Dementia diagnosis, pharmacological and non-pharmacological interventions

Dementia: Diagnosis, Pharmacological & Non-Pharmacological Interventions AIGNA Masterclass 12 November 2015

Dr Rónán O’Caoimh MB MSc PhD Senior Lecturer / Consultant Physician in Geriatric Medicine NUIG/UHG Research Fellow Centre for Gerontology & Rehab, UCC

Overview § Diagnostic Pathways: When to treat? § Pharmacological Interventions. § Non-pharmacological Interventions. § Q and A

Part 1: Diagnosis of dementia

h"p://www.alz.org/alzheimers_disease_facts_and_figures.asp

Natural History of Cognitive Decline

Normal SMC Mild Cognitive Impairment (MCI) Dementia No Subjective Subjective Memory loss Functional Memory Memory No/subtle Functional Impairment Impairment loss Complaints Some changes on screening tests Deficiencies on more in-depth Neuro-psych testing

5-10% convert each year In 8 years, c100% conversion

�  In summary: �  Memory impairment: �  And difficulty with @ least 1 of the following: �  Language �  Coordinating �  Planning �  Recognising �  With loss of function (social or occupational) �  Course is gradual & persistent. �  Other causes including delirium have been excluded.

Diagnosing dementia

Diagnosing dementia

Dementia ? Reversible causes ?

Depression ? Delirium ?

MCI ?

Acute onset Stepwise

Risk factors Gait

Neurological

Gradual onset Memory loss

Normal examination

Hallucinations Fluctuations Visuospatial

Parkinsonism

Behavioural Language Family hx

Young onset

Frontotemporal Dementia

Lewy Body Dementia

Alzheimer’s Disease

Vascular Dementia

Why screen? § Early Diagnosis allows prompt initiation of appropriate care. §  Important to differentiate between MCI, NC & Dementia –

Different Rx & prognosis. § Allows identification of reversible causes – 10 -50 % of

referrals to memory clinics ( <1.5% cases of mild to mod dementia).

§ Screening for vascular risk factors. §  Initiation of lifestyle advice. § Planning for the future (advanced care plans/power of

attorney). § Potential for future treatments & reducing stigma.

Screening for cognitive impairment § Detecting & distinguishing mild dementia & MCI is a challenge. Ref MCI represents a heterogeneous group of disorders of memory impairment.

§ How can the “worried well” be differentiated from patients with MCI?

§ Need sensitive & specific cognitive screening instruments.

Löppönen et al Age and Ageing 2003

§ Sensitivity: If I have the disease, is the test positive? § Specificity: If I do not have the disease, is the test

negative? § Too Sensitive: over diagnose, normal's misdiagnosed

(including the “worried well”). § Too Specific: under diagnose, people with the disease

called normal (“miss highly educated”). § Many screening instruments with different sensitivities &

specificities.

Screening for cognitive impairment

§ How to use short cognitive screens to improve diagnosis? § Which test to use? §  Adjust for :

- Patient specific factors: age & education other patient specific factors. - Pre-test probability ( do you suspect MCI or dementia based upon history & examination?).

§ An example....


?

Clock Drawing

Registration Orientation Recall

Verbal Fluency Logical Memory © R O Caoimh, D W Molloy 2012

Group Normal MCI Dementia Number of subjects 630 154 181 Age

Mean 67.4 73.6 78.1 Median 67 75.5 79 range 44 - 92 50 - 88 49 - 93

Education (years in education) mean 13.8 12.2 11.0 median 13 12 10 range 5 - 29 5 - 26 3 - 20

Qmci (median with IQR)

76 (83-69=14)

62 (68-53=15)

36 (45-23=22)

SMMSE (median with IQR)

29 (30-28=2)

28 (29-27=2)

22 (25-18=7)

Initial Validation





76 (83-69=14)

62 (68-53=15)

36 (45-23=22)


29 (30-28=2)

28 (29-27=2)

22 (25-18=7)

Results





76 (83-69=14)

62 (68-53=15)

36 (45-23=22)


29 (30-28=2)

28 (29-27=2)

22 (25-18=7)

Initial Validation

§ Large variety of cognitive scores available for any test based upon sensitivity & specificity.

