Dementia
Michael A Hill, MD
Professor Of Psychiatry
Dementia
An acquired syndrome characterized by:
• Short-term memory impairment (i.e.
learning) AND
• At least one of the following:
–
–
–
–
Aphasia - language memory impairments
Apraxia - motor memory impairments
Agnosia - sensory memory impairments
Abstract thinking / Exec. function impairments
• Impairment in social and/or occupational fn
• Sxs not explainable by another disorder
Etiology & Pathogenesis
• Dementia results from impaired functioning of
multiple brain systems in both cortical and subcortical areas that are associated with short-term
memory (i.e. learning) and other higher cognitive
functions. Generally this is due to structural
brain damage that is often progressive and
relatively irreversible
Delirium vs Dementia
(summary)
• General rules of thumb:
Delirium
Dementia
acute
chronic
reversible
irreversible
physiological
structural
primary attention primary memory
deficits
deficits
• Delirium and dementia can coexist; in fact
delirium is very common in demented
patients
Clinical Presentation of Dementia
• Always associated with cognitive disturbances
and functional impairments
• Visuospatial impairments and behavioral
disturbances are usually seen as well
• Specific symptoms will vary by type of dementia
(Frontal lobe dementias present with personality change
and executive dysfunction to a much greater degree than
memory impairment)
Memory Impairments
• Difficulty learning or retaining new information
(repeated conversations)
• Information retrieval deficits (can’t recall names,
list generation deficits)
• Personal episodic memory impairment
(misplacing items)
• Declarative (semantic) memory (WHAT) >
procedural memory (HOW)
Language Deficits
• List-generation deficits – verbal fluency (esp. in
AD)
• Word-finding difficulties (naming problems)
• Less complex sentence structure
• Relatively preserved auditory comprehension
(can understand directions)
Visuospatial impairments
• Visual recognition impairments (trouble recognizing
familiar faces - CAPGRAS syndrome possible)
• Spatial deficits (getting lost in familiar surroundings,
3-D drawing deficits, constructional apraxia)
Functional Impairments
• Deficits appear first in IADLs (managing finances,
driving, shopping, working, taking medications, keeping
appointments)
• Eventually problems with ADLs (feeding, grooming,
dressing, eating, toileting)
• Rate and specific pattern of loss will vary by
individual and somewhat by diagnosis
• NB: Functional impairment and performance on cognitive
testing may not correlate strongly early in the course of dementia
Behavioral Symptoms
• Nearly universal and often the main focus of
treatment. Inability to manage these symptoms is highly
correlated with institutional placement.
• PERSONALITY CHANGE: Occurs early
– passivity (apathy, social withdrawal)
– disinhibition (inappropriate sexual behavior or
language, loss of social graces, aggression)
– self-centered behaviors (childishness, loss of
generosity)
Epidemiology: Prevalence increases with age
Age Prevalence*
Age
Incidence
>65 5-10%
65-74
0.5-1%
>75 10-20%
75-84
2-4%
>85 25-50%
85+
6-8%
>95 40-70%
May level off or
declince after age 100
*Lower numbers represent moderate to severe dementia
Incidence Of Alzheimer’s Disease by Age
9
8
Incidence
7
6
5
4
3
2
1
0
65-69
70-74
75-79
Age
80-84
85+
Diagnostic Approach
Early Detection & Screening
• Careful history from patient and reliable
informant
• PE with focus on neurological exam and
cognitive testing
– Cognitive testing tools such as MMSE are helpful.
Score below 24-27 often concerning depending on
premorbid abilities
– Functional Assessment tools such as the Functional
Activities Questionnaire
Primary Care Screening Tools
• MMSE (‘normal’ varies somewhat by age and educational level
•
•
•
•
– an 80 y/o with only 4 years of education would be expected to
only get a 19/30)
Clock Test – easy to do, quick. Draw a clock, put numbers in
correct locations, set hands to ‘10 til 2’.
List generation – number of animals that can be named in 60
seconds. <12 is definitely abnormal, 12-18 is marginal. Can also
do words beginning with letter ‘F’. 10+ in one minute is
normal. Often very impaired in Alzheimer’s and some types of
FTDs.
