WHAT IS
DEMENTIA?

Syndrome of brain disorders
• Slowly ↓ memory &
reasoning
• Erodes independence

• Impairment in cognition that
impairs ability to function on
a daily basis

Projected Percentage Increase in Dementia 2020-2050

597,300 Canadians
living with dementia
in 2020

Rising Tide of Dementia

Results in great personal strain for
those with dementia & their
caregivers
• 55% Canadians with dementia live at
home
• Causes > disability than other diseases
• Severe financial burden for family &
caregivers ($10.4 billion out of pocket
expenses)
• Caregiver stress → ↓ health

Rising Tide of Dementia

1 in 4 require assistance with ADLs
• 1 in 4 exhibit behaviors
• 1 in 4 experience symptoms of depression
• 1 in 4 hospitalized over 3 months
• 1 in 5 visit emergency over 3 month

Reducing the dementia
Risk

•Diet
• Physical activity
• Assess & manage hearing loss
• Sleep
- Manage sleep apnea
- Avoid sleep deprivation
- Good sleep hygiene
• Increase or maintain
engagement in cognitively
stimulating exercises
• Social engagement
• Minimize exposure to
anticholinergic medications
• Annual influenza vaccination

?????MILD
COGNITIVE
IMPAIRMENT
or COGNITIVE
IMPAIRMENT
NOT
DEMENTIA (pliz edit )

• ↓ cognition
• Usually memory
• Executive function
preserved
• Maintains ability
to carry out IADLs

Types of
Dementia

-alzheimers

-lewy body dementia

-vascular dementia

-frontotemporal dementia

-others; parkinson's, huntington's,

-mixed dementias

what are the Pathobiology Hypotheses for Alzheimer’s Dementia

-Tau Hypothesis

-Cholinergic Hypothesis

-Beta-amyloid hypothesis

Additional Hypotheses
• Inflammatory
• Oxidative stress
• Serotonergic
• others

-Cholinergic Hypothesis

dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease

amyloid hypothesis

Amyloid Plaques

it is pathological accumulations of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, that act as the root cause of AD and initiate its pathogenesis

Plaques
• Block neurotransmission
• Promote inflammation → neuron death
• Weaken blood vessels
• Initiates phosphorylation of tau proteins

Amyloid as a Target for Pharmacologic
Intervention

• ↓ β-amyloid
production
• Prevent β-amyloid
aggregation
• ↑ removal of β-
amyloid
• Active vaccines
• Passive vaccines

The tau hypothesis

The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs. Tau protein is a highly soluble microtubule-associated protein (MAP).

Tau Tangles

• Non-functioning microtubules
• Apoptosis

ALZHEIMER
DEMENTIA

• Gradual onset
• ↓ cognition from baseline
• Amnestic deficits
- Impaired learning &
short term memory
deficits
• Executive dysfunction
-Reasoning, judgment,
problem solving
• Not due to any other cause

VASCULAR
DEMENTIA

• Associated with cerebrovascular risk
factors & disease
• Abrupt onset
• Stepwise decline
• Temporal relationship between
vascular insult & cognitive decline

LEWY BODY
DEMENTIA

• Spontaneous parkinsonism
• Early, recurrent visual hallucinations
• Falls
• Orthostatic hypotension
• Antipsychotic sensitivity

FRONTOTEMPORAL
DEMENTIA

• Insidious onset with slow progression
• Two primary types
• Semantic
• ↓ ability to verbalize
• Behavioral
• Disinhibition, repetitive behavior
• Social consequences
• Marital-family, occupation, social
problems

PATIENT
EVALUATION

Four question approach
1. Is there a memory
problem?
2. Is function impacted?
3. What is the cause of the
memory problem?
4. What can we do?

IS THERE A
MEMORY
PROBLEM?

