B&B 8 Aging, Dementia, Sleep Flashcards Preview

Brain & Behavior > B&B 8 Aging, Dementia, Sleep > Flashcards

Flashcards in B&B 8 Aging, Dementia, Sleep Deck (151):
1

What is cognition?

What makes you YOU

2

Episodic Memory

• Forgets events
• repeats stories, questions
• loses objects frequently
• miss appts
• disoriented

This is what describes Alzheimers Disease
(hippocampus shrivels up and shrinks)

3

Agnosia

Failure to recognize objects or faces

4

An individual seems to have no filter and is saying things that he is saying without any restraint. This individual has lost the ability to filter what they are saying.

What is the lesion?

Orbitofrontal Cortex

5

►Orbitofrontal Cortex

►Insular Cortex

►Social Cognition

►Anterior Cingulate

►Orbitofrontal Cortex
– repsonse inhibition

►Insular Cortex
– emotion, language
– Autonamic fucntion

►Social Cognition
– Motivation, empathy
– Inhibition (appetite, prepotent responses)

►Anterior Cingulate
– drive
– motivation

6

Neuroanatomy Overview

►BASAL GANGLIA – MOVEMENT (Parkinsoniam, Dystonia, Chorea)
– caudate
– putamen
– globus pallidus
– subthalmic nuclei
– substantia nigra

►BRAINSTEM
– dysarthria
– dysphagia
– diplopia
– dizziness
– nausea / vomting
►CEREBELLUS
– ataxia, gait, speech

►PNS

7

Dementia

• gradual, progressive, permanent loss of intellectual faculties
• memory impairment and at least one of the following: aphasia, apraxia, agnosia or executive dysfunction.
• Impaired cognition (multiple domains)
• Impaired function
• Not related to a medical condition/medication
• Decline from previous function
• Not related to learning disability
• interferes with social or occupational function.

8

Dementia

What medical conditions cause it?

• Alzheimer’s Disease
• Vascular Disease
• Lewy Body Dementia
• Frontotemporal Dementia
• Parkinson’s Disease Dementia
• Huntington’s Disease

9

Dementia

Misfolded proteins

Lewy Bodies
– abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease

10

Delirium

What are characteristics?

• Acute onset
• Fluctuating course
• Inattention
• Cognitive Impairment
• Perceptual Abnormalities
• “Crazy Hospital Inpatients”

11

What are the bedside cognitive tests?

Tests of Attention
MMSE
MoCA

12

Attention / Working Memory

What are examples of how we test it?

Digit Span
(count forwards by 6)

Spell "WORLD" backwards

13

MMSE

...vs...

MOCA

NOTE: These tests are cross-sectional only. They do not enable us to differintiate between Dementia and Delirium.

MMSE
< 24/30 = dementia
• Reproducible
• Gives us a easy answer
• quick screen
• useful once we have definite cognitive decline

MOCA
< 26/30 = dementia
• tasks are more complicated
• more sensitive test
• stresses the mind more
• score reflects severity
• better for picking up mild cognitive function (recall 5 words, not just 3)
• 3 different versions available
• available in different languages
• useful at picking up mild cognitive impairment
• involves clock drawing

14

Short Term Memory

Give me 3 words!

Apple, Table, Penny

Ball, Chair, Man

15

What is being examined in these neurological tests?

What is this (holding up pen)?
...or...
White a sentence

Intact Language Function
• Primary Auditory Cortex
• Wrenches' Area
• Broca's Area

16

Delirium

MYTH: Delirium is a cross-sectional diagnosis

What is the reality?

Requires 24 hour observation

17

Delirium

MYTH: Delirium leads to agitation and
behaviour problems

What is the reality?

Watch for “Apathetic” (hypoactive) Delirium

18

Delirium

MYTH: Delirium always has an identifiable
cause

What is the reality?

May not find a single cause

MULTIPLE factors with geriatric delirium

19

Delirium

MYTH: Delirium is a transient phenomenon

What is the reality?

May persist or lead to permanent cognitive and/or functional sequelae in elderly

20

Delirium

DSM5 Criteria
(part 1)

A. A disturbance in attention (ie: reduced ability to direct, focus, sustain, or shift attention) and awareness (reduced orientation to the environment).

B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.