Trails B testing is useful if frontal lobe deficits suspected (e.g.
fronto-temporal dementias, AIDS dementia)
‘Go No-Go’ Testing (inability to inhibit responses)
MMSE ‘norms’ by Age and
Educational Level
Educational level
AGE
18-24
0-4y
23
5-8y
28
9-12y
29
>12y
30
35-39
23
27
29
30
50-54
22
27
29
30
70-74
21
26
28
29
80-84
19
25
26
28
Diagnostic Work-Up
• This is done to
– (1) rule out disorders besides dementia (e.g. delirium)
– (2) to identify reversible/treatable dementias (13+%)
– (3) to clarify the specific dementia syndrome
• Routine Assessment: CBC with diff, serum electrolytes,
Ca++, glucose, BUN/CR, LFTs, TFTs, B12 & folate, U/A, RPR,
head imaging
• When indicated: Sed. rate, HIV, CXR, heavy metals, LP, EEG,
functional imaging, Lyme titers, endocrine studies, rheumatologic
studies, Neuropsychological Testing
Guidelines For Use of Specialized Testing
• LP: Suspicion of metastatic CA, CNS infections, neuropsyphilis,
hydrocephalus, vasculitis. Also for dementia <55 and rapidly progressive
dementias
• Neuroimaging - consider in all new cases. However without focal
symptoms or signs, seizures or gait disturbances in an individual over age 70
- consider this optional
• Functional Imaging (SPECT, PET, MRS, fMRI): to clarify type
of dementia when necessary (and in the future to track course of illness and
response to tx)
• EEG - can help distinguish delirium from dementia, can help with seizure
disorder and JCD
Neuropsychological Testing
• Cognitive testing and functional testing are at odds
or there is suspicion of early dementia in a high IQ
individual with normal MMSE
• Mild impairment in a person with: low IQ or limited
education, trouble with English, impairments less
than 6 months
• Determining capacity for legal purposes when deficits are mild
Mild Cognitive Impairment
• Some cognitive deficits apparent on testing but not to
dementia level (MMSE 24-29) range
• Minimal, if any, functional impairments
• 13-15% per year progress to dementia (A.D.) but not all
progress and some improve
• Predictors of progression: ApoE4 alleles, poor
performance on cued recall and hippocampal atrophy
by MRI
Pseudodementia
• More appropriately called ‘reversible dementia’
• The classic case is ‘depressive pseudodementia’ with
‘overstated’ cognitive impairments due to decreased
concentration and poor effort
• However, depression may be a risk factor for dementia
• 50% of elderly patients with depressive
pseduodementia have Alzheimer’s at 5 year follow-up
Late-Life Depression
• Def ’n: First Major Depressive Episode occurs
after age 65
• High correlation with dementia (50% go on to
develop dementia within 3 years!)
• Many of these depression may be vascular or
post-stroke depressions
Most Common Dementias
•
•
•
•
Alzheimer’s Disease (AD) (50-75%)
Lewy Body Dementias (DLB) (10-30%)
Vascular Dementias (VaD) (15-20%)
Alcohol-related dementias (including
Korsakoff ’s (infrequent) and etoh-induced))
• HIV dementia - most common dementia in
those under age 55
Classification of Dementias
• Primary versus secondary based on the pathophysiology
leading to damaged brain tissue
• Cortical versus sub-cortical depending on the cerebral
location of the primary deficits
• Reversible versus irreversible depending on optimal
treatment expectations
• Early (before age 65) versus late onset
Economic Burden
• $80 to $100 billion per year in total treatment costs
• Alzheimer’s disease is the third most expensive
disease to treat in the United States, following
cancer and heart disease
• Currently 4 million people have Alzheimer’s disease
in the U.S.