• Interview patient
• Obtain collateral information (without patient present)
• Ask about memory
• Types of problems – specific examples
• Forgetting appointments, repetitive questions
• Changes in activities – activities or hobbies dropped
• Course of changes
• DON’T ACCEPT “IT’S BECAUSE OF MY/THEIR AGE”

Simple cognitive tests

• MMSE
- Favors educated
- Hearing & vision
- > 3 points “true change”
• MoCA
- Language, visuospatial ability, memory & recall, abstract thinking
http://www.mocatest.org/
- Now requires licensure
- Alternatives include RUDAS,
..>Tests memory, visuospatial orientation, praxis, visuoconstructional drawing, language & judgement
• BCRS
-Concentration, recent & remote memory

Functional checklists

Functional assessment staging tool (FAST)

IS FUNCTION
IMPAIRED?

Types of assistance
• None
• Supervision
• Prompting
• Minimal hands-on care
• Total hands-on care
• Distinguish what can be done from what
is done

IS FUNCTION
IMPAIRED?

• Instrumental ADLs
• Managing money
• Managing
medications
• Driving
• Cooking
• Housekeeping
• Laundry
• Using telephone
• Basic ADLs
• Dressing
• Grooming
• Bathing
• Feeding
• Toileting

FUNCTIONAL
ASSESSMENT
STAGING
TOOL

mild=4

moderate=5

severe=6

very severe= 7

I

R

A

N

I ADLS

R-epetitive dressing

A DLS: a) difficulty dressing

b)bathing

c) toileting

d) incontinence

N o speech and step

coverage for stages 4 and 5

??(edit )

compare and contrast delirium and dementia

-onset and duration

delirium onset=sudden(hr to days) while dementia is gradual

duration

delirium =short day to weeks

dementia= chronic

compare and contrast delirium and dementia

attention and LOC

delirium= attention is impaired , in dementia its usually unaffected.

LOC(delirium)=up and down while in dementia its usually unaffected

compare and contrast delirium and dementia

course and thoughts, memory

delirium thoughts disorganized , dementia's are impaired.

course

delirium=fluctuating, dementia=stable

memory(delirium)= reduced as well as in dementia

DELIRIUM

Acute confusion
• New confusion in someone who was
normal before
OR
• Worsening confusion in someone who was forgetful before or previously
diagnosed with dementia.

Important to understand baseline cognition
• Baseline MMSE (6th vital sign?)
• Collateral history from family – those that know patient well

DIAGNOSING
DELIRIUM

• Confusion Assessment Method
• Acute onset & fluctuating course
AND
• Inattention
AND
• Disorganized thinking
OR
• Change in level of consciousness

WHAT IS THE
CAUSE of delirium?

• Consider depression
• Depression can cause some symptoms of
dementia
• Executive dysfunction
• Depression can also be presenting
symptom of dementia
• If apathy, low mood, poor
appetite/weight loss, early morning
awakening are present AND prominent
consider trial of antidepressant

WHAT
ABOUT
REVERSIBLE
CAUSES of delirium ?

< 10% patients seen in clinic
• < 50% actually reverse
• Common causes
• Medications – sedatives, anticholinergic
burden
• Depression
• Hypothyroidism & B12 deficiencies are
usually coincidental rather than causative

WHAT CAN
WE DO?

• Non-pharmacologic interventions
• Address safety issues – e.g. driving, wandering
• Caregiver support
• Community resources – refer ALL
patients/caregivers to Alzheimer Society
• Medico-legal issues
• While still have capacity to do so, appoint:
• Substitute decision maker
• Power of attorney for finances

what are the pharm options

Pharmacologic interventions
• Cholinesterase inhibitors
- Donepezil
- Galantamine
- Rivastigmine
• NMDA receptor antagonist
- Memantine
• Aducanumab
- Anti-beta amyloid
- Recently available in US – controversial
- Not approved by Health Canada

RECOMENDATIONS

• Vascular Cognitive Impairment
• Treatment of hypertension in
vascular MCI
• If > 140/90
• Receive guideline
recommended treatments for
primary/secondary stroke
prophylaxis as appropriate
• Use of ASA not recommended
• Brain imaging → white
matter lesions of
presumed vascular origin
+/- stroke history

All 3 ....... can be considered for mild-moderate AD

cholinesterase inhibitors (ChEIs)

No significant differences in
..................between agents
• Select based on type of dementia,
dosing, side-effect profile,
comorbidities, potential drug
interactions

efficacy/effectiveness

Many dementia cases involve > 1 type
usually .......