C. An additional disturbance in cognition (eg: memory, orientation, language, visual-spatial, perception)

21

Delirium

DSM5 Criteria
(more ... part 2)

D. The disturbances in A and C are not better explained by another pre-existing, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma.

E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequences of another general medical condition, substance intoxication or withdrawal, or exposure to toxin, or is due to multiple etiologies.

22

Delirium

What is the prognosis?

Not good for the majority of elderly patients who develop it

23

Delirium Subtypes

►Hyperactive (agitated)
– Differentiate from anxiety
– Differentiate from dementia

►Hypoactive (apathetic)
– Differentiate from depression
– Less sleep-wake reversal
– under-recognized because these folks are just thought to have dementia &/or bad eyesight

24

Subtle Signs of Delirium in Elderly

(these were smaller things before someone possibly progresses to the full blown syndrome)

• 24 hr. observation, including sleep-wake cycle
• anxiety
• new incontinence
• unsteady gait, falls
• dysarthria/incoherence
• mood/affect lability
• subtle paranoia and hypervigilance
• sleep disturbance

TIP: Ask specifically about vivid dreams or nightmares!
"Was there anything that you saw or heard that perhaps other didn't?"

25

Once resolved, how do people recall the delirium season?

• Most do NOT remember it
• Or, they might recall it as a bad dream or distressing experience.
• May lead to anxiety, paranoia, and even PTSD

26

How do we screen for Delirium?

CAM
Cognitive Assessment Method

►Acute onset and fluctuation
... AND...
►Inattention
... AND...
►Disorganized thinking
... OR...
►Altered LOC

Excellent sensitivity, good specificity

27

Delirium
What are current hypotheses of pathogenesis?

• Oxygen deprivation
• Neurotransmitter dysfunction
• Systemic Inflammation and cytokines
• Physiologic stress: BBB and HPA

28

What does EEG show in pts with Delirium?

(Electro-encephalographic)

►Decreased Alpha (fast) waves
►Increased Slow waves
– Theta (4-7 Hz)
– Delta (<4 Hz)

29

What is a DT?

Delirium Tremens
"Alcohol withdrawal Delirium"

• Increased cerebral metabolism
• HUGE increased noradrenergic / sympathetic response
• EEG: low to moderate voltage fast activity

30

What percentage of in-patients have delirium?

about 20%

31

What is our theory of Neurotransmitter status in Delirium?

►Anticholinergics
– Ach (eg: atropine) can induce delirium and can slow EEG
– Reversed by physostigmine (experimental)

►Dopamine (DA)
– Dopamine agonists can induce (eg: L-Dopa) 
– Antipsychotics can treat

►Noradrenaline (NE)
– increased

32

What is a DT?

Delirium Tremens
"Alcohol withdrawal Delirium"

• Increased cerebral metabolism
• HUGE increased noradrenergic / sympathetic response
• EEG: low to moderate voltage fast activity

33

DT

What are possible clinical features?

Two (or more) features developing within
several hours to a few days:

• Autonomic hyperactivity
• Increased hand tremor
• Insomnia
• Nausea or vomiting
• Transient hallucinations or illusions
• Psychomotor agitation
• Anxiety
• Grand mal seizures

Tx: Benzos

WATCH FOR CONCURRENT MEDICAL ILLNESS

34

How do we treat DT?

DT: Benzos

However, normally we treat Delirium with Anti-psychotics (Dopamine Blocker)

35

Alcohol Withdrawal

What is the correct sequence of events?

►12-24 hours
withdrawal Sx

►24-48 hours
seizures

►72-96 hours
delirium tremens (DT)

36

Differentiating the 3 Ds

Onset

►Delirium
Sudden, abrupt

►Dementia
Slow, insidious

►Depression
Abrupt or slow,
stressors

37

Differentiating the 3 Ds

Attention

►Delirium
Impaired or fluctuates

►Dementia
Usually intact

►Depression
Usually intact, concentration may diminish

38

Differentiating the 3 Ds

Perception

►Delirium
Illusions, visual hallucinations

►Dementia
May have hallucinations

►Depression
Illusions and hallucinations uncommon

39

Differentiating the 3 Ds

Insight

►Delirium
May be present when lucid

►Dementia
Often absent

►Depression
Often present

40

Differentiating the 3 Ds

Duration of illness

►Delirium
Hours to weeks

►Dementia
Months to years

►Depression
At least 2 weeks duration

41

4 P's of Delirium

Predisposing
Precipitating
Perpetuating
Protective/Preventive

42

What are predisposing factors to Delirium?