• More than $213,000 per family for the remainder of
the patient’s life, including direct and indirect
treatments costs ($47,000 per patient per year)
General Treatment Principles
• Treatment Of Underlying Disease Process
(Primary Treatment)
• Management Of Behaviors and Symptoms
(Secondary Treatment)
• Caregiver Support and Education
Reversible Dementias
• May become irreversible if not treated soon
enough
• Many dementias may be arrestible if not fully
reversible
• Rule out ‘depressive pseduodementia’ and
delirium which can mimic dementia
• Some reversible dementias include: hypoT4,
B12 def., some infections and tumors, druginduced syndromes, etc.
Primary Treatment Strategies
(for progressive dementias)
• 1. Prevention
– Identify risks and mitigate
– Develop neuroprotective strategies for those at risk
• 2. Slow or halt progression of illness
– Understanding pathophysiology leads to treatment ideas
– 5 year delay in onset ---> 1/3 decrease in prevalence
– Delaying institutionalization by 1 month saves $1.2 billion/yr
• 3. Reverse symptoms
– Compensate through augmentation of remaining neurons or other
systems
– Reversal of destructive processes & regeneration of tissue
Delayed Onset Incidence
Incidence Figures
Incidence (% )
10
8
6
4
2
0
65-69 70-74 75-79 80-84 85-89
AGE
90+
ALZHEIMER’S Pathophysiology
• Neuritic plaques -extracellular - abnormal insoluble
amyloid protein fragments
• Neurofibrillary tangles - intracellular - disturbed taumicrotubule complexes (hyperphosphorylated tau)
• Cholinergic system degeneration with significant loss of
neurons in certain areas (such as Nucleus Basalis of
Meynert)
• Degeneration often begins in enterorhinal cortex and
progresses to other limbic structures
CHOLINERGIC SYSTEM
STRATEGIES
•
•
•
•
Reduce Serum anticholinergic load
Precursor strategies (e.g. lecithin and choline)
Receptor/synaptic strategies
Metabolic strategies (anticholinesterases)
Serum Anticholinergic Load & Cognitive
Impairment
o 90% of community elderly sample had
detectable SA levels
o An SA level >2.8 pmol/Ml was 13X more likely to be
associated with an MMSE of 24 or less in the
general elderly population than in those with
undetectable SA levels
Univ Of Pittsburgh, AAGP 5th Annual Meeting, 2002
Commonly Prescribed Non-Psyciatric
Drugs with Significant Anticholinergic
Activity
o
o
o
o
o
o
o
•
cimetidine & ranitidine
prednisolone
theophylline
digoxin/Lanoxin
furosemide
nifedipine
diphenhydramine (OTC)
To a lesser extent: codeine, warfarin,
dipyradimole, isosorbide dinitrate
Current AChE Inhibitors
Donepezil
(Aricept)
Rivastigmine Galantamine
(Exelon)
(Razadyne)
BuChE
Small
Yes
Small
Nicotinic
modulation
Half-life
No
No
Yes*
50-70 hrs
½-2 hrs
5-7 hrs
Starting Dose 5 mg/day
1.5 mg bid
4 mg bid
Ending Dose 5-10 mg/day
3-6 mg bid
8-12 mg bid
*promotes binding of acetylcholine
Anticholinesterase Side Effects
(i.e. procholinergic)
• GI – nausea, vomiting, diarrhea, increased
gastric acid secretion
• Muscle cramps
• Fatigue
• Insomnia
• Syncope (2% vs 1% for placebo) (?bradycardia)
STRATEGIES TO SLOW OR HALT
PROGESSION




Calcium channel modulation and excitatotoxic
systems attenuation (such as memantine)
Anti-inflammatory/immunosuppressive
strategies(e.g. NSAIDs)
Gene therapy for defective protein regulation
Toxin removal (Desferroxamine, clioquinol) /
Ventriculoperitoneal shunting (COGNIShunt)


Amyloid Protein strategies
Other Neuroprotective strategies
Neuroprotective Strategies








Nerve Growth Factor
Acetyl-l(levo) carnitine (ALCAR)
Estrogen
Homocysteine reduction( folate, B6, B12)
Antioxidants (Vit E, Gingko, deprenyl)
‘Statins’ (Lipitor, Pravachol) (may lower abnormal
amyloid levels)
Rosiglitazone (Avandia) -anti-inflammatory, amyloid
processing modulation activities
Nutraceuticals
Nutraceutical Strategies
• Vitamin E (antioxidant)
• Homocysteine Reduction (folate, B6, B12)
• Beta-carotene –
– Physician’s Health Study II found a cognitive
protective effect of 50 mg every other day over two
decades of use
• Gingko (antioxidant)
• Resveratrol
Vitamin E







Potent antioxidant properties
Has been shown to slow progression at least as much
as Deprenyl in one head-to-head study
Recent study showed no difference from placebo in
preventing progression from MCI to AD over 3 yrs
Few side effects even in high doses, though recent
studies in Europe suggest a higher death rate in those
on hi-dose Vitamin E
Doses used in recent studies: up to 1000 IU bid
Consider 400-800 IU per day for prevention
May work better if combined with Vitamin C
Days
Estrogen
• At this point the summary of many studies suggests
that Hormone replacement therapy (HRT) is
questionably effective in slowing the onset of
AD in some women
• The earlier started, the better. Limited exposure
may be best.
