dementia
A brief overview of diagnosis and treatment
Amy Sanders MD
Assistant Professor of Neurology
Einstein Aging Study
Einstein-Montefiore Brain Aging Center
Albert Einstein College of Medicine
Coming Up
•
•
•
•
•
Dementia: definitions
Dementia: evaluation
Dementia: subtypes
Alzheimer’s Disease: diagnosis and Rx
Other Dementia Subtypes: diagnosis and Rx
Hebert LE, Arch Neurol 2003
13.2
million
7.7
million
4.5
million
2000
2030
2050
• What is
dementia?
A species of insanity characterized by failure
or loss of the mental powers…….
• A syndrome defined by a non-acute decline
in cognition that interferes with functioning
in everyday living
Multiple cognitive deficits, including MEMORY
IMPAIRMENT and at least one of
- aphasia (language impairment)
- apraxia (impaired motor activity)
- agnosia (impaired recognition)
- executive function disturbance (planning)
Disturbance interferes significantly with work
or usual social activities/relationships [“ADLs”]
WHAT IS DEMENTIA?
Memory
loss
Problem solving
Judgment
Social skills
Language
MORE THAN 6 MONTHS
NO
NO
Diagnostic Procedures
? LABS
?IMAGING
?LP
?EEG
?GENETIC TESTING
Laboratory Tests
•
•
•
•
AAN Guideline:
AAN Guideline:
AAN Guideline:
Other labs:
B12, thyroid function
maybe syphilis serology
depression screening
CBC, basic chemistry,
LFTs, parathyroid
Imaging
• Structural Neuroimaging: CT, MRI
• Volumetrics: labor-intensive, research
• PET: adjunctive, AD vs FTD
• Amyoid imaging: PIB, research
Pittsburgh compound B
Klunk, et al. Ann Neurol 2004
Active research: biomarkers
EEG: non specific
GENETICS
• Not currently recommended for routine clinical
diagnosis
• Complex genetics for late-onset AD
• APOE ε4 allele: susceptibility gene for AD
• Progranulin mutations: FTD
Medication Review
• MANY medications may worsen cognition
–
–
–
–
–
–
–
Some anti-hypertensives (ß-blockers, CCBs)
Anti-cholinergics
Prednisone
Digitalis
Opiates/narcotic analgesics
Benzodiazepines
Even NSAIDS
DEMENTIA SUBTYPES
ALZEIMER’S DISEASE
• Age-related neurodegenerative disease associated
with cognitive decline
• Memory, judgment, language
• Behavior and mood
• Pathology: deposition of amyloid (plaques) and
hyperphosphorylation of tau (NF tangles)
• Neuronal cell death and impaired neuronal
function
• ? Complex Genetics, vascular risk factors,
Oxidative Stress, inflammation, hormones?
Struldbrugg – race of immortals who “turn to
dotage and entirely lose their memories…”
Impaired memory, aphasia, erratic behaviour,
paranoia and auditory hallucinations
Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde.
Allgemeine Zeitschrift fuer Psychiatrie 1907; 64:146–8.
K. Maurer, S. Volk, H. Gerbaldo. Auguste D and Alzheimer's
disease. Lancet 1997; 349: 1546-1549
Why is AD Important?
• Incidence rising—longer lifespans
• Most common neurodegenerative disease
• Most common illness leading to nursing
home placement
• $156 billion worldwide cost in 2003
• Treatment available
• Long-term planning (HCP, long-term care)
a new . . . GREAT SUCKING SOUND
Alzheimer’s Disease
• NINCDS-ADRDA criteria (probable AD)
• Dementia - established by clinical exam,
documented by screening tests
confirmed by neuropsych tests
• Deficits in 2 or more areas of cognition
• Progressive worsening of memory/cognition
• No disturbance of consciousness
• onset 40-90 years, usually > 65y
• Absence of other systemic/brain disorders
Ten Warning Signs – Alzheimer Association
• Memory loss that affects job skills.
• Difficulty performing familiar tasks.
• Misplacing things.
• Problems with language.
• Disorientation to time and place.
• Poor or decreased judgment.
• Problems with abstract thinking.
• Changes in mood or behavior.
• Changes in personality.
• Loss of initiative.