§ Represent “transition points” between different cognitive states.

§ Placing emphasis on cut-offs, rather than profiles of impairment or clinical judgement, can therefore be misleading.

§ Individual variations in age and educational level.


Crum et al, JAMA, 1993.

Norma&ve Data for the MMSE

à>12, >75 = 27 à<12, >75 = 22 à>12, <75 = 28 à<12, <75 = 25

The Quick Memory Check

?

Clock Drawing

Registration Orientation Recall


Orientation


ROC curves demonstrating sensitivities and specificities of the Qmci, MoCA, SMMSE & QMC in

differentiating (a). Cognitive Impairment (MCI & dementia) and (b) Dementia

(a). Cognitive Impairment from Normal

(b). Dementia

QMC User Satisfaction

0

10

20

30

40

50

60

Easy to understand Too &me consuming Happy to use again

Strongly agree

Agree

Neither

Disagree

Strongly Disgree

N=51

The Quick Memory Check

Conclusions § Rising prevalence of cognitive impairment (MCI and

dementia) § Under-diagnosed § Clinical diagnosis § Early diagnosis allows assessment & management of cause. § New modalities in cognitive screening may improve patient

and carer experiences with the diagnostic process.

Part 2. Pharmacological Management of dementia

Pharmacological Management of Dementia: Overview

§ Symptomatic management: -Cholinesterase inhibitors (ChEIs) & Memantine. -Ginkgo biloba § Vitamin supplementation -Vitamins B, E & folate § Anti-hypertensives. § Management of the Behavioural & Psychological Symptoms of

Dementia (BPSD).

Cholinesterase Inhibitors § 4 FDA (AD) approved agents: §  -Tacrine §  -Donepezil §  -Galantamine §  -Rivastigmine § All improve cognition & global function. § Little difference (cognition/behaviour) between agents. § Statistical improvement but small clinical benefit. § Dose-response effect with higher doses.

Raina P et al, Annals of Intern Med 2008 Burns A et al, Dem & Geri Cog Dis 1999,10:237-44.

Cholinesterase Inhibitors


Winblad B et al Neurology. 2001;57:489-495. Tariot PN et al Neurology. 2000;54:2269-2276. Corey-Bloom J et al. Int Jour of Geri Psychopharm. 1998;1:55-65.


Burns A et al, Dem & Geri Cog Dis 1999,10:237-44.

CD

R-S

B s

core

Time

Cholinesterase Inhibitors Name Donepezil Mechanism of Action Degrades acetylcholinesterase, increasing the

neurotransmitter acetylcholine. Indication Originally mild to moderate AD,

Evidence for efficacy in severe dementia Dose 5mg at night +/- increased to 10mg Titration Over one month Duration of Rx Unknown. Indefinitely?? When to stop. Side effects GI, dizziness, headaches. SA, AV block Cautions Sick Sinus Syndrome, PUD, Asthma, COPD, sleep

disturbances USP (unique selling point)

Greatest evidence base OD regime Evidence in AD & VaD


Cholinesterase Inhibitors Name Galantamine Mechanism of Action Degrades acetylcholinesterase Indication Mild-moderate AD/VaD Dose 4 bd increased to 8-12mg bd Titration Over one month Duration of Rx As per Donepezil Side effects GI, dizziness, headaches. Caution Sick sinus syndrome, CCF,PUD, asthma, COPD, GI

obstruction. USP (unique selling point)

Validated in AD & VaD (Bär KJ, et al. Stroke 2007;38). Single study shows improved carer burden scores.


Cholinesterase Inhibitors Name Rivastigmine Mechanism of Action Degrades acetylcholinesterase Indication AD, and Parkinson's dementia Dose 1.5mg-6mg bd Titration 1.5mg bd increasing by 1.5mg bd per two weeks Duration of Rx As per Donepezil Side effects GI, dizziness, headaches. Rarely PUD, pancreatitis. Cautions PUD, Sick sinus syndrome,asthma, COPD, Bladder

outflow obstruction. USP (unique selling point)

Indication for Parkinsons Available in patch Some evidence of improved ADLs v placebo


Quaseem A et al. AIM 2008;148:370-378.


