2. Dementia – epidemiology
Worldwide