• cognitive impairment
• sleep deprivation
• immobility
• visual impairment
• hearing impairment
• Dehydration

TIP: Ask about use of visual and hearing aids! Carry a voice amplifier

43

Delirium

DDx

DIMS-R

DRUGS
• Prescribed (narcotics, steroids, anticholingergic, NSAIDs)
• OTC (dimenhydrinate, diphenhydramine)
• Drug Intoxication or Withdrawal

INFECTION
• UTI, Lungs, Skin, Blood

METABOLIC DISTRUBANCES
• Fluid (dehydration, hypovolemia)
• Electrolytes (Na, K, Mg)
• Nutrition (malnutrition, thiamine def, anemia)

STRUCTURAL INSULTS
• CV (angina, MI, CHF)
• CNS (stroke, Ischemia, Concussion)
• Pulm (Hypoxia, COPD exacerbation)
• GI (bleeding, C diff, colitis)

RETENTION PROBLEMS
• urinary retention
• stool impaction

44

What is the effect of physical restraint on an individual?

Physical restraints increase risk of developing delirium by 4.4x

Avoid limb or posey restraints in the frail elderly!

45

Severity of Delirium Predicted by 6 Factors

• Absence of reading glasses

• Absence of aids to orientation

• Absence of family member

• Absence of glass of water (dehydration!)

• Presence of bed rails and other restraints....

• Prescription of two or more new medications

46

From our Delirium Lecture ...

What are the practical tips?

► Ask specifically about vivid dreams or nightmares!

► Ask about use of visual and hearing aids! Optimize sensory input. Carry a voice amplifier.

► Check for urinary retention with a bladder scanner!

47

From our Delirium Lecture ...

What are potential pitfalls?


►Restraints are necessary to prevent morbidity such as falls, and help with managing delirious pts.

►Delirium is reversed quickly once physical factors addressed

48

Dementia

Who gets it?

1/11 Canadians over 65
(1/3 over 85)

Estimated lifetime risk = 10-12%

49

What is the average time between diagnosis and death of a patient with Alzheimers

8-9 yrs

50

Early AD
...vs...
Late AD

Early:
• Before the age of 65

Late:
• After 65

51

Dementia

What IS it?

Dementia
• umbrella term for set of Sx

>70 different causes of dementia
(Alzheimers is 1 of those 70!)

52

Dementia

What are the 4 most common causes?

4 most common causes:
• AD (~66% of cases)
• Vascular dementia (~10-20% of cases)
• Lewy Body dementia (~10-20% of cases)
• Frontotemporal dementia (~5-15% of cases)

53

What is the hallmark finding of Alzheimer's Disease?

“Plaques and Tangles”

►Plaques
– Protein: Amyloid Accumulation of β amyloid plaques ("Aβ proteins")

►Tangles
– Neurofibrillary tangles of tau protein

54

Dementia

How do we diagnose it?

Diagnosis of Exclusion
– must rule out everything else
– maybe in the future we will have PET scans that are able to detect amyloid deposits ... stay tuned ...

The only way we can determine if it was Alzheimers is to perform an autospsy. The brain is "shrunk" and there is “Plaques and Tangles”

55

Dementia

What causes it?

There is no single gene!
Multifactoral
Aging is the single greatest risk factor for developing AD (however, we do see sporadic AD in younger pts)
Combination of environment & genetic predispiostion

56

Who gets Sporadic AD?

6-8% of developing Sporadic AD

If you have a relative with it, there is a greater risk of getting Sporadic AD (about 15-30%)

57

What gene is associated with familial AD?

APOE gene
(same as Chol!)

3 alleles:
– APOE2
– APOE3 - most common!
– APOE4 - binds to Aß and traps it

APOE4 = high risk allele for sporadic AD
• heterozygotes – 3x population risk
• homozygotes – 8x population risk*

58

Patient wants to know about their APOE status

Do we screen?

We do not screen for it. You can live your whole life with 2 copies of APOE4 and NEVER get sporadic AD.

Likewise, people who have no APOE4 alleles can get AD.

It is NOT clinically recommended. People can go and over a test privately. However, we don't recommend it. There are limitations to the test.

Bottom line: Poor sens & spec

59

How CAN we prevent AD?

