dementia and alzheimer’s disease - cmg...
TRANSCRIPT
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Dementia And Alzheimer’s Disease
• Functional decline due to cognitive deficits
• 2010 : 35 million people worldwide, 2030: 60 million, 2050: 115 million worldwide.
• Ireland: 4,000 new cases every year- currently around 50,000
• AD- most common cause
• Insidious onset after age 70
• Predominantly amnestic symptoms
• Gradually progressive
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Pathology of AD
1906
Multimodal Pathological Mechanisms
- Lifestyle Events/ Risk Factors
- Vascular Risk Factors- Neuroinflammation- Genetic Risk Factors
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Amyloid hypothesis…sink and tap….
…and interplay of vascular ischaemia and brain blood flow
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Everyone develops Tau pathology as they age Some people develop Amyloid pathology too In them- Tau pathology spreads and prompts a microglial and
astrocytic neuro-inflammatory response This leads to AD Vascular, metabolic and other factors impinge
What most agree on..
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NINCDS ADRDA Alzheimer's Diagnostic Criteria Mc Khann 1984
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Definitions and terminology around AD and the like…
NIA Alz Assoc Working Group Criteria 2011 (Mc Khann)
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Predictive markers and symptoms of AD
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Do these criteria transfer to clinical relevance??
Prodromal AD: 60% progression to AD within 2.5 years versus 4-18%
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So what should the diagnostic paradigm for AD look like now??
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Multi-domain Cognitive, psychological, physical Assessment- Hospital Anxiety Depression Scale- GDS- Cornell Scale Depression in Dementia- Delirium screening- Frontal Assessment Battery- Addenbrookes Cognitive Examination
Executive Function
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Biomarkers are no longer just part of AD research….
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Biomarker of neuronal injury.. Global cortical and Medial temporal lobe atrophy (CT/MRI)
Normal Prodromal/Mild AD Advanced AD
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CSF Amyloid and neuronal injury biomarkers…
• INBIND consensus document
• Online training module
• 4 week turnaround
• Central Lab in SJH:• ↓Aβ 42
• ↑Tau
• ↑ P-tau
http://www.tcd.ie/research/inbind/resources/CSFbiomarkermodule/index.html
AD CSF profile
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Amyloid PET scans: Florbetaben (Priamal April 2017)Others: Florbetapir (Eli Lilly) and Flutemetamol (GE healthcare)
FlorbetabenShelf life up to 10 hours
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AD- “Dangers” of an early diagnosis…
REDUNDANT DEBATE!!!
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Timely diagnosis…
Identification and management of reversible causes or alternative diagnosis
Symptomatic treatment
INFORMATION AND EDUCATION
Patient directed advance care planning
CARER SUPPORT
Mobilisation of support
Management of BPSD- DEPRESSION/ ANXIETY etc.
Key thing is to
ensure support
services in
place
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Dementia Prevention- FINGER study (Finnish)
A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus
control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial
Kivipelto Lancet June 2015
- 1250 participants, population sample, high risk vascular with MCI- Standardised Exercise Program with 3 individually tailored
assessments by physio aerobic/non aerobic, balance and posture- 3 meetings with dietician- Cognitive training: group and individual sessions- Social activities mediated though group sessions- Vascular and metabolic risk factors monitored- Control group: Given information - Only 12% drop out!!- Seven year extension underway
25% higher
83% higher
150% higherOR 1.31
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Cognitive Stimulation…
Wisconsin Registry for Alzheimer’s Prevention (WRAP) 1500 participants
339 (Age 40-65) (Mean age 60) 69% female Cognitively normal
Overall activities measured and “CAS Games: cards, crosswords, puzzles)
Amnestic MCI participants 12 week computer based memory-attention program Improvements in episodic memory and recall At 6 month f/u assessment improvements maintainedNeuropsychologica, 2012
Brain Imaging and Behaviour, 2015
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AD Treatments…A lot of false dawns and reporting
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Disease- modifying treatments
Solanezumab (Eli Lilly)- Passive Immunotherapy humanized monoclonal
IgG1 antibody directed against Aβ peptide- Phase 1 demonstrated changes in CSF/Plasma Aβ
- EXPEDITION 1+2 Phase 3 trial in 2,000 Mild/mod AD, Monthly infusion: Negative overall but…Statistically significant benefit was seen in a pooled analysis of patients with mild AD in both trials
- EXPEDITION 3: 2,100 Mild AD and Amyloid+ Missed primary endpoint!!
- Also: EXPEDITION PRO study (Amyloid +MCI)- just started enrolling
Creneuzumab (Genetech)- Very similar to Solaneuzamab- CREAD Study Phase 3 study in Prodromal AD
started 2016- Graduated dosing protocol
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Aducanumab (Biogen)
- High-affinity, fully human IgG1 monoclonal antibody binds aggregated forms of Aβ, not monomer. In the brain it preferentially binds parenchymal over vascular amyloid- important from SE perspective
- Nature paper Sept 2016- Aducanumab- Phase 2 study 165 mild AD: 4 doses and placebo. Removed amyloid and slowed decline!!
- Monthly infusion for a year- Very few SE’s but a third had ARIA-E’s- Phase 3 studies started ENGAGE and EMERGE
STUDY’S (MCI and Mild AD and PET/CSF amyloid +)
- Recent 2 year data maintained positive results.
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AD prevention studies
DIAN (Dominantly inherited AD Network) (Treatment arm- 2 years Rx with Solaneuzamab or Ganteneurmab) Age 18-80 years and First degree relative with AD gene.
A4 study: Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (PET+) (Rx 39 months Solanuzamab) Age 65-85
Alzheimer’s Prevention Initiative: Autosomal Dominant AD study (300 members of Colombian family with rare genetic
mutation) Crenezumab Generation Study: 1,300 Cog normal people (Age 60-75) APOE ε4 +/+: CAD106 (GSK
active immunotherapy vs CNP520 (Amgen BACE inhibitor)
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In Summary….
International political/societal commitment (G8 declaration)
Better understanding of “life course” of AD- more accurate diagnosis
Pipeline of potential treatments…very cautious optimism!!
Have started thinking in terms of AD Prevention
Key message: Healthy Heart equals Healthy Brain!!
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Thank you