Dementias (Macintyre)

Question 1

Effect on Health Care

Answer 1

Alzheimer’s Dz now affects some 5 million Americans and 47 million people worldwide. U.S. residents ≥65yo living with Alzheimer’s is expected to nearly triple to 13.8 million by 2050 (est 135 million people living w/dementia by 2050)
Alzheimer’s Dz costs Americans $259 billion/yr. Expected to rise to up to $500 billion/yr by 2040 (sustainable economically??)
USA Today 3/19/2013: 1 out of 3 older adults dies with dementia.
Alzheimer’s deaths increased 68% from 2000-2010. Deaths from Alzheimer’s Dz nearly doubled in last 15 yrs. Alzheimer’s is 1 of 10 leading causes of death in US, 6th leading cause of death in the US, 5th leading cause of death between ages 65-85
NEJM April 2013: Dementia prevalence >70yo = 14.7%.
Washington Post Feb 2015: $1 trillion a year in costs by 2050

But wait…some good news from this year: prevalence of dementia in US fell from 11.6% to 8.8% from yrs 2000-2012 (role of education? Better CVD tx?) and recent research suggest age-specific dementia risk in high-income countries may be declining

Question 2

EPIDEMIOLOGY

Answer 2

Some basic stats:
1.5% >65yo
16-25% >85yo
Nearly 50% >90yo?
50-60% of dementias are Alzheimer’s
15-30% of dementias are Vascular
NCD with Lewy Bodies approximately 20% of all dementias
Remaining dementias:  trauma, neurodegenerative, infectious, nutritional, metabolic, inflammatory, etc.

Question 3

Major

Dementia

Answer 3

• not independent

Significant cognitive decline documented by knowledgeable reporter
Testing confirms significant impairment
Deficits interfere w/ADLs (not independent)
Not due to delirium or other mental d/o

Question 4

Mild dementia

Answer 4

• can be independent

Modest cognitive decline documented by knowledgeable reporter
Testing confirms modest impairment
Deficits do not interfere w/ADLs (is independent)
Not due to delirium or other mental d/o

Question 5

CHARACTERISTICS

Answer 5

Decline in cognitive domains:

• Complex attention
• Executive function (planning, organizing, abstracting, sequencing)
• Learning/memory
• Language
• Perceptual-motor
• Social cognition

Signs: aphasia (language disturbance); agnosia (inability to recognize); apraxia (inability to carry out motor activities)

** Progressive onset, steady course (important way to distinguish from delirium)

No clouding of consciousness (except NCD w/LB)

Question 6

A WORD ABOUT NEUROTRANSMITTERS

Answer 6

Cholinergic neurons are lost through toxic damage or cell death  decreased acetylcholine transmission
In all dementias, avoid anticholinergic meds
Acetylcholine is the major neurotransmitter addressed in dementia
Dopamine may play a role in some dementias

Question 7

TYPICAL PRESENTATION

Answer 7

72yo female is brought to clinic because her family is worried about her. She is increasingly forgetful, leaves the stove on unattended, and wandered away from the house in the middle of the night last week, was very confused, but cleared the next day. She has had one or two “rage attacks” per the family. She is pleasant, cooperative, and states that there is nothing wrong with her but she appreciates her family’s concern.

Question 8

neurocognitive disorders come in 2 flavors

Answer 8

dementia and delirium

Question 9

avoid at all costs

Answer 9

anticholinergics

avoid them in the elderly anyway!

Question 10

MEDICAL WORKUP

Answer 10

* Vital signs
History & Physical
Cognitive testing (MMSE, MOCA)
Labs (Complete blood count, comprehensive metabolic profile, HIV/Syphilis tests, ammonia, thyroid, B12/Folate, Urinalysis, EKG, CXR)
Neuroimaging when indicated

Question 11

DIFFERENTIAL DX on our example lady

Answer 11

Delirium
Pseudodementia
Benign senescent forgetfulness (ie, normal aging)
Medical illness

Question 12

REVERSIBLE DEMENTIAS

Answer 12

10-15% of dementias can be reversed if treated before reversible damage occurs
B12 deficiency, folate deficiency, infections, tumors, subdural hematoma, NPH (normal pressure hydrocephalus)
Focal neurological signs…?