§ Similar side effects: -gastrointestinal (up to 25%), -cardiovascular (1-10% dizziness and syncope, arrhythmias, < 1%). § SE’s are infrequent: -Of 162 older patients newly started none developed neg chronotropic effects, arrhythmia,or hypotension after 1/12. § Treatment is usually initiated after an ECG.

Turan Isik A et al. Am J AD & Other Dem 2012;27( 3): 171-74.


Rowland JP et al. Advances in Psychiatric Treatment 2007;13: 178-184.


Monitoring ChEIs § Unknown which patients are likely to respond. § While similar, ChEIs differ in how they are taken and SE’s. § Switching?: When intol SE’s or lack of efficacy. §  -SE’s: Stop the first agent & wait until SE’s have resolved for 48-720. §  -Efficacy: Direct switch 240 after stopping first agent. §  -Benefits of switching is unknown.

Quaseem A et al. AIM 2008;148:370-378. Figiel GS. J Clin Psychiatry 2008;10:291-8.

§ Approx 15% of patients will stabilise/improve with ChEIs.

§ NNT=10 (4-point improvement in ADAS-cog). § Short cognitive tests can be used to follow

patients, but may be insensitive to small changes (MMSE).

§ Expectations need to be explained to patients & families.

Bowie P et al. Lancet 1999;354:1527-8. Lanctôt KL et al. CMAJ 2003;169:557-64.

Monitoring ChEIs

§ Evidence for benefit in advanced dementia (299 patients, mean MMSE 11.7/30).

§ Adverse events…up to 83% of donepezil….80% of placebo patients.

§  If patients are stable there is a risk of deterioration when medications are discontinued.

§ This may be overcome with gradual dose reduction. § Little evidence in end-stage dementia. § Resistance from families to stopping.

Feldman H et al. Neurology 2001;57(4):613-20. Pakrasi S, et al. Int J Geriatr Psych 2006;21:719-21 Shega JW et al. Journal of Pall Med 2009, 12(9):779-783.

Cholinesterase Inhibitors When to stop?

Cholinesterase Inhibitors When to stop?

Memantine § Neuropeptide-modifying agent. Partial antagonist of the N-methyl-D-

aspartic acid receptor. § Licenced for Mod-Severe AD/VaD. § Little evidence for efficacy in mild dementia. § Prevents excess stimulation of the glutamate system, which

influences memory and learning. § With or without ChEIs: Improved benefits over ChEI montherapy. § Slows cognitive and functional decline. § Few SE’s at all stages of cog impairment/ § Can be used as monotherapy.

Tariot PN, et al. JAMA 2004;291(3):317-24. Gautier S et al. Alzheim Dem 2013 9(3):326-31. Howard R et al. NEJM 2012,366(10):893-903. Ng B et al. AIM 2011;155(10):JC5-10.

Memantine Name Memantine Mechanism of Action Partial antagonist of the N-methyl-D-aspartic acid

receptor, limiting excess stimulation of the glutamate system.

Indication Mod-severe dementia (AD/VaD). Dose 5-20mg Titration By 5mg per week to 20mg. (BD versus OD prep) Duration of Rx As per ChEIs Side effects GI, dizziness, headaches. Very rarely seizures or

pancreatitis Caution Hx of convulsions, renal impairment**.

** Reduce to 10mg od (Periclou A et al. Clin Pharm Ther 2006;79(1),134–143).

USP (unique selling point)

Reduced agitation reported in clinical trials Evaluated in those with both AD & VaD Apparent improved QoL

Memantine

Memantine & BSPD § When prescribed alone in moderate to severe AD, results in

less: §  - Agitation, §  - Aggression, §  - Psychotic symptoms (delusions and hallucinations). §  - Memantine can prevent onset of these symptoms.

Reisberg B et al. NEJM 2003; 348:1333-1341. Cummings JL et al. Neurology 2006;67(1):57-63. Wilcock GK et al. J Clin Psych 2008;69(3):341-8. Gauthier S et al. Int J Geri Psych 2008;23(5):537-45.

