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front 1 WHAT IS DEMENTIA?	back 1 Syndrome of brain disorders • Slowly ↓ memory & reasoning • Erodes independence • Impairment in cognition that impairs ability to function on a daily basis
front 2 Projected Percentage Increase in Dementia 2020-2050	back 2 597,300 Canadians living with dementia in 2020
front 3 Rising Tide of Dementia	back 3 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
front 4 Rising Tide of Dementia	back 4 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

front 5 Reducing the dementia Risk	back 5 •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
front 6 ?????MILD COGNITIVE IMPAIRMENT or COGNITIVE IMPAIRMENT NOT DEMENTIA (pliz edit )	back 6 • ↓ cognition • Usually memory • Executive function preserved • Maintains ability to carry out IADLs
front 7 Types of Dementia	back 7 -alzheimers -lewy body dementia -vascular dementia -frontotemporal dementia -others; parkinson's, huntington's, -mixed dementias
front 8 what are the Pathobiology Hypotheses for Alzheimer’s Dementia	back 8 -Tau Hypothesis -Cholinergic Hypothesis -Beta-amyloid hypothesis Additional Hypotheses • Inflammatory • Oxidative stress • Serotonergic • others

front 9 -Cholinergic Hypothesis	back 9 dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease
front 10 amyloid hypothesis Amyloid Plaques	back 10 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
front 11 Amyloid as a Target for Pharmacologic Intervention	back 11 • ↓ β-amyloid production • Prevent β-amyloid aggregation • ↑ removal of β- amyloid • Active vaccines • Passive vaccines
front 12 The tau hypothesis	back 12 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).

front 13 Tau Tangles	back 13 • Non-functioning microtubules • Apoptosis
front 14 ALZHEIMER DEMENTIA	back 14 • 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
front 15 VASCULAR DEMENTIA	back 15 • Associated with cerebrovascular risk factors & disease • Abrupt onset • Stepwise decline • Temporal relationship between vascular insult & cognitive decline
front 16 LEWY BODY DEMENTIA	back 16 • Spontaneous parkinsonism • Early, recurrent visual hallucinations • Falls • Orthostatic hypotension • Antipsychotic sensitivity

front 17 FRONTOTEMPORAL DEMENTIA	back 17 • Insidious onset with slow progression • Two primary types • Semantic • ↓ ability to verbalize • Behavioral • Disinhibition, repetitive behavior • Social consequences • Marital-family, occupation, social problems
front 18 PATIENT EVALUATION	back 18 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?
front 19 IS THERE A MEMORY PROBLEM?	back 19 • 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”
front 20 Simple cognitive tests	back 20 • 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

front 21 Functional checklists	back 21 Functional assessment staging tool (FAST)
front 22 IS FUNCTION IMPAIRED?	back 22 Types of assistance • None • Supervision • Prompting • Minimal hands-on care • Total hands-on care • Distinguish what can be done from what is done
front 23 IS FUNCTION IMPAIRED?	back 23 • Instrumental ADLs • Managing money • Managing medications • Driving • Cooking • Housekeeping • Laundry • Using telephone • Basic ADLs • Dressing • Grooming • Bathing • Feeding • Toileting
front 24 FUNCTIONAL ASSESSMENT STAGING TOOL	back 24 mild=4 moderate=5 severe=6 very severe= 7

front 25 I R A N	back 25 I ADLS R-epetitive dressing A DLS: a) difficulty dressing b)bathing c) toileting d) incontinence N o speech and step
front 26 coverage for stages 4 and 5	back 26 ??(edit )
front 27 compare and contrast delirium and dementia -onset and duration	back 27 delirium onset=sudden(hr to days) while dementia is gradual duration delirium =short day to weeks dementia= chronic
front 28 compare and contrast delirium and dementia attention and LOC	back 28 delirium= attention is impaired , in dementia its usually unaffected. LOC(delirium)=up and down while in dementia its usually unaffected

front 29 compare and contrast delirium and dementia course and thoughts, memory	back 29 delirium thoughts disorganized , dementia's are impaired. course delirium=fluctuating, dementia=stable memory(delirium)= reduced as well as in dementia
front 30 DELIRIUM	back 30 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
front 31 DIAGNOSING DELIRIUM	back 31 • Confusion Assessment Method • Acute onset & fluctuating course AND • Inattention AND • Disorganized thinking OR • Change in level of consciousness
front 32 WHAT IS THE CAUSE of delirium?	back 32 • 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

front 33 WHAT ABOUT REVERSIBLE CAUSES of delirium ?	back 33 < 10% patients seen in clinic • < 50% actually reverse • Common causes • Medications – sedatives, anticholinergic burden • Depression • Hypothyroidism & B12 deficiencies are usually coincidental rather than causative
front 34 WHAT CAN WE DO?	back 34 • 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
front 35 what are the pharm options	back 35 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
front 36 RECOMENDATIONS	back 36 • 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