Question 13

MAJOR/MILD NCD DUE TO ALZHEIMER’S DISEASE

Answer 13

Most common cause of dementia
Dx at autopsy
Diffuse atrophy, enlarged ventricles
Fatal usually within 10 yrs
Focal neurological signs usu absent until late (if at all)
Risk factors: Down Syndrome (extra APP), female sex, hx head trauma, lower education level, ApoE alleles
Genetic component (possibly chromosomes 1, 14, 21)
***Apolipoprotein E: ε4 allele increases risk, ApoE ε2 is protective

Question 14

Major NCD due to alzheimer’s disease

* not on exam

Answer 14

NCD criteria met
Probable: evidence of Alz Dz genetic mutation from testing or family hx OR evidence of clear decline in memory/learning & at least 1 other cognitive domain; steady/progressive cognitive decline; and, no evidence of any other cause.
Possible: “Probable” symptoms are not diagnosed

Question 15

mild NCD due to alzheimer’s disease

* not on exam

Answer 15

NCD criteria met
Probable: evidence of genetic mutation or fam hx
Possible: no evidence of genetic mutation + evidence of clear decline in memory/learning & at least 1 other cognitive domain; steady/progressive cognitive decline; and, no evidence of any other cause.

Question 16

Two abnormalities in alzheimer’s

Answer 16

amyloid plaques and neurofibrillary tangles
Plaques: APP (amyloid precursor protein) cleaved improperly to ** amyloid β42

plaques (extracellular)
Tangles: Mostly phosphorylated tau protein folds and accumulates (intracellular)

Both –> neuronal death directly and via inflammatory pathways

Question 17

Behavioral disturbances and alzheimer’s

Answer 17

are common.  Some estimates for the prevalence:
Psychosis 40-60%
Depression 20-40%
Agitation 70-90%
Sundowning  ?%

Treatment of these issues can be difficult (black box warning, elderly population sensitive to side effects, side effects of drug classes, etc)

Question 18

alzheimer’s: Recent research suggests that the disease attacks male & female brains differently

Answer 18

Men
May be younger at dx
May have atypical sx
Dz spreads more quickly and affects behavior, language, motor skills (affects cortical area more)

Women
Spread of dz likely slower
Tends to typically affect hippocampus leading to memory problems

Question 19

alzheimer’s acetylcholine

Answer 19

Acetylcholine transmission impaired

Tx with acetylcholinesterase inhibitors

• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Remiryl)

Note: Pharmacotherapy will not stop the progressive neuronal degeneration

Question 20

prescribing meds on old people

Answer 20

start low, go slow

Question 21

problem with benzos in elderly

Answer 21

greatly increases falls and mortality. NEVER in the elderly!!!

Question 22

MAJOR/MILD VASCULAR NCD

Answer 22

NCD criteria met
Deficit onset relates to a cerebrovascular event & decline prominent in complex attention & frontal/executive fxn
More common in men
More abrupt onset, step-wise decline
Focal neurological signs may be present
Exam may show dysrhythmia (emboli), murmurs, bruits
Important to control risk factors (smoking, BP, glucose, aspirin, etc)
Can try acetylcholinesterase inhibitors

Question 23

MAJOR/MILD FRONTOTEMPORAL NCD

Answer 23

NCD criteria met
Insidious onset/gradual progression w/2 variants:
– Behavioral (disinhibited, apathetic, dramatic personality changes, ritualized bx, hyperoral, decline in social/executive fxn)
– Language (production, naming, grammar, etc)
Be sure that stroke is ruled out
Atrophy of frontal & temporal lobes

More common in men, roughly 5% of dementias
Overreaction

** Earlier onset, usu in 50s (a way to distinguish it from alzheimer’s)

Can try acetylcholinesterase inhibitors (or mood stabilizers to target aggression)

Question 24

MAJOR/MILD NCD WITH LEWY BODIES

Answer 24

NCD criteria met
Lewy inclusion bodies (intraneuronal protein aggregates, mostly α-synuclein) –> cell death