• Progesterone may be detrimental
• Tacrine response can be enhanced by Estrogen
• WHY? neurotrophic effects, incr. ChAT, high
serum E2 suppresses Apo E
Statins
• Lovastatin(Mevacor), pravastatin(Pravachol), simvastatin(Zocor),
atorvastatin(Lipitor)
• May prevent aggregation of B-amyloid* in the brain by
preventing cholesterol build up. May activate alpha-secretase.
• Conflicting evidence – recent U of Wash study did not find a
benefit, but looked at older individuals on statins only a short
while.
• Earlier studies were more positive
• Not sure if all these drugs are equal… Ability to enhance tissue
plaminogen activator (tPA) and thus production of plasmin may
be important. Plasmin may activate alpha-secretase and can also
increase production of BDNF.
*AKA amyloid-beta peptide or ABeta
Memantine
• Glutamate is the principal excitatory neurotransmitter in brain
regions associated with cognition and memory (i.e. it
stimulates cholinergic neurons)
• Glutamate hypothesis of dementia suggests that
overactivation of these neurons leads to excitatoxic damage
to these brain areas (by allowing calcium to continuously
‘leak in’ to cells). It is post-synaptic receptor sensitivity
rather than excess release of glutamate that is the problem.
• Memantine is a weak antagonist of glutamate-gated NMDA
receptor channels which prevents overactivation during
memory formation but allows normal function
NSAID Use & AD in Elderly
Patients
• 2708 patients enrolled
• Examined NSAID use and prevalence of
Alzheimer’s Disease
• NSAID users had ~50% lower risk of being
affected by AD
• Aspirin trended this way but was not significant
• Treatment studies have not shown any
consistent benefits yet however.
Landi, et al, Am J Geriatric Psychiatry, March-April, 2003
Abnormal Amyloid Protein Strategies
 Most genetic mutations associated with AD affect amyloid
processing
 Senile plaques contain abnormal amyloid B fragments
(that precipitate out of solution easily)
• Attack enzymatic pathways that lead to production of abnormal
type and amount of amyloid ( beta or gamma-secretase inhibitors)
• Enhance alpha-secretase system to promote normal amyloid
• Prevent aggregation (NSAIDS may do this!)
• Alter the abnormal gene expression
• GAG mimetics (glycosaminoglycans) –Alzhemed – interferes with
formation of insoluble amyloid protein fragments
Reversal Strategies

Destroy the current plaques/amyloid


Vaccination Strategy: AN-1792 vaccine is in testing. This is an
amyloid B protein fragment which can induce antibodies that
bind to plaques and activate microglial destruction processes.
Trial halted b/o menigoencephalopathies
‘Plaque busters’




Alzhemed prevents Amyloid B fragments from forming fibrils
Clioquinol - A metal-protein-attenuating compound (MPAC) that
inhibits zinc and copper ions from binding to beta-amyloid,
thereby helping to dissolve it and prevent it from accumulating.