►mental stimulation

►vascular health
– exercise
– diet
– hypertension
– high cholesterol
– diabetes

►head injury (just one thing among a sea of many that may add to risk.

►mood disorders/stress → manage it!

Vitamins/herbal remedies: no research ... can certainly take it if no clear

60

Patient comes in concerned. She wonders if she will get AD since her mother had it (passed away recently)

What can we do for her?

►recurrence risk estimates based on empiric data:
– 15-30% if mother had sporadic AD

►genetic testing for APOE status not recommended, but available

►review environmental risk factors implicated in sporadic AD

►autopsy arrangements/DNA-banking for living affected relatives

►baseline cognitive assessment

61

Family comes in and wants to know if the child will get AD one day. Grandpa and dad both had it.

What is the risk?

Risk is 15-30%
(increased since two generations affected)

Bottom line: the more family members affected, the greater the risk.

62

Familial Alzheimer's Disease

(very Rare!)

• 5-25% of all AD cases
• clinically indistinguishable from sporadic AD
• can be early- or late-onset

NOTE: Age-of-onset does not determine genetic etiology!
(only 13% of early-onset AD cases display familial AD pattern of inheritance*)

63

Familial Alzheimer's Disease

What are the genes involved?

3 causative familial AD genes identified to date:

►Presenilin 1 (PS1)
(chromosome 14)

►Presenilin 2 (PS2)
(chromosome 1)

►Amyloid precursor protein (APP)
(chromosome 21 - Down's Syndrome)

These genes are ONLY associated with early-AD.

64

Familial AD

Family wants to know risks and inquires about genetic testing. What can be done?

OPTION 1:
Research testing available at U of T
• strict inclusion criteria
• no cost
• turn around time = ~12 months

OPTION 2:
• clinical labs in US
• must be ordered by a physician
• ~$2500 for all three genes (not covered by MSP)

65

Familial AD

Bottom line:

Genetic testing for familial AD:

►relevant only if early-onset familial AD

►initiate testing process with DNA sample from an affected individual (i.e. diagnostic testing)
• negative test result → does not rule out possibility of familial AD
• positive test result → confirms familial AD diagnosis

►option of predictive genetic testing for at-risk family members

66

Alzheimer's Disease

Summary

• not all dementia is AD

• AD most often occurs as a sporadic condition with multifactorial etiology; familial AD is rare

• genetic testing for AD is not relevant in most cases

67

Clinical Neuropsychology (NP)

What is it?

• An applied neuroscience concerned with identifying the nature of brain-behavior abnormalities

• Involves standardized cognitive tests to address diagnosis, planning and treatment for neurocognitive issues

• May be used to correlate cognitive function with neuro-imaging (etc. to aid diagnostics_

• NP determines degree of impairment relative to age/educ norms, to factor out such variables

• NP has greater sensitivity to mild deficits relative to screens (MMSE/3MS)

68

Early Alzheimer’s Disease

Typical Cognitive Profile ...

►Greatest relative impairment is in memory (& is often one of the earliest complaints)

►May show early evidence of expressive language deficits (naming, verbal fluency)

►Complex executive functions may also be affected in early AD (i.e., frontal variants)

►Visuo-spatial skills and attention are typically relatively preserved very early in disease process

69

"I went to the hospital and had a sleep study done."

WHAT is this?

Polysomnogram (PSG)
►EEG [electroencephalogram]
– leads on scalp

►EMG [submentalis, ant. tibialis]

70

Can we test for Sleep Apnea with a finger oximeter?

NO!

Pulse Oximeter on finger is NOT an acceptable diagnostic modality of sleep apnea!

71

What is the relationship between depth of sleep and muscle tone?

Muscle tone decreases with depth of sleep

The least muscle tone is during REM A persion should be paralyzed during REM! If you are not paralyzed during REM, you will actually act out dreams.

72

Elderly patient comes in and complains that they had better sleep when they were younger. Used to sleep 8 hours straight but now only gets about 6 hours even though in bed for 9 hours.

How to respond?

Reassure patient. Sleep need decreases with age. This is likely is the new NORMAL for patient.

Elderly people ...
– spend long periods of time in quiet rest.
– exercise less than they did when younger.
– sleep may be more fragmented
– have decreased number of EM's in REM

NOTE: Once you start napping during day it is harder to consolidate sleep at night.