Appropriate To con&nue

Appropriate To discon&nue

Condi&onal

Treatment of Parkinsons, Lewy Body Dementia. § Cochrane review (2012) supports use of ChEI in PDD

(rivastigmine). §  Insufficient evidence for ChEIs in LBD. § Benefits of Memantine in PDD are uncertain. § Memantine improved global functioning & BPSD in those with

mild to mod LBD.

Rolinski M et al. Cochrane Database Syst Rev. 2012 Emre M et al. Lancet Neurol 2010;9(10):969-77.

§ Cholinergic system not affected. § No effect of memantine. § Personality & mood changes are common. § Mixed data for Selective Serotonin Reuptake Inhibitors

(SSRIs). § Recent RCT suggests that they can impair learning/cognition,

with little effect on behaviours.

Sowden JS et al. BJP 2002;180:40-3. Vercelletto M et al, JAD 2011;23(4):749-59. Deakin JB et al. Pyschopharm 2004;172:400-8.

Treatment of Parkinsons, Lewy Body Dementia.

Ginkgo biloba

“Gingko” § Also known as the Maidenhair tree. § Unique species of tree with no living relatives. § A “living fossil”, 270 mil years old. § Native to china. § Extracts from leaves.

Ginkgo biloba § Herbal remedy with antioxidant effects. § No benefit in healthy adults or in the prevention of dementia. § ? Mechanism: mitochondrial stabilization? § 120-240mg. § Statistically significant improvement in cognition v placebo

(AD, VaD & Mixed). § Small effect (3%), limited f/u (52 weeks).

Weinmann S et al, BMC Geriatrics 2010

Vitamin E

Vitamin E § Group of 8 fat soluble compounds. § Lipophilic antioxidant. § Protects membranes from oxidative damage by free radicals. § Doses > 1000mg/day (1500iu) à Vit K def/bleeding

diathesis.

Vitamin E- Evidence

§ No effect on preventing conversion of MCI to dementia. § Concern that high-dose (>400iu/day) Vit E supp may increase

mortality. § Recent study in patients with mild-mod AD (MMSE 12-26)

established on a ChEI. § Pts randomised to Vit E (2000iu) +/-memantine or placebo. § Vit E group 19% RRR without increased mort.

Peterson R et al NEJM 2005; 352:2379-2388. Edgar R et al. AIM 2005;142(1):37-46. Dysken MW et al. JAMA 2014;311:33.

B12 & Folate § Folate is one of the most common nutritional deficiencies in

developed world. § B12/folate lower homocystine levels. § Cochrane review (2003): No evidence that B12 or folate

improve cognition in those with dementia.

Malouf R et al. Cochrane Database Syst Rev 2003.

Mood in dementia § Depression is associated with cognitive impairment and is

highly prevalent in patients with dementia: up to 50% in some studies.

§ “ Are you depressed?” , “Do you often feel down-hearted & blue?”.

§ Geriatric Depression Scale (short-form:15 questions:>5 à depression), best in MMSE >15.

§ Cornell scale (care provider administered), best in more severe dementia .

§ SSRI are typically first line agents e.g Escitalopram

Chahine et al, Int J Geri Psych 2007

§ Good blood pressure (BP) control is associated with a reduced incidence & progression of CI (MCI & dementia).

§ Complex association: some studies suggest anti-hypertensives increase CI & mortality!

§ Few studies designed specifically to examine the effects of anti-hypertensive agents on CI are available.

§ Several antihypertensive agents have been proposed. § Centrally acting agents may reduce rates of cognitive &

functional impairment.

Rosenberg P et al. Am J Geriatric Psychiatry 2008;16:883-892. Kehoe PG et al. J Alzheimer's Disease 2013;33(4):999-1008. Gao Y et al. BMJ Open Jan 7;3(1). O’Caoimh R et al, J Alzheimer's Disease 2014; 40 (3):595-603. O’Caoimh R et al, J Alzheimer's Disease 2014;42 S 4:575-86.

Hypertension & Cognitive Impairment

Behavioural & Psychological Symptoms of Dementia (BPSD) § 90% of patients & prevalence increases with severity. § Patient centred care and psychosocial interventions proven. § Memantine (AD, VaD & LBD). § SSRIs have little role in managing the BPSD unless co-

morbid depression. § Anti-psychotics are associated with increased mortality &

stroke. § Co-administration of ChEIs: Donepezil & Olanzapine but not

Quetiapine can precipitate Extrapyramidal SE’s.