Transthyretin shows promise at interfering with toxic effects
Generate new tissue 

neuroregeneration strategies (STEM cells)
neurotransplantation strategies
Other Drugs in the Pipeline
• Tau protein modulators (to prevent abnormal
phosphorylated ‘tau’ protein
• Beta and gamma-secretase inhibitors
• Alpha secretase stimulators
• Bryostatin – CA drug that stimulates brain protein
production. Reduces B-amyloid levels in mice,
enhances memory and learning.
• New generation NSAIDS (flubiprofen) – testing in
humans looks promising
• Immune enhancers (immunoglobulin)
• New vaccines and new anticholinesterases (huperzine)
Caregiver Burden
• Alzheimer’s caregivers spend an average of 69 to 100
hours per week providing care
• Caregivers of patients suffering from
dementia(compared to control subjects) reported:
– 46% more physician visits
– Over 70% more prescribed drugs
– More likely to be hospitalized
• More than 50% of caregivers are at risk for clinical
depression
Staging of Dementias
• MILD: difficulties with checkbook maintenance, complex
•
•
•
•
meal preparations, complicated medication schedules
MODERATE: difficulties with simple food preparation,
household or yard work. May need some assistance with
self-care
SEVERE: Need considerable assistance with feeding,
grooming and toileting
PROFOUND: Largely oblivious to surroundings, totally
dependent
TERMINAL: Bed bound; require constant care
Common Associated Problems
depression (occurs in 20-40% - esp. AD and
VaD)
psychosis (occurs in 30- 50%) - usually see
paranoid delusions (theft, infidelity)
wandering/purposeless activity
agitation/threatening behavior
sleep disturbances
delirium - minor insults can lead to major
decompensations
Behavioral Problems in AD
• Almost universally a problem at some point
• 60% of AD at any one time exhibiting significant symptoms
(usually delusions and/or agitation)
• Common problems by order of prevalence:
– agitation
– depression
– delusions/psychosis
• Additional behavioral problems
– disinhibition, apathy, personality change, anxiety,
wandering, insomnia
Causes of Behavioral Problems
• Biological (due to the disease process itself
e.g.)
• Psychological (loss of function and
autonomy, attempts to maintain some
control, denial of deficits, etc.)
• Social (family distress, economic issues,
family conflicts over care)
• Environmental (increased sensitivity to
changes, issues of safety, etc.)
General Treatment Strategies
• Define symptoms clearly
• Rule out other psychiatric illness (e.g. MDD)
• Rule out medical causes for the symptoms (e.g.
intercurrent illness, medication reactions, etc.)
• Identify non-pharmacologic strategies
• Pharmacotherapy
Environmental Strategies
• Identify provocations and rectify if possible
• Appropriate re-orientation strategies
• Optimize sensory input [i.e. correct visual and
hearing impairments]
• Behavior management strategies that respect the
patient’s need for control and autonomy
(announcing intentions, single-step instructions e.g.)
• Optimize physical activity, social stimulation,
reminiscing
Management Issues
•
•
•
•
•
Alleviate patient’s distress
Reduce care-giver burden
Delay institutionalization
Assure safety
Patient’s often become ‘more like themselves’
Caregiver information and support
Caregivers should:
– Encourage independence for the Alzheimer’s patient
without sacrificing security
– Assist the patient, but only if necessary (i.e. allow the
patient as much control as possible)
– Learn to compromise
– Develop ways to share activities
– Establish a support network; get other family involved
– Educate themselves (alzheimers.org)
Depression and Alzheimer’s
• Common early in the course of the illness
• Incidence 40-50%
• Use SSRIs first; avoid anticholinergic
antidepressants
• ECT can be helpful but may temporarily worsen
cognitive symptoms
Treatment of Depression
• Recognize that irritability and/or apathy
/withdrawal may be indicative of depression
• Allow patient choices and control
• Identify pleasurable activities (such as singing
old songs, pet therapy, etc.)