73

Stages of Sleep

►Stage 1
– light sleep, transitional change
– When increased, indicates sleep disruption

►Stage 2
– 50% of night

►Stage 3
– Deep Sleep
– 15-20% of night
– most restorative
– can be reduced by Benzos
– enhanced by Zopiclone

►REM Sleep
– Different from other phases
– Dream sleep
● Phasic - EMs, twitches, variable autonomic activity
● Tonic - muscles are relaxed, penile tumescence

74

When do the stages of sleep occur?

Enter REM at about 90 min into sleep and then keep cycling in and out of REM sleep

75

What is a Hypnogram?

Compression of all sleep stages across night

76

When does Sleep Apnea occur?

Often the worst during REM sleep because this is when muscles are most relaxed.

77

Insomnia

def

Insomnia

difficulty getting to sleep
...or..
difficulty maintaining sleep

78

What is the relationship between sleep and age?

Teenagers have a delayed sleep phase
– Evolutionary Advantage?

Elderly tend to want to go to bed earlier and walk up earlier

79

Patient wants to stay up later in evening. How to counsel them?

Increased bright light in evening → increases Melatonin secretion from Pineal Gland.

80

Sleep Apnea

Types

►Obstructive Sleep Apnea (OSA)
– apnea cessation of airflow for at least 10 sec
– due to collapsing of airway
– blocked upper airway
– site of obstruction is base of tongue
– thick neck or enlargement of tonsils can contribute (>16" in women; >17" in men)

►Central Sleep Apnea
– brain not telling body to breathe
– chest and abdomen are trying to move

►Mixed Sleep Apnea

81

OSA

Sx

82

Kids with sleep apnea were found to have what disorder?

Possibilities:
– ADHD
– Huge tonsils

83

What system do we use for assessing airway?

Mallampati Classification

Class 1 - best!
Class 4 - least room!

84

What's the problem with Benzos & Sleep Apnea?

Benzos further suppress muscles required for respiration

85

What makes OSA worse in patients?

Opioids
Cardiac Disease
Stroke

86

Restless Leg Syndrome (RLS)

Essential Features
►urge to move the limbs often associated with paresthesias or dysesthesias (“painful” in 50%)
►Sx worse or present only during rest
►Sx partially or temporarily relieved by activity

87

RLS

Dx?

Dx usually make clinically

... but MUST be confirmed through the Standardized Immobilization Test (SIT)

88

RLS

Tx?

• response to dopaminergic therapy in almost all cases (but can become less effective over time and need dosage increase)
• PLM’s occur during sleep or wakefulness in 80-90% of patients
• usually progressive with age
• no clear medical/physical pathology (primary form)

89

RLS

What are Secondary Causes

• pregnancy (dilutional anemia due to more fluid being on board)

• End stage Renal Disease

• Iron Def. → Check Ferritin! (Iron is involved in synthesis of Dopamine

90

RLS

Tx

►Treat underlying cause (Ferritin?)

►MEDS:
– Gabapentin, Pregabalin
– Dpamine Agonists
– Clonazepam
– Opioids in VERY severe cases

91

Periodic Limb Movement Disorder
(PLMD)

What is it?

When and how to treat it?

Abnormal excessive limb movement

There must be a clinical sleep disturbance for us to actually treat it

Tx: same as RLS

92

REM Sleep Behaviour Disorder
(RSBD)

Essential Features
►presence of REM sleep without atonia (the person is moving when they should be paralyzed!)

►At least one of the following is present:
– sleep related injurious, potentially hazardous,
or disruptive behaviors by history
– abnormal REM sleep behaviors documented during PSG (polysomnogram)

►absence of EEG epileptiform activity during
REM sleep

93

RSBD

Features

• injury is common secondary to violent dream
enactment
• episode ends when individual awakens quickly, becomes alert, and reports the dream
• sleepwalking is uncommon
• dream enactment typically occurs at least 90 min
after sleep initiation
• may have prodrome of sleep talking, yelling, twitching
• patients often present after injury to self or bed
partner

94

RSMB

Who get is it?

• Males predominate

• usual onset after age 50

• 0.5% prevalence in elderly (about 2/3 of these pts will go on to develop further deterioration of the brain → Parkinsons or Lewy Body Dementia)

• 1/3 of patients with diagnosed Parkinson’s have RSBD

• 90% of patients with Multiple System Atrophy have RSBD

95

Narcolepsy

aka "hypnolepsy"

chronic neurological disorder involving the loss of the brain's ability to regulate sleep-wake cycles normally

Pts experience frequent excessive daytime sleepiness

96

RSMB

What can cause it?

