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Translating dementia research into practice

Dementia research update

Professor Henry BrodatyDirector

Dementia Collaborative Research Centre – Assessment and Better Care

© DCRC/Brodaty 2012

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What’s new in What’s new in diagnosis?diagnosis?

Translating dementia research into practice © DCRC/Brodaty 2012

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Developments in diagnosisDevelopments in diagnosis

• New diagnostic criteria for DSM-V– “Major Neurocognitive Disorder”– Perminder Sachdev



New diagnostic criteria New diagnostic criteria 1. Preclinical AD: Earliest signs of disease,

before symptoms are noticed– Measurable changes in biomarkers

2. MCI due to AD: Mild changes to memory & thinking abilities

– Measurable but do not affect everyday activities

3. Dementia due to AD: Memory & thinking changes that impact daily life

Albert et al, Alzheimer’s & Dementia. 2011; 7(3): 270-279; Dubois et al, Lancet Neurol. 2010; 9:1118-1127; McKhann et al, Alzheimer’s & Dementia. 2011; 7(3): 263-269; Sperling et al, Alzheimer’s & Dementia. 2011; 7(3): 280-292.

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Advances in biomarkersAdvances in biomarkers• Cerebrospinal fluid

– Amyloid Protein (A) – Tau Protein (t and p)

• MRI scans – serial, fMRI• SPECT scans + dopamine label• PET Scans + amyloid ligands

– PiB and florbetapir Scans from the - online newspaper of Prof Yasser Metwally http://yassermetwally.wordpress.com/dementia-alzheimer-type-and-others/neuroimaging-of-dementia/

Healthy

MCI

AD

Healthy



Progressively increasing cerebral amyloid burden disclosed by Pittsburgh Imaging Compoud B (PiB) positron emission tomohraphywith increasing APOE ε4 gene dose in asymptomatic individuals age 50–69 years old, and in patients with probable Alzheimer’s disease.

Caselli & Reiman. J Alz Dis. DOI 10.3233/JAD-2012-129026


Consequences of biomarkersConsequences of biomarkers

• Presymptomatic diagnosis• Alzheimer’s disease without dementia!• Issues – Conceptual – what is disease

– Ethical – Dx without Rx– Technical – reliability of tests– Cost– Availability - rural, dev. world



Definition of diseaseDefinition of disease

• What is AD?• Can there be Pre-symptomatic AD?• “A disease is any disturbance or anomaly

in the normal functioning of the body that probably has a specific cause and identifiable symptoms”


http://www.ict-science-to-society.org/Pathogenomics/disease.htm


Multiple pathologiesMultiple pathologies

• 20-30% of people with brain pathology of AD at post-mortem did not have dementia in life

• 75% of dementia occur in people aged 75+ • With older age correlation between AD

pathology and clinical symptoms decreases as vascular and other pathologies increase

• In Honolulu Asian Ageing Study best correlate with dementia was micro-infarcts not plaques



Dementia is a dimensional disease, on which Dementia is a dimensional disease, on which we apply categorical distinctionswe apply categorical distinctions

• Similarly apply cut-offs for pathology – eg number of

plaques at autopsy or on PiB imaging


Procrustes at work


Which combination of biomarkers best Which combination of biomarkers best predicts dementia?predicts dementia?

• Which aMCI are most likely to convert to AD?• What value is added by biomarkers over a selection

strategy based on cognition + genotype?

Strategy: 2 yr follow-up, sample from ADNI• aMCI converters (n = 25) vs. stable (n = 38)


Yu et al 2012 J Alz Dis DOI 10.3233/JAD-2012-120832

Which combination of biomarkers best predicts dementia?


Accuracy in aMCI for biomarker combinations in addition to ApoE genotype, ADAS-Cog & MMSE (= ‘none’) predicting AD within 2 years


Which combination of biomarkers best Which combination of biomarkers best predicts dementia?predicts dementia?

• Most of increased power of tests due to MRI • FDG-PET & CSF incremental benefits• Considering time and costs



Combination Se Sp Costs Time

ApoE, ADAS-Cog, MMSE 52 68 -26% 1.85yr

MRI, ApoE, ADAS-Cog, MMSE 76 79 -26% 0.63yr

MRI, FDG-PET, CSF , ApoE, ADAS-Cog, MMSE

81 80 +19% 0.47yr


Preclinical AD & pre-symptomatic interventionPreclinical AD & pre-symptomatic intervention

• Interventions after cognitive symptoms develop may be too late

• Distinguish preclinical AD from normal ageing– Genetic factors– Neuropathology– Imaging– CSF– Neuropsychology


Caselli & Reiman. J Alz Dis. DOI 10.3233/JAD-2012-129026

Is amyloid hypothesis Is amyloid hypothesis still tenable?still tenable?