front 37 All 3 ....... can be considered for mild-moderate AD	back 37 cholinesterase inhibitors (ChEIs)
front 38 No significant differences in ..................between agents • Select based on type of dementia, dosing, side-effect profile, comorbidities, potential drug interactions	back 38 efficacy/effectiveness
front 39 Many dementia cases involve > 1 type usually .......	back 39 AD + another pathology
front 40 ChEIs appropriate for:	back 40 • AD + Vascular component • PDD • LBD • Change to CCCDTD5 – use of ChEIs may be considered for vascular dementia

front 41 ChEIs moa	back 41 • ChEI’s inhibit AChEsterase activity • ↑ ACh
front 42 ChEIs – DO THEY WORK?	back 42 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
front 43 HOW DO MOST PEOPLE RESPOND?	back 43 Some get better Some stabilize Some get worse
front 44 ChEIs drugs	back 44 donepezil- slower titration Rivastigmine -Gi upset-PO issues galantamine-some require 32 mg daily

front 45 SWITCHING BETWEEN AGENTS	back 45 • Why • Poorly tolerated due to adverse effects • Poor response in early disease • Generally only switch once
front 46 • 72 year old started on donepezil 5 mg daily- Severe nausea with anorexia – losing weight ,Consideration of switch to galantamine Recommendations for switching agents?	back 46 ?
front 47 galantamine side effects sympathetic and parasympathetic effects plus...	back 47 -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
front 48 OTHER ADVERSE EFFECTS (galantamine)	back 48 • 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

front 49 PHARMACODYNAMIC INTERACTIONS	back 49 • 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
front 50 PHARMACOKINETIC IMPLICATIONS & INTERACTIONS	back 50 • 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
front 51 ADDITION OF MEMANTINE? • ChEIs & memantine have different MOAs • Does this result in additional benefit?	back 51 • 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)
front 52 MEMANTINE	back 52 Cautions : Active seizure disorder D/C -if skin rash presents Indications AD – approved LBD – off label PDD – off label VD – off label

front 53 Adverse Effects-MEMANTINE	back 53 Agitation, confusion, dizziness, fatigue, N/V
front 54 Deprescribing Considerations	back 54 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
front 55 SOMETHING TO CONSIDER	back 55 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?
front 56 New & Emerging Agents – Targeting β-Amyloid	back 56 ↓ β-amyloid production • Prevent β-amyloid aggregation • ↑ removal of β- amyloid • Active vaccines • Passive vaccines

front 57 Targeting β-Amyloid	back 57 • Aducanumab • Health Canada application withdrawn • Controversial FDA approval • Lecanemab • Approved by US FDA • Awaiting approval by Health Canada • Donanemab • Awaiting approval in US & Canada
front 58 Targeting β-Amyloid	back 58 • 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
front 59 BPSD –Behavioral and psychological symptoms of dementia RESPONSIVE BEHAVIOURS	back 59 • Common behaviours in dementia • Agitation, aggression, restlessness, wandering, disinhibition, repetition, insomnia • Other common issues in dementia • Depression, apathy, anxiety, personality changes, psychosis – hallucinations/delusions,
front 60 subtypes of agitation	back 60 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.

front 61 COMMON CAUSES OF RESPONSIVE BEHAVIOURS	back 61 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
front 62 RESISTANCE VS AGGRESSION	back 62 • 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
front 63 PREVENTING RESPONSIVE BEHAVIOURS	back 63 • Can be triggered by: • Unmet needs • Lack of understanding of person with dementia • Important to gather information about the individual
front 64 MEDICATION RESPONSIVE AND LESS RESPONSIVE BEHAVIOURS	back 64 • 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

front 65 systematic approach to manage BPSD	back 65 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.
front 66 PRECIPITATING FACTORS	back 66 • 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
front 67 GENERAL APPROACH TO MEDICATIONS IN MANAGING RESPONSIVE BEHAVIOURS	back 67 • 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
front 68 ANTIPSYCHOTIC AGENTS ARE CONTROVERSIAL IN DEMENTIA	back 68 • 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

front 69 ANTIPSYCHOTICS – OTHER SIDE EFFECTS TO CONSIDER	back 69 Sedation, confusion, falls • Hypotension • EPS can be mistaken for worsening behaviour • Tardive dyskinesia • Weight gain, hyperglycemia
front 70 What To Do? • Best evidence for severe BPSD	back 70 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
front 71 OTHER AGENTS TO CONSIDER	back 71 • 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
front 72 SUMMARY OF MANAGING BEHAVIOURS	back 72 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

front 73

ROLE OF THE
PHARMACIST
IN DEMENTIA
CARE

back 73

• 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

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