Tx?

medication withdrawal

Best Tx:
► Clonazepam: prevents most cases of violent dream enactment

► Melatonin (mystery!)
– beneficial effects for shift workers and jet lag
– not clinically very potent
– Best way to use it: 1mg 12 hrs before planning to wake up
– works for some people, if so, use it!
– effectiveness may decrease over long term use

97

With Geriatrics in general, what is the Mantra for Medications?

Start low, go slow!

98

Meds for Sleep

Zopiclone
• "Benzo-like"

Doxepin (Silenor)
• sleep medication
• great safety profile
• good studies for use in elderly
• just released within past year in Canada

99

Rebound Insomnia

What is it?

Taking Zopilcone every night for some time and then stopping will actually make the Insomnia worse

Must taper off slowly.

100

Are naps ok?

Naps are great if you are unable to get enough sleep and night and you don't have insomnia

Naps are really only a problem for those who already have insomnia and lose their drive to sleep as a result of the napping

101

In the family practice setting, what is another non-pharmacological treatment option?

►CBT
• set restrictions on sleep. For example, get out of bed no later than 8am and don't go to bed until tired. If is still doesn't work, narrow the sleep window even more

►Excellent book: "Say Goodnight to Insomnia"
The Six-Week, Drug-Free Program Developed At Harvard Medical School
$14 off Amazon

102

What is the number 1 cost to health care system?

Dementia
• requirement for high levels of care that costs extraordinary amounts of money

103

Causes of Dementia

primary neuro-degenerative disease is the MOST common, but the others must be ruled out!

►primary neuro-degenerative disease
►cerebro-vascular disease
►infectious/inflammatory disease
►toxic disorders
►metabolic disorders
►endocrine abnormalities
►structural lesions
►trauma

104

Alois Alzheimer was a German psychiatrist who described a 56 year-old woman who died of progressive dementia in 1907.

On autopsy, what did he find in the post mortem brain?

FOUND IN CEREBRAL CORTEX

►neurofibrillary tangles
...and ...
►senile plaques
(dystrophic neurites are related)

105

What is the role of neuro-imaging in workup for AD?

►Examine atrophy of brain
– narrow gyri
– wide suclus
– shrinkage of cerebral tissue
– cerebellum is spared
– ventricles are enlarged

►Also to rule out other pathology

106

senile plaques

Describe them

(1) extracellular deposit of protein in brain tissue

(2) black linear structures - dystrophic neurites (dendrites & axons that have become abnormal

107

Amyloid Deposits

Where do they deposit?

in senile plaques

in blood vessels

Amyloid is a extracellular protein

108

What is the Aß protein?

– small peptide

– major constituent of amyloid deposits in AD; senile plaques and Congophilic angiopathy.

– abnormal (minor) metabolite of normal cellular protein; amyloid precursor protein (APP).

– occurs ONLY in brain

– We are all generating some measure of the AB protein. Whether or not it will accumulate and progness to AD, is much more complicated.

109

What is APP?

Amyloid Precursor Protein
– encoded by chr 21
– family of membrane inserted glycoproteins
– expressed by neurons and other cells
– function unknown
– highly concentrated in areas where cells are in contact

110

Familial AD

What is the risk among affected families?

50% chance of getting it!

111

What is the relationship between Down's Syndrome (Tr21) and Alzheimers?

All patients with DS develop Alzheimers Pathology in erarly adulthood

Three copies of APP gene, they are always producing 50% more APP protein.

112

Amyloid Cascade Hypothesis of AD

APP Gene
⬇︎ (DS, head trauma)
APP
⬇︎(mutations: APP, PS!, PS2)
AB
⬇︎(APOE4
Amyloid
⬇︎
Alzheimer's Disease (AD)

NOTE: Long-term anti-inflammatory drugs slow down the pathway and delay the onset of AD

113

How is head trauma associated with AD?

There is a great surge of APP during brain healing following severe head trauma

If brain is already genetically primed to develop Alzheimers, the onset of AD can be accelerated.

114

Neurofibrillary Tangle

What is Tau?

How does it contribute to AD?