Difficult to distinguish, overlap with other dementias especially PD

Psychosis (esp visual hallucinations); parkinsonian features; occasional fluctuating mental function can mimic delirium and confound dx

Paradoxical antipsychotic tx reaction (psychosis and ↑ side efx); consider acetylcholinesterase inhibitor

Question 25

MAJOR/MILD NCD DUE TO PRION DISEASE

Answer 25

For example, Creutzfeld-Jakob Disease
NCD criteria met
Rapid onset/course
Motor features of prion dz (clonus, ataxia, biomarker evidence)
** Triphasic waves on EEG for CJD (“waves of three, CJD”)
Tx supportive
Fatal

Question 26

MAJOR/MILD NCD DUE TO TBI

Answer 26

NCD criteria met along w/evidence of TBI as causative agent
Consider things such as Chronic Traumatic Encephalopathy, can be marked by impulsivity, dysarthria, and emotional lability
Tx with acetylcholinesterase inhibitors, valproic acid, SSRI.
Avoid anticholinergics

Question 27

NCD Due to Huntington’s Disease

Answer 27

AD, 50% inheritance

** CAG trinucleotide repeat –> mutant protein –> neuronal death

Abulia, psychomotor slowing

Complex tasks first, memory/language later

Motor abnormalities (chorea)

Mood disturbances and/or psychosis is common

Tx: antipsychotics, acetylcholinesterase inhibitors, mood stabilizers, SSRI

Question 28

NCD Due to Parkinson’s Disease

Answer 28

α-synuclein or tau protein in substantia nigra; Lewy Body involvement common
20-30% of those with PD develop dementia (maybe as high as 60%?)
Psychomotor slowing
Tx of PD symptoms (ie, dopaminergic agents) can cause psychosis; tx can be difficult but Nuplazid is showing promise
Distinguish from NCD w/Lewy Body by time frame (NCD PD requires cognitive decline ≥1 yr dx of PD)

Question 29

Substance/Medication-Induced NCD

Answer 29

Impairments exist after intoxication/withdrawal

Substance is capable of producing the decline (eg, solvent)

Question 30

NCD Due to Another Medical Condition (eg, MS)

Answer 30

Lesions

Language and verbal intelligence can be less affected

Question 31

NCD Due to HIV Infection

Answer 31

HIV-infected macrophages  neurotoxicity
≤30% of HIV+ pts develop dementia, higher in AIDS
Early, aggressive tx lowers chance; presence of dementia risks HIV tx compliance

Question 32

A WORD ABOUT PSYCHOSOCIAL SUPPORT

Answer 32

Become familiar with dementia care referrals
Talk to family about increased care levels, driving privileges, general safety (stoves, etc.), advance directives
Remember the caregivers and respite care

Question 33

75yo female w/DM, HTN, both of which have been poorly controlled. Her husband says she asks him the same questions over and over and can’t remember answers. She has forgotten how to make coffee and has difficulty operating the remote control and even the sink sometimes. Husband states she didn’t recognize one of her grandchildren recently. He says things have gradually been growing worse ever since she had a stroke 2 yrs ago. She is, at times, anxious about her confusion and was started on “some anxiety pill,” that “turned her into a zombie,” according to the husband.

Husband gives you a list of her medications, which are numerous.  Eliminating which class of medications might help improve cognition?
A)  Acetylcholinesterase inhibitors
B)  Anticholinergics
C)  Antibiotics
D)  Benzodiazepines
E)  B and D

Answer 33

E) B and D

Question 34

You examine Marjorie and find that she has poor general strength, is slow to process, and shows no emotion whatsoever.  She has slightly diminished reflexes on the L side of her body and is slow to start and complete any movement, especially standing and walking.  She has difficulty repeating phrases and saying the word “Christmas.”  A likely origin of her presentation might be:
A)  Frontotemporal NCD
B)  NCD due to Parkinson’s Disease 
C)  Vascular NCD
D)  Normal pressure hydrocephalus
E)  B and/or C

Answer 34

E) B and/or C