• Cognitive enhancers (e.g. Aricept) may help
• Consider Ritalin for apathy, poor appetite
Agitation
• Non-aggressive
– verbal: complaining, constant requests for attention,
repetition of words, constant talk, screaming
– physical: pacing, disrobing, stereotypies, trying to get to a
different place
• Aggressive
– Verbal: threats, name calling, obscenities
– Non-verbal: biting, scratching, spitting, kicking, pushing,
swinging fists
Treatment of Agitation/Violence
• Identify and reduce provocative stimuli if
possible
• Optimize communication with patient
• Environmental modifications
• Pharmacotherapy - target underlying cause
(neuroleptics, antidepressants, mood stabilizers,
beta blockers, buspirone, trazodone)
Medications for Agitation
•
•
•
•
•
•
•
•
Buspirone – Takes a while to work
Antidepressants (SSRIs, Trazodone)
Anticonvulsants (esp. valproate)
Atypical Antipsychotics (stroke risk concerning)
Low dose narcotics?
Marinol?
Estrogen?
Benzos – ataxia, worsening memory and disinhibition
are problematic.
Treatment of Psychosis
• Recognize common delusions as relating to
impaired STM (improving memory may help - e.g. donepezil)
• Delusions often fade with time even without tx
• Traditional antipsychotics
– Low potency (chlorpromazine)– orthostasis, sedation,
anticholinergic
– High potency (haloperidol)– EPS/TD but otherwise well
tolerated
• New generations drugs (e.g. olanzapine, quetiapine,
risperidone)- less EPS/TD but still see anticholinergic, BP and
sedative effects
Atypical Antipsychotics & Risk of
Serious Adverse Events
• Retrospective review revealed a small (2-3%) but ~2
fold increase in risk of stroke in demented patients
receiving these agents compared to placebo.12
• FDA required ‘Black Box’ warning due to 1.6 to 1.7fold increase in mortality in pooled sample of >5000
persons with dementia exposed to these agents (in
particular this was found in studies of olanzapine,
risperidone and aripiprazole)
12Hermann
N, et al. CNS Drugs 2005;19(2):91-103
Atypical Antipsychotics & Risk of
Serious Adverse Events
• The risk with traditional antipsychotics may be
even higher.13
• Recent meta-analysis of 15 trials (some
unpublished) by Schneider in JAMA14 confirmed
a small increase in death with these agents
compared with placebo. This was significant for
the pooled data but not the individual drug data.
The OR was 1.54
13Gill
S, et al. BMJ 2005;330(7489):445
2005;294(15):1934-1943
14Schneider
LS, et al. JAMA
Recommendations on Use of
Antipsychotic Agents in Dementia
• Have a justifiable use -> severe, distressing
psychotic symptoms e.g. Do not use first-line for
non-psychotic behavioral disturbances.
• Use lowest amounts for shortest possible times
• Caution patients and family about risk but
remember that older agents may be worse, and
there is little data on other psychotropics to
suggest that they are safe.
Treatment of Wandering
• Lock doors (but in a way that is confusing for
AD patient but not others)
• Wander guards
• Decrease agitation (see above)
• Environmental changes (such as using visual
patterns to redirect wandering, wander gardens)
Treatment of Insomnia
• Sleep hygiene (avoid caffeine, etc.)
• Treat causative psychiatric or medical disorders
• Phsysiological remedies - melatonin, warm milk,
lavendar oil
• Medications - Benadryl, benzos, sedating
antidepressants or antipsychotics (all these drugs can
make memory and confusion worse)
• Light Therapy - to reset natural circadian rhythms
for sleep
Sexually Disinhibited Behavior
• Includes: sexual talk, sexual acts, implied sex
acts, false reporting
• Treatment or sexual aggression and/or
disinhibition
– Psychosocial : reminders, move to private room,
clothing modification, staff education
– Pharmacological: SSRIs, antiandrogens
(medroxyprogesterone acetate, cyproterone
acetate), estrogen patches
Wandering Behavior
• 4-26% of dementia patients in Nursing Homes
wander
• If not located within 24 hours, 46% will die
(usually of hypothermia or dehydration)
• TX: Vigilance, wander guards, complicated exits,
reduce agitation
• Safe Return – nationwide identification program
– alert system for law enforcement officials, TV
stations