– normal neuronal structural protein
– cross-links microtubules
– we NEED normal Tau
– Tau is normally phosphorylated

In AD, the Tau protein becomes Hyper-phosphorylated Tau. This causes it to accumulate in the cells to become Neurofibrillary Tangles

115

What comes first?

Amyloid or Tangles?

Amyloid accumulates. This is the first step.

Then, in response to neuronal toxicity that occurs, the Tau gets hyperphosphorylated and becomes abnormal. This results in the Neurofibrillary Tangles.

The amyloid gets the ball rolling ... but once the tangles start it is almost like its own destructive machine and no longer relies on amyloid.

116

AD is characterized by severe and focal inflammation

massive up-regulation of immune cells

massive upregulation of Microglial cells

(the brain mounts an immune inflammatory response against the amyloid)

117

nucleus basalis

What is it?

– main source of Ach
– one of the first areas to be affect in AD

Therefore, the only drugs that are currenlty used in AD are those that help increase the level of Ach.

118

3 Key Pathological Findings of AD

Hammer it home!

►Atrophy of brain, esp Hippocampus (visualize by CT)

►Neurons damaged and decreased in number

►Progressive accumulation of abnormal material
– Amyloid plaques (amyloid core)
– Neurofibrillary tangles (p-tau)

119

DSM 5 - Major Neurocognitive Disorder
►Criteria?

aka Alzheimers

• Cognitive decline from prior level of function - one or more areas (complex attention, executive function, learning, memory, language, perceptual motor or social cognition)
• Corroborated by informant; demonstrated on standardized testing
• Functional problems; Rule out other conditions (Hypothyroidism, B12 def ...)

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DSM 5 - Minor Neurocognitive Disorder
►Criteria?

aka "Mild Cognitive Impairment (MCI)"
(we monitor these people and watch it like "Borderline Diabetes")

• Modest cognitive decline from prior level of function - one or more areas (complex attention, executive function, learning, memory, language, perceptual motor or social cognition)
• Demonstrated on standardized testing
• NOT enough to impair daily function

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To what level of certainly can we say that someone has AD?

The best that we can clinically do is say that someone has "probable AD."

The only way to definitively give a diagnosis is an autopsy!

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SPECT

"single photon emission computed tomography"

• are available and can be ordered
• similar to PET
• used to detect Temporoparietal hypoperfusion in AD

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PET scan

• probably better than SPECT
• In the future we will likely be using this instead of SPECT
• allows for visualization of increased metabolism
• can be used to look for amyloid accumulation

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CSF Study

• Low levels of CSF Aß42 is seen in people with AD

• These seems backwarrds, but as Aß increases in the brain, it is lost from the CSF

SUMMARY:
• increased tau, decreased Aß42 suggests AD

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What is the drawbacks of these diagnostic modalities?

It doesn't change our management ..... maybe in the future!

Requires Lumbar Puncture

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What is the main help we can give our AD patients?

Support
Education
Resources

Alzheimer BC Website

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The drugs we have do NOT modify the disease. All we can do is treat Sx.

Cholinesterase Inhibitors → only work for a season before neurons die (simply temporary symptomatic Tx). Boosts up Ach
• Donepezil
• Rivastigmine
• Galantamine

NMDA Receptor Antagonists
• Memantine

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Memantine

(used for moderate to severe AD)

• Glutamate is major excitatory neurotransmitter in CNS

• Increase of extracellular glutamate can lead to excessive activation of NMDA receptors and intracellular Ca+2 accumulation, which can result in neuronal death (cell is overstimulated by glutatmate

• By temporarily slowing down the action of glutamate, we can decrease the high Ca from entering the cell and exerting its toxic effects

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What are the types of dementia?

►Alzheimer’s (60-70%)
►Vascular (20%)
►Lewy body dementia (0-30%)
►Other Dementias (10%)
– Frontotemporal dementia
– AIDS dementia
– Parkinson’s and other basal gangial syndromes such as Huntington’s, etc
– AD in Down’s Syndrome
– Prion [CJ] dementia → movement disorders

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Vascular Dementia

Vascular dementia has a stepwise course with sudden deteriorations and sporadic decline in different functions. Due to episodic vascular events triggering

There may be neurological S/S of arterial disease, and also the presence of risk factors for vascular disease

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Lewy Body Dementia

►Parkinsonism Features

►Complex Visual Hallucinations (see people in the house / bugs on the floor)

►Fluctuating
"Grandma has a bad mornings and then bad afternoons"

Visual-spatial problems can be common

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Patient has cognitive decline

What investigations?