Translating dementia research into practice© DCRC/Brodaty 2012

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16

CSF Aβ42

Amyloid imaging

FDG-PET

MRI hipp

CSF tau

Cog

Function


Protective mutationProtective mutation

• 0.5% of people in Iceland have a protective gene that prevents cognitive decline in old age 5x > likely to reach 85 with no AD

• Mutation reduces ability of enzyme (BACE) to break APP into smaller amyloid-β chunks


Jonsson et al. 2012: doi:10.1038/nature11283

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Aβ Deposition in Autosomal Dominant AD yrs before expected clinical symptoms

Carriers

Noncarriers

- 20y - 10y 0 yEstimated yrs from Sx onset

Bateman et al. N Engl J Med 2012; 367:795-804


DIAN study – appearance before DIAN study – appearance before expected symptom onsetexpected symptom onset

• -25 years: CSF Aβ42 • -15 years: Aβ deposition detected by PiB PET• -15 yrs: CSF tau protein & brain atrophy• -10 y: cerebral metabolism; episodic memory• - 5 yrs: global cognition (MMSE, CDR)• 0 – estimated symptom onset• + 3 yrs: criteria for dementia met 3 years after SxBateman et al, 2012


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What’s new in drug What’s new in drug treatment of treatment of

Alzheimer’s disease?Alzheimer’s disease?



Amyloid Amyloid plaqueplaque


Tangles – tau proteinTangles – tau protein

Partner logo hereProteolytic Processing of APP Gives Rise to Proteolytic Processing of APP Gives Rise to

CP1217358-1

sAPPsAPP

C83C83

sAPPsAPP

AICDAICD

sAPPsAPP

Courtesy of Ron Petersen

Partner logo hereBest target for disease-modifying drug?Best target for disease-modifying drug?

-secretase inhibitor?

-secretase inhibitor?

•A oligomer?

•Aggregated fibrillar A ?

•A clearance mechanism?

•APP/ A processing?

Slide courtesy of Colin Masters

Partner logo herePartner logo hereSome failed strategiesSome failed strategies• Block -secretase: semagecestat X• Block amyloid aggregation: Alzhemed X• Selective Amyloid Lowering Agent: Tarenflurbil X• Mitochondria: Dimebon X• Immunotherapy: bapineuzemab X solanezumab X

ponezumab Abandoned• Leutinising hormone antagonist: Leuprolide X• Rosiglitazone X, Statins X, Anti-inflammatories X


Partner logo hereSemagacestat Semagacestat

(gamma secretase inhibitor)(gamma secretase inhibitor) Phase III trial (“IDENTITY”)

Active arm deteriorated more rapidly Toxicity

Rash, skin cancers Hair whitening Diarrhoea


Strategies under trialStrategies under trialBlock β-secretase: Merck

Immunotherapy: Gantenerumab

- Intravenous Gamma Globulin (IVIG)

Intranasal insulin

Metal ions: PBT2

Tau: Rember

234 intervention trials now recruiting www.clinicaltrials.gov.au (22.09.2012)


http://www.clinicaltrials.gov.au/


Patents expirePatents expire

• Galantamine • Memantine • Donepezil March 2013 • Rivastigmine (patch few years)

• Generics come on market, costs decrease


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Non-pharmacological Non-pharmacological treatmenttreatment



Physical activity = protectivePhysical activity = protective• Several studies show physical

activity protective against cognitive decline, dementia, Alzheimer’s, vascular dementia

• More is better – puffed, weights

• At least 3x per week; > 150 mins/wk

• Check with your doctor1Jedrziewski et al (2007). Alz Dem; 3:98-108; 2 Lautenschlager et al (2008) JAMA; 300(9):1027-1037; 3Ravaglia et al (2007) Neurology; 4Larson et al (2006) Ann Intern Med; 144:73-81; 5Laurin et al, Arch Neurol 2001;58:498-504; 6Middelton et al, PLos ONE 2008;3(9):e3124

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Aerobic exerciseAerobic exercise• Meta-analysis of RCTs: aerobic exercise

training improves attention, processing speed, executive function & memory; effects on working memory less consistent

Smith et al. Psychosomatic Medicine 2010;72:(3) 239e252.


