk

Antipsychotics

NO if you suspect
DLB

Antipsychotics
Risperidone (0.5 BID)
Olanzepine (zyprexa): 2.55 mg/day
Quetiapine (seroquel)

Rapid titration, use in PD

12.5200 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 7080 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