►Collateral History

►Laboratory:
• CBC, electrolytes, renal function, calcium, fasting glucose, thyroid, B12, lipids, urine analysis

►Others directed by history & examination

►CT / SMRI - "structural MRI" much better

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AD

Early Clinical Features

• Forgetfulness, e.g. names/words, addresses, shopping items. Main deficit is in recent memory

• Patients are often aware of their symptoms, so may become anxious and depressed → Suicide Risk

• No distinguishing features on physical examination

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Inability to dress oneself

What do we call this?

Apraxia

(motor disorder in which someone has trouble completing a task)

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AD

Medial Term Clinical Presentation

• Significant memory loss, e.g. close family members, well- known routes, places

• Self-neglect

• Disorientation in time and space

• Inability to undertake simple tasks, e.g. dressing

• Reduced range of thinking (intellectual deficits)

• Delusions/overvalued ideas

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AD

Advanced Clinical Presentation

• Dysphasia with disordered and fragmented speech

• Incontinence, urinary & faecal

• Immobility, rigidity and recurrent falls

• General physical deterioration

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Sharing an AD diagnosis with an individual

"There is evidence of memory problems here."

Then we can go on to say ...

This is something that is very common. It affects 20% of the elderly population.

How things have been is highly suggestive of how things will continue. As the AD rate of progression has been exponential, so will it continue to progress.

People do not die from dementia, rather it is from the other complications that occur.

(note - NOT for vascular dementia, we can have a plateau for quite some ...)

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What do we need to be aware of with treating Lewy Body Dementia?

50% of patients will have strong reactions to Anti-psychotics

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How do we treat the behavioural and psychological symptoms of dementia?

• Risperidone, olanzepine and quetiapine can
be used for ‘severe’ agitation and aggression or psychotic symptoms but not licensed for this use

• Benzos prn low dose

• Trazodone & SSRIs in Fronto-temporal Dementia

• Start low, go slow

• Reassess after 6 months of stability

• 3Ts; treat the symptom, titrate up, time limit

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Parkinson's

What is it?

• Neurodegenerative disease. Movement is normally controlled by dopamine, a chemical that carries signals between the nerves in the brain

• Sx appear when when cells that normally produce dopamine die

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Parkinson's

Most common Sx?

Other Sx?

MOST COMMON SX:
• Tremor
• Slowness and stiffness
• Impaired balance
• Rigidity of the muscles

OTHER:
• Fatigue
• Soft speech
• Problems with handwriting
• Stooped posture
• Constipation
• Sleep disturbances

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Which of the following are associated with ...
AD?
Parkinsons?

►Lewy bodies in the cerebral cortex
►Neurofibrillary tangles in the cerebral cortex
►Pick bodies in the hippocampus

Parkinson's
►Lewy bodies in the cerebral cortex

AD
►Neurofibrillary tangles in the cerebral cortex
►Pick bodies in the hippocampus

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What pattern of cerebral infarction is most likely to cause dementia?

Multiple small infarcts throughout the brain

This is due to the widespread distribution of higher intellectual functions throughout the brain.

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In which patients do we find Aß postmortem?

(amyloid ß)

Aß is present in higher amounts in patients with...
• AD
• amyloid angiopathy (amyloid in blood vessel walls)

Pts with APOE4 genotype are more likely to have higher levels of Aß ... however, Aß can be present in people with ANY APOE4 genotype.

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paired helical filaments

What are they?

This the name that we give tau when it becomes hyperphosphorylated

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paired helical filaments

Fast Facts

• composed primarily of hyperphosphorylated tau protein

• present in neuritic senile plaques

• present in neurofibrillary tangles in conditions other than AD

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What genetic finding has been linked to early onset familial AD?

Mutations in the presenilin genes

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Patient is a snorer and has increased daytime somnolence

What type of Apnea?

OSA

NOTE:
As the patient is snoring, he has ventilatory effort which suggests obstruction → OSA

If he had lack of ventilatory effort he would not snore → therefore Central Sleep Apnea.

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The PRIMARY brain function that is disrupted in delirium is:

Attention

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All patients with suspected AD should be screened for ....

B12

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What does Dopamine say?

Eat food
Have Sex
Bond with your clan