Physical exercise & cognitive trainingPhysical exercise & cognitive training

• Physical exercise interventions– Improvements to cognition were associated

with biomarkers• Increased hippocampal blood flow• Increased levels cortisol, insulin, BDNF

• Cognitive training also showed assocn between cognition & neuroplasticity biomarkers


Amoyal & Fallon Topics in Geriatric Rehabilitation 2012;28(3,): 208–216.

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-1

-0.5

0

0.5

1

1.5

6 mths 12 mths 18 mths

mea

n di

ffere

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on A

DAS

-Cog

fr

om b

asel

ine exercise group

control group

Improvement

Decline

Exercise

© DCRC/Brodaty 2010Lautenschlager et al (2008) JAMA; 300(9):1027-1037

N =138 memory complainers

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The power of physical activityThe power of physical activity

Erickson et al., 2011


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Mind your brain: Mind your brain: Accumulating evidence Accumulating evidence

for mental exercise/ for mental exercise/ cognitive trainingcognitive training


Mental Activity & Dementia Mental Activity & Dementia 1,21,2

• Meta-analysis of 22 studies, 29,000 people• Lifetime: Education, occupation, IQ, leisure

each reduce risk by about half• Late life: ↑ complex mental activity ↓ risk of

dementia by half

• Dose - response relationship evident• Complex patterns of mental activity in early,

mid- and late-life associated with ↓ dementia

1Valenzuela MJ. Sachdev P. (2006). Psychol Med. 36(4): 441-454; 2Valenzuela MJ. Sachdev P. (2006) Psychol Med. 36(8): 1065-1073


Cognitive interventions healthy older Cognitive interventions healthy older adults & people with MCIadults & people with MCI

• Systematic review articles 2007-2012; 27 RCTs, 8 clinical studies. Cognitive training

• Majority - memory was outcome measure• 21 RCTs w healthy adults - memory improved in 17/20• 6 RCTs with MCI - memory improved in 4/6• Do improvements generalise to everyday activities??• Benefits preserved for 1-4 months; longer ??


Reijnders, J., et al., Ageing Res. Rev. (2012), doi 10.1016/j.arr.2012.07.003


Work & hippocampal atrophyWork & hippocampal atrophy

• 151 cognitively intact; mean age 80.8yrs• Follow-up over 2-3 years• Supervisory work in mid-life associated with

5x slower hippocampal atrophy in late-life• Not age, sex, Px activity, Apoε4, depressn

• Suggests link between mid-life cognitive lifestyle & long-term neuroplasticity


Suo et al NeuroImage 2012; 63: 1542-1551.


Cognitive stimulation for dementiaCognitive stimulation for dementia• Cognitive stimulation

– Activities for PWD eg reality orientation • Meta-analysis (n = 718; 15 RCT)• Benefit to cognition ES 0.41 (95% CI 0.25-0.57)

– 377 intervention/ 281 control; 15 studies• Benefit to communication & social interest

– ES 0.44 (0.17-0.71); 132/91; 4 studies • Also self rated well being & QoL

© DCRC/Brodaty 2012Aguirre, E., et al., Ageing Res. Rev. (2012), doi10.1016/j.arr.2012.07.001

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Cognitive training in ADCognitive training in AD• RCTs of multidomain CT in AD have

demonstrated positive effects on global cognitive measures and functional measures

Gates N, Valenzuela M. Current Psychiatry Reports 2010; 12:20-27


Study of Mental & Regular Training (SMART)Study of Mental & Regular Training (SMART)

• Aim: Does increased mental activity lead to decreased dementia risk?

• Intervention: 3 days/wk for 6 months– Memory series + stretching/callisthenics– Memory series + strength exercise – Memory & thinking exercises +

stretching/callisthenics – Memory & thinking exercises + strength

• Follow up after 1 year to test for lasting benefits


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Sleep, meditationSleep, meditation• Sleep – night (& daytime naps) enhance

memory, creativity• Meditation training: meta-analysis

– medium to large effect sizes for changes in emotionality and relationship issues

– medium effect sizes for attention– smaller effects on memory and several other

cognitive capacities (Sedlmeier et al., in press)

Dresler M et al, 2013 Neuropharmacology

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tDCStDCS

• Transcranial direct current stimulation (tDCS)– 1-2 mAmps, safe– Correct polarity and placement– Enhance memory and learning– Especially combined with cognitive training

• Trial for MCI in 2013 at CHeBA– Mohan, Martin, Loo, Brodaty, Sachdev

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PreventionPrevention


Environment and ADEnvironment and AD

• Up to 50% of population attributable risk of AD cases from 7 environmental factors

• If 25% lower prevalence of these risk factors 3 million fewer AD cases worldwide


Barnes D & Yaffe K, 2011


How much AD can be attributed to How much AD can be attributed to environmental factors?environmental factors?