Peters KR et al. Neurology 2006;66(4):523. Fossey Je al. BMJ 2006;332(7544):756-61. Sink KM et al. JAMA 2005;293(5):596. Nirogi R. Eur J Drug Metab Pharmacokinet. 2012.

BPSD: Antipsychotics NICE guidelines recommend

Appropriate starting doses:

Haloperidol PO / IM 0.5 mg od or bd Olanzapine PO tablet 2.5 mg od or bd

Olanzapine PO wafer 5mg od or bd

QueIapine PO 12.5mg od or bd Risperidone PO 0.5 mg od or bd

Slide courtesy of Dr S Kennelly

BPSD typically not responsive to pharmacologic management § Wandering and disorientation. (There is no drug that makes a wandering patient sit by their bed!) § Hiding and hoarding. § Repetitive Activity. § Inappropriate Voiding. § Eating inedible objects. § Vocally Disruptive Behaviour. § Inappropriate (un)dressing.

Slide courtesy of Dr S Kennelly

Future? § Tau aggregation inhibitors. § AD characterised by accumulation of B-Amyloid & the

microtubule associated protein: Tau. § TAI directly interfere with self-assembly of tau microtubules. § Plans to target intra & extracellular Tau molecules.

Bulic B et al. J Med Chem 2013;13;56(11):4135-55.

Future? § Monoclonal antibody therapy. § Preliminary evidence that Bapineuzumab lowers CSF

biomarker levels in patients With mild-mod AD. § Phase 3 trials of Solanezumab for mild-mod AD failed to

show improvement. § Similarly Bapineuzumab treatment despite differences in

APOE E4 carriers failed to showed clinical improvement. § Recent secondary (July 2015) analysis from the

Solanezumab trial showed some benefits (?34% reduction) on slowing disease progression (Eli Lilly).

Blennow K et al. Arch Neurol. 2012;69(8):1002-1010. Doody RS et al. NEJM 2014; 370:311-321. Salloway S et al. NEJM 2014; 370:322-333.

What should your patient be getting? § No evidence for pharmacological treatment in MCI.

§ Start ChEI only when clear evidence of functional impairment. § Consider addition of Memantine in Moderate-Severe dementia. AD à Donepezil, Galantamine +/- Memantine. VaDà Donepezil, Galantamine +/- Memantine. PDDà Rivastigmine +/- Memantine. FTDà No established treatment. LBDà Memantine. §  Increase to max dose tolerated.

What to give your patient? § Monitor & Rx Hyperchol & consider Vitamin E. § Monitor & Rx HTN (use a centrally acting anti-hypertensive in

preference?). § Vitamin supplementation. ? Vitamin E in those with mild AD. § Avoid antipsychotics. § Patient centred care and psychosocial interventions are the

mainstay of treatment.

Pharmacological Treatment?

Part 3. Non-pharmacological interventions

Overview of Non-pharmacological Management § Cognitive Stimulation Therapy: Memory Gyms including

cognitive (brain) training. § Lifestyle modification. § Art therapy. § Alzheimer Cafés.

Memory Intervention & Support Services (MISS) at St Finbarr’s Hospital

MISS

Memory Clinic

Memory Gym

Memory “Café”

MISS

Memory Clinic

Memory Gym

Carers Training Program

Memory “Café”

Memory IntervenIon & Support Services (MISS)

Cognitive Training § Guided practice with batteries of standardized tasks

reflecting particular cognitive domains such as memory, attention, language and executive function.

§ Tasks are designed to increase or at least maintain cognitive function.

§ Can be categorized as compensatory or restorative. § Compensatory approaches teach new ways to perform

cognitive tasks to partly overcome existing cognitive deficits. § Restorative approaches aim to maintain / enhance

functioning in specific domains.

§ Mixed evidence. § Restorative cognitive training has modest treatment effects in

Alzheimer' disease. § A 2012 meta-analysis of patients with mild to moderate dementia

indicated trends towards benefit in cognition. § Small but again inconsistent improvement in ADLs. § “Brain training” apps have shown similar success to direct

instructional techniques, with significant cognitive benefit up to 24 weeks post treatment.