Memory
Non-memory
Abnormal behaviors & AD
Symptom
Calculation defect
Language
Irritability
Gait disorder
Wandering
Sleep disorder
Violence
Incontinence
Months after memory
25
31
39
47
50
51
64
67
Folstein & Bylsma,1999
AD: presentation
• Helpful to have informant
• Insidious onset of short-term memory
complaint
• Trouble with names, word-finding difficulty
• Getting lost, forgetting parking location
• Trouble calculating – e.g. tips, checkbook
• Planning – recipes, trip planning
AD: behavioral components
•
•
•
•
•
Apathy – loss of initiative
Depressive symptoms – up to 30%
Anxiety
Paranoia, delusions – later stage disease
Agitation – late disease
AD: Treatment
• Treat the disease: pharm and nonpharm
• Treat the collateral sx – behavior, mood
• Take care of the caregiver
-respite
-health lit
AD Pharmacotherapy
• Cholinesterase inhibitors
-donepezil (Aricept)
-galantamine (Razadyne [reminyl])
-rivastigmine (Exelon)
• NMDA receptor antagonist
– Memantine (Namenda)
– Moderate to severe AD, may be additive
Pointers
• Discussion with patient/family: expectations
• Start low and titrate: for all AChI
• Most common side effects: GI (N/V/D)
• Can switch agents
• Withdraw when no longer benefitting or no longer
able to interact with family members
Donepezil
• 5 mg qd starting dose (minimum therapeutic dose)
• With or without food, take in a.m.
• Increase to 10 mg after 4-6 weeks
• Half life 70 hours, hepatic metabolism
Galantamine
–
–
–
–
–
–
Start at 8 mg qd (minimum therapeutic = 16 mg)
Take with food (full meal)
Increase to 16 mg after 4 weeks
24 mg is maximum dose
Most common side effect: GI
If treatment interrupted for more than 1 week, restart at 8 mg and repeat titration
– Half-life 7 hours, hepatic metabolism
Rivastigmine
–
–
–
–
–
–
Start at 1.5 mg BID (minimum therapeutic = 6 mg)
Take with food (full meal) for both doses
Stepwise increase monthly (1.5, 3, 4.5, 6 mg)
12 mg (6 mg BID) is maximum dose
Most common side effect: GI
If treatment interrupted for more than 1 week, re-start at
1.5 mg BIDand repeat titration
– Half-life 90 minutes, renal clearance
Memantine
–
–
–
–
–
–
Start at 5 mg qd
Take with or without food
Stepwise increase weekly by 5 mg
20 mg (10 mg BID) is maximum dose
Side effects fewer than with AChI (dizzy, HA)
Half-life 70 hours, partial hepatic clearance
Pharmacologic Treatment of
Behavioral Symptoms
•
•
•
•
•
NOT FIRST LINE
Complicated; generally off-label
Rule out other causes
Start low, go slow. Briefest use possible.
Agitation: atypical neuroleptics, anticonvulsants,
benzodiazepines
• Depression: SSRIs, S-NE RI, other
• Insomnia: trazodone, alprazolam, zolpidem,
ramelteon (may cause carryover sedation)
Vascular Dementia
• 2nd-most common subtype
• May be present even in cases
without prominent memory loss
• Executive function often
predominates
• Vascular risk factors
• Gait dysfunction
Diffuse
Lacunes
Multi-infarct
Chui, Arch Neurol, 2000
Variations on the Theme
• “stroke” dementia
• Subcortical pattern: lacunes, severe WMD
• CADISIL
• Often “mixed” with AD
VaD Treatment
•
•
•
•
No targeted pharmacologic therapy
Modification of vascular risk factors
Aspirin used anecdotally
Symptomatic treatment of affective
symptoms
Dementia with
Lewy Bodies
Central Feature: dementia is ESSENTIAL
Core Features:
Parkinsonism (spontaneous)
Visual hallucinations-recurrent, vivid/detailed
Fluctuations-attention and alertness especially
Suggestive Features:
Severe neuroleptic sensitivity -- worsening
REM sleep disorder -- acting out dreams
Low dopamine transporter uptake in BG (SPECT/PET)
McKeith, Neurology, 2005
DLB Treatment
• COMPLICATED
–
–
–
–
Parkinsonism
Cognition and fluctuations
Hallucinations, psychosis, agitation
REM sleep behavior disorder
“The cold within him froze his old features ... and stiffened his
gait.”
“…vivid and detailed hallucinations featuring friends and relatives
are common. And like Scrooge’s visions, these phantasms are
distressing, often terrifying. Finally, in Lewy body dementia,
hallucinations occur early in the disease, frequently before the
cognitive deficits are apparent.”
Sanders, “Diagnosing with Dickens,”
Sunday NYT Magazine 12/17/06
Frontotemporal dementias
Core
•
•
•
•
•
insidious onset, gradual progression
Early decline in social skills
Early decline in regulation of personal conduct
Early emotional blunting
Early loss of insight
Supportive
Behavioral disorder
Speech and language disturbances
Physical signs – frontal signs, parkinsonism, labile BP
Investigations: neuropsychology, EEG, MRI
Neary, Neurology, 1998
Initial-Carving
Doctor Banned
'Dr. Zorro' Blamed
Brain Disorder for
Scarring Patient
FTD Treatment
•
•
•
•
•
Few options
AChI not effective, may cause agitation
Perhaps some role for SSRIs
Safety assessment
Depression common in caregivers and can
be a reason for earlier nursing home
placement