• 2% diabetes mellitus (type 2)• 2% midlife obesity*• 5% midlife hypertension• 10% depression• 13% physical inactivity*• 14% smoking• 19% cognitive inactivity/education#


Barnes D & Yaffe K, 2011

Dementia risk reduction signposts

MIND your DIET

MIND your BODY

MIND your BRAIN

MIND your HEALTH CHECKS

MIND your SOCIAL LIFE

MIND your HEADMIND your HABITS

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Translating dementia research into practice

Study 1: • > adherence to Mediterranean

diet dementia risk ↓• “Dose” dependent effect Study 2: • N= 2364 Ss, FU 4.5 yrs• 275 incidents of MCI• Effects on incident MCI and

progression from MCI to AD

Scarmeas et al, Arch Neurol. 2006;59:912-921 Scarmeas et al, Arch Neurol. 2009;66(2)216-225

Mediterranean Diet to Prevent MCI & ADMediterranean Diet to Prevent MCI & AD

K.Seeher

7 categories: dairy, meat, fruits, vegetables, legumes, cereals and fish, for beneficial components 0 if below median, 1 if above median, for detrimental components 1 if below median, 0 if above median.8th category: fat intake: ration of daily consumption of unsatured to satured lipidsalcohol intake: 0 = no consumption or >30g/day, 1=moderate consumption.


Mediterranean diet & cognitionMediterranean diet & cognition

• Prospective cohort study N = 1410• Med diet assoc with fewer MMSE errors• Not associated with

– Incident dementia– Other cognitive tests (IST, BVRT, FCSRT)


Feart et al. JAMA. 2009;302(6):638-648


Mediterranean DietMediterranean Diet

• PATH Through Life study• N = 1528 (60-64 yrs); Follow-up 5yrs• 10 MCI, 19 CDR=0.5, 1491 healthy• 37 transitioned to any impairment at f/up• Med diet not protective against cognitive decline• Fish intake was protective for non clinical group


Cherbuin & Anstey. Am J Geriatr Psychiatry 2012 20:7, 635-639.


Fruit & vegetablesFruit & vegetables

• Cohort studies, 6months +• 9 studies, N = 44,004• Increased vegetable intake associated

with lower dementia risk & slower rates of cognitive decline

• Evidence for fruit intake is lacking


Loef & Walch. J Nutrition, Health & Aging. 2012 ; 16(7): 626-630.

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BPSDBPSD


Pharmacological interventions apathyPharmacological interventions apathy

• Review of pharmacological interventions– NHMRC Levels of Evidence (I-IV)

• Drugs reviewed:– Cholinesterase inhibitors– Memantine – Antipsychotics– Antidepressants– Stimulants– Other


Berman K et al. Am J Ger Psychiatry Epub Aug 11 2011, doi:10.1097/JGP.0b013e31822001a6


Pharmacological interventions apathyPharmacological interventions apathy

• Cholinesterase – supportive for their use• Memantine – limited evidence• Antipsychotics – no sound evidence for benefits in

general. Some evidence that atypical antipsychotics may help but ??? dependent on psychosis– Risks of stroke and death in dementia

• Antidepressants – good evidence they are not effective


Berman K et al. Am J Ger Psychiatry Epub Aug 11 2011, doi:10.1097/JGP.0b013e31822001a6


Non pharm interventions for apathyNon pharm interventions for apathy

• Therapeutic activities – has the best evidence for effectiveness

• Music therapies – some evidence, no RCTs• Exercise – RCT no sig effect• Multi-sensory – RCT no sig effect• Animal therapies – some positive trials


Brodaty H & Burns K. Am J Geriatr Epub Aug 19 2011, doi:10.1097/JGP.0b013e31822be242


CG interventions for BPSD in communityCG interventions for BPSD in community

• Reviewed effectiveness of community based psychosocial interventions

• 23 RCT or pseudo-randomised• Effective at reducing BPSD

– ES 0.34 (95% CI=0.20–0.48, p < .01)• Improved CG reactions to symptoms

– ES 0.15 (95% CI=0.04–0.26, p = .006)

Brodaty H & Arasaratnam C Am J Psychiatry 2012;169:946-953


The Sydney Multisite Intervention of The Sydney Multisite Intervention of LaughterBosses and ElderClowns (SMILE)LaughterBosses and ElderClowns (SMILE)

• Significant decrease in agitation in humour group vs controls at post and follow-up

• Depression and quality of life improved if allow for dose of intervention, commitment of Laughterbosses and Management support

• Key is resident engagement resident engagement which is facilitated by Laughterbosses & Management



Clinically significant?Clinically significant?