Cognitive Training

Memory Gyms § Memory gyms (also referred to as brain or dementia gyms)

have emerged, predominantly in the United States, as commercial entities, with the aim of maintaining a healthy mind and body.

§ These gyms can be physical spaces or websites. § Provide both physical and mental exercise programmes to

people with normal cognition who are worried about memory loss and those diagnosed with MCI or dementia.

Cork Memory Gym

§ Case-control study. § Comparing a six-week “memory-gym” group-therapy

programme to usual care. § Consecutive patients diagnosed with either MCI or early

dementia. § Single university hospital memory clinic. § Patients were included only if baseline and end-point

(standardised at 6 months apart) scores were available for the following:

-SMMSE, Qmci, Caregiver Scores (Modified Zarit § One six-week programme with one booster session at three

months with Facebook support.

Memory Gym

Memory Gym

Life-style modification Foods §  -Omega 3 fatty acids supplements reduced cerebrovascular disease (Chowdhury et

al BMJ 2012). §  -Beetroot (high nitrate content) reduces Hypertension. (Ahlualia et al Hypertension

2013). §  -Alcohol- Red wine ? All types: Inverse relationship with memory disorders

(Wayerer et al Age and ageing 2011) & lowers BP (Chiva-Blanch et al Circ Res 2012). §  -Chocolate lowers Stroke (Larsson Neurology 2012) & BP too (Ried et al Cochrane review

2012). §  -Coffee & Green Tea; esp in midlife reduced risk of memory loss (Journal of AD

Eskelinen et al 2009).

§  -Mediterranean Diet (Olive oil & nuts) reduced incident CI (Tsivgoulis et al Neurology 2013).

Exercise §  -Aerobic exercise reduces mild cognitive impairment (Baker et al Arch Neuro 2010).

§  - Association between midlife cardiorespiratory fitness levels and later-life memory loss ( Defina et al Ann Intern Med 2013)

Art & Memory § Art therapy uses artistic creativity to encourage

communication, increase attention and stimulate participation.

§ Can trigger dormant memories. § Useful in those with reduced verbal skills or difficulties with

communication including behaviours that challenge. §  Improves quality of life.

§ Systematic review: different interventions: music, visual arts, drama therapy, dance/movement therapies.

§  (1) inadequate elucidation of study design, including description of activities and methods utilized;

§  (2) poor or unspecified, if any, measurement tools; §  (3) over-emphasis on clinical outcomes: vast majority of

patients (>80% in some studies) expressed pleasure with visual arts.

Beard L. Dementia 2011, 11(5) 633–656.

Evidence Base

Figure 1. Life expectancy at age 50 of male artists (acoustic, literary and visual), the elite born between 1700 and 1899 and the middle class born between 1850–1899.

Mirzada F, Schimberg AS, Engelaer FM, Bijwaard GE, van Bodegom D, et al. (2014) Arts and Ageing; Life Expectancy of Historical Artists in the Low Countries. PLoS ONE 9(1): e82721. doi:10.1371/journal.pone.0082721 http://127.0.0.1:8081/plosone/article?id=info:doi/10.1371/journal.pone.0082721

Health benefits.....??

Alzheimer/Memory “Cafés”

Alzheimer/Memory “Cafés” § Post-diagnostic support groups for patients/families/others

(carers etc). § Offer strong educational component. § Run 10-12/year in a café style atmosphere. § Sessions last around 1½- 2 hours. - ½ hr: socialization/tea/music/Q&A - ½ hr: education session - ½ hr: linked activity § Drop in/ no formal referral required.

Cork Alzheimer Café

Final thoughts.... § Diagnosis of cognitive impairment remains clinical although this

may change over time. §  Increasing prevalence means that if treatments improve early

diagnosis will become more important and screening may occur in community settings.

§ A cure is unlikely but multiple pharmacological and non-pharmacological approaches will reduce the incidence.

§ Dementia management in Ireland is where cancer care was 20 years ago: The “A” and the “D” words are equivalent to the big “C”.

§  Increasing awareness and risk modification is key and is everyone's responsibility.

Questions?

Dementia diagnosis, pharmacological and non-pharmacological interventions

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