AD + another pathology

ChEIs appropriate for:

• AD + Vascular component
• PDD
• LBD
• Change to CCCDTD5 – use of
ChEIs may be considered for
vascular dementia

ChEIs moa

• ChEI’s inhibit AChEsterase activity
• ↑ ACh

ChEIs – DO THEY WORK?

ChEIs – DO THEY WORK?
• Evidence in mild-moderate AD
• Cochrane Library Systematic Review

Some data supporting use of donepezil in moderate to severe disease
(Black et al. Neurology 2007; 69:459-69, Winblad et al, Lancet 2006)
• Short duration, does not address issue of when to discontinue
• Donepezil is approved for moderate to severe disease
• Some evidence in PDD and LBD
• Cochrane Library Systematic Review

HOW DO
MOST PEOPLE
RESPOND?

Some get better
Some stabilize
Some get worse

ChEIs drugs

donepezil- slower titration

Rivastigmine -Gi upset-PO issues

galantamine-some require 32 mg daily

SWITCHING
BETWEEN
AGENTS

• Why
• Poorly tolerated due to adverse effects
• Poor response in early disease
• Generally only switch once

• 72 year old started on donepezil 5 mg daily- Severe nausea with anorexia – losing weight ,Consideration of switch to galantamine
Recommendations for switching agents?

?

galantamine side effects

sympathetic and parasympathetic effects plus...

-Miosis

-COPD NOT a contraindication
Respiratory outcomes similar between ChEI users & non-users
Bradycardia & syncope
– Bradycardia – 6.9 vs 4.4 events/1000 pt years
– Syncope 31.5 vs 18.6 event/1000 pt years
GI upset – nausea & vomiting

OTHER ADVERSE EFFECTS (galantamine)

• Insomnia
• Take donepezil & galantamine in morning
• If PO rivastigmine – 2nd dose no later than 4-6 pm
• Agitation
• Urge type urinary incontinence??
• Leg cramps – most common with donepezil
• Health Canada warning – rhabdomylosis with donepezil
• Overall risk is low – warning based on 1 Canadian case report + 88 internationally
• 1 per 1667 prescriptions based on Ontario study (Fleet JL, et al. CMAJ 2019 September 16;191:E1018-24. doi: 10.1503/cmaj.190337)
• Risk appears greater with donepezil compared to galantamine or rivastigmine
• Consider monitoring parameters to identify rhabdomylosis

PHARMACODYNAMIC
INTERACTIONS

• Doesn’t make sense to concomitantly use drugs with anticholinergic activity
• Attenuate therapeutic effect? (Lu CJ & Tune LE Am J Geriatr Psychiatry
2003;11:458-61)
• Cholinergic agents (e.g. pyridostigmine) have
potential to enhance adverse effects
• Exacerbate adverse effects via different mechanism (e.g. bradycardia)
• Beta-blockers
• Digoxin

PHARMACOKINETIC
IMPLICATIONS &
INTERACTIONS

• Applies to Donepezil& Galantamine
• Metabolism via CYP2D6 and CYP3A4
• Implications
-Inhibition of CYP2D6 and/or CYP3A4
...>↑ serum concentrations → ↑ adverse effects
- Slow metabolizers of CYP2D6
...>Should be partially accounted for by intact CYP3A4
but potential for:
↑serum concentrations → ↑adverse effects
• Induction of CYP3A4
• Potential for ↓ serum concentrations → ↓
effectiveness
• Fast metabolizers of CYP2D6
• Potential for ↓serum concentrations → ↓
effectiveness

ADDITION OF
MEMANTINE?

• ChEIs & memantine have different MOAs
• Does this result in additional benefit?

• ChEIs + memantine is safe but insufficient
evidence to recommend for or against
• Domino-AD – combination therapy no better than
single therapy (NEJM 2012;366:893-903)

MEMANTINE

Cautions : Active seizure disorder
D/C -if skin rash presents

Indications AD – approved
LBD – off label
PDD – off label
VD – off label

Adverse Effects-MEMANTINE

Agitation, confusion, dizziness, fatigue,
N/V

Deprescribing
Considerations

Appropriate indications
• AD, PDD, LBD or VD
• Should be deprescribed if MCI or FTD
• Clinically meaningful worsening of
cogntion/function in past 6 months not due to other medical conditions or environmental factors
• No clinically meaningful benefit observed at any time during treatment
• Severe or end-stage
• Intolerable adverse effects
• Non-adherence safety risk or unable to assess effectiveness

SOMETHING
TO CONSIDER

Why would you not start the ChEI
desprescribing process for 6 to 8 weeks
following admission to a long-term care
facility?
• Time to settle into facility
• If new onset or exacerbation of
behavioral sx’s
• Is it due to new environment or is
it due to discontinuation of the
ChEI?

New & Emerging Agents – Targeting β-Amyloid

↓ β-amyloid
production
• Prevent β-amyloid
aggregation
• ↑ removal of β-
amyloid
• Active vaccines
• Passive vaccines

Targeting β-Amyloid

• Aducanumab
• Health Canada application withdrawn
• Controversial FDA approval
• Lecanemab
• Approved by US FDA
• Awaiting approval by
Health Canada
• Donanemab
• Awaiting approval in US & Canada

Targeting β-Amyloid

• Amyloid related imaging abnormalities-edema (ARIA-E)
- Also includes microhemorrhages (ARIA-H)
...> Consideration of concomitant use with anticoagulants, antiplatelet agents, NSAIDs, SSRIs
- More common with higher doses & APOE4 positive
• Homozygotes > heterozygotes
• While biologically plausible benefit many questions remain:
• Is the effect size clinically detectable?
• Are the effects reproducible?
• Is the Canadian Health Care system equipped to provide aducanamab?
• Requires specialist-based evaluation & monitoring
• Availability of specialized equipment (PET scans)
• Invasiveness of monitoring
• Including lumbar puncture
• Regular MRI scanning
• Capacity for monthly infusions

BPSD –Behavioral and psychological symptoms of dementia
RESPONSIVE
BEHAVIOURS

• Common behaviours in dementia
• Agitation, aggression, restlessness,
wandering, disinhibition, repetition,
insomnia
• Other common issues in dementia
• Depression, apathy, anxiety, personality
changes, psychosis –
hallucinations/delusions,

subtypes of agitation

cohen-mansfield agitation inventory

-important to define the problem behavior, especially when documenting

1. physically non-aggressive -generally restless, pacing

verbally non agressive -negativism, constant requests for help, repetition.

physically aggressive- hitting, pushing, scratching, grabbing things.

verbally aggressive-verbally threatening, cursing.

COMMON
CAUSES OF
RESPONSIVE
BEHAVIOURS

Misinterpretation
• Environment
• Caregiver
• Signals/clues
• Intimate care (dressing,
bathing, toileting,
feeding) # 1 cause of
aggression
• Delirium - ↑ confusion
• Pain – dental, skin
breakdown, MSK

• Fear
• Boredom
• Fatigue

RESISTANCE
VS
AGGRESSION

• Resistance
• Opposition or
counteracting force that
is protective
• Attempt to protect from
perceived harm
• May be instinctual
reaction to not
understanding
environment or
expectations in the
context of cognitive
impairment
• Occurs in relation to
an action

• Aggression
• Angry & destructive
behaviour intended to
cause harm
• Aimed at domination
• Offensive action
• Occurs without
provocation

PREVENTING
RESPONSIVE
BEHAVIOURS

• Can be triggered by:
• Unmet needs
• Lack of understanding of person with
dementia
• Important to gather information
about the individual

MEDICATION
RESPONSIVE
AND LESS
RESPONSIVE
BEHAVIOURS

• Responsive
• Psychosis – if distressing
• Physical aggression if
safety of individual or
others is compromised
• Depression
• Low mood, apathy,
amotivation
• Anxiety

• Less likely to respond
• Wandering
• Verbal non-aggression
• Uncooperative
• Frequent repetition
• Bothering others

systematic approach to manage BPSD

1. assessment(id/describe target behavior)

2. rule out precipitating factors

3. trial non-pharmacologic interventions

4. if medn-responsive trial pharmacologic intervention

5-reassess and monitor on regular basis-behavioral tracking

trial dose reduction/discontinuation.

PRECIPITATING
FACTORS

• Delirium related to acute illness
• e. g. Infection, heart failure,
metabolic abnormalities
• Pain – acute or chronic
• Some evidence to support “round
the clock” analgesia in chronic pain
• Medications
• Anticholinergic, sedatives,
corticosteroids, alcohol-nicotine-drug
withdrawal
• Environment

GENERAL
APPROACH TO
MEDICATIONS IN
MANAGING
RESPONSIVE
BEHAVIOURS

• Identify target symptoms
• Behavioural tracking is crucial
• Start medication that is appropriate to
the behaviour
• Start low – go slow
• Increase dose to benefit or side effects
• Some side effects mimic behaviour
• Re-evaluate & trial tapering doses

ANTIPSYCHOTIC AGENTS ARE CONTROVERSIAL
IN DEMENTIA

• Harm
• Health Canada warning 2005 - ↑
risk of death with atypicals
• 2005 meta-analysis - ↑ mortality
• ARI – 1.2%, NNH = 83
• Retrospective cohort x 15 yr
• Dose dependent ↑ cardiac death for
both atypical & conventional agents

Benefit
• Systematic review
• Aggression
• Risperidone > placebo
• Psychosis
• Risperidone, olanazepine>placebo
• ↑ dropouts with APs
• ↑ CVA with APs
• ↑EPS with APs
• 2nd systematic review
• Aggression
• Haloperidol > placebo
• ↑ ADE – sedation, EPS

ANTIPSYCHOTICS
– OTHER SIDE
EFFECTS TO
CONSIDER

Sedation, confusion, falls
• Hypotension
• EPS can be mistaken for worsening behaviour
• Tardive dyskinesia
• Weight gain, hyperglycemia

What To Do?
• Best evidence for severe BPSD

risperidone, olanzapine &
aripiprazole
– Quetiapine not appropriately dosed in clinical trials
• Insufficient evidence to recommend for or against
• Modest efficacy – be realistic in determining outcomes
– Re-evaluate over time
• Agents can be withdrawn without worsening of BPSD
(Cochrane Database Syst Rev. 2018 Mar 30;3:CD007726. doi:
10.1002/14651858.CD007726.pub3)cihi
• Balance risk/benefit ratio
– 1 patient death for every 9-25 who benefit (Schnieder, JAMA, 2005)
– Discussion with family/caregivers
• Palliative care model of dementia
– Consider
• Patient impact
• Caregiver impact
• Severity of symptoms – harm related to not treating

OTHER
AGENTS TO
CONSIDER

• SSRIs
• Depression, anxiety, some evidence for “agitation” & psychosis (citalopram –CitAD study)
• Leonpacher AK, et al Am J Psychiatry
2016 May 1;173(5):473-80
• SNRIs
• Depression with apathy
• Mirtazepine
• Depression with poor sleep & weight loss
• Allow 6-8 weeks at target dose

SUMMARY
OF
MANAGING
BEHAVIOURS

Non-Pharm interventions first
• Other classes when appropriate –
depression, anxiety
• Atypical antipsychotic agent for targeted
symptoms (e.g. hallucinations, delusions,
aggression) with severe behaviours causing
distress &/or harm
• Informed consent & documentation
• Monitor closely – behavioural tracking is
essential
• Trial dose reduction to discontinuation if
stable > 3 months

ROLE OF THE
PHARMACIST
IN DEMENTIA
CARE

• Advocate for patient/caregiver
• Refer EVERY patient/caregiver to Alzheimer Society
• Support patients/caregivers in medication
management
• Recognize & assist with managing side effects
• Recognize & assist with managing clinically
important drug interactions
• Appropriate use of medications
• Goals of care
• Patient/caregiver values/preferences
• Support patient/caregivers through
deprescribing process when appropriate