• 20% reduction in agitation symptoms in SMILE• The same effect size as is achieved by

antipsychotic medications used to treat agitation

OR


Antipsychotics and dementiaAntipsychotics and dementia• Antipsychotics only partially successful at reducing

agitation & other behavioural problems• Increase risk of stroke and death• 180,000 PWD (UK) treated with antipsychotics

– 36,000 derive some benefit– 1800 might die– 1620 might suffer cerebrovascular event


Banerjee 2009. The use of antipsychotic medication for people with dementia


Analgesics and BPSD Analgesics and BPSD

• Cluster RCT; N = 352 RACF residents; mod-severe dementia; clinically sig behavioural disturbances

• Stepwise protocol for Rx pain (8wks) vs. usual Rx• Intervention: individual Rx of pain w. paracetamol

(70% of residents), buprenorphine transdermal patch, morphine or pregabaline

• Primary outcome: agitation (CMAI)


Husebo et al. BMJ. 2011; 343: d4065.



Cohen-Mansfield agitation inventory scores, with 95% confidence intervals, over study period

Husebo et al. BMJ. 2011; 343: d4065.


Dementia time to deathDementia time to death• The impact of dying decreased with age• Survival times varied (1.1- 8.5 yrs• longest max survival = AD

• Absolute loss of life was greatest for women, patients with YOD, FTD, DLB, young-onset AD, & mod/severe dementia

• Patients w. YOD, VaD, FTD & severe dementia lost at least 50% of remaining life expectancy

Brodaty H, Seeher K, Gibson L Int Psychog, 24:7, 1034-1045


Sydney Centenarian StudySydney Centenarian Study

• Currently 3154 centenarians in Australia• Fastest growing age group world wide

– Models of ‘successful ageing’• Aims: better understand physical & mental

health of this group– Which factors contribute to longevity?

• 274 people aged 95+ recruited


Sachdev P et al., 2012 Under review


Sydney Centenarian StudySydney Centenarian Study

• 95-106 years old; 41 were 100+ years old• 28% men; 55% lived in private home• 87% impaired on ADLs• 72% satisfied with their general health• Cognitively and functionally impaired, yet the

exceptionally old demonstrate ability to view life with satisfaction and majority continue to live independently in the community


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Diagnosis of Dementia in a Centenarian Cohort N=274Cases with complete data

Cases above or below dementia cut-off

N n %MMSE 255 136 53ADL 185 155 83BADL 156 68 43CDR 110 61 55IQCODE 104 53 51Previous diagnosis of dementia 123 28 22

MMSE and ADL 171 94 55MMSE and BADL 146 38 26MMSE and CDR 96 43 44

(MMSE or ADL) and previous diagnosis of dementia 122 19 15(MMSE or BADL) and previous diagnosis of dementia 119 16 13

(MMSE or CDR) and previous diagnosis of dementia 121 15 12

(MMSE and ADL) or previous diagnosis of dementia 109 76 69(MMSE and BADL) or previous diagnosis of dementia 98 44 45

(MMSE and CDR) or previous diagnosis of dementia 65 35 53

Rate of dementia =12 – 83%

If exclude need for previous formal Dx and 1 outlier, rate of dementia = 26 –55%

Overall, median 50% have dementia

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• Wave 1: 36.1% (99/274)

• Wave 2: 31.1% (28/90)

• Impaired cognition defined as MMSE < 24, or if test missing because person judged too cognitively impaired to do the test

• Impaired function classification was based on 4 impairment variables:– ADL > 12– B-ADL ≥ 3– CDR 4 (household tasks) >3– IQCODE > 3.31

Impaired if >2 of above

DementiaDementia

Partner logo hereThank you and Megan HeffernanThank you and Megan Heffernan

www.dementiaresearch.org.au

Jeanne Calment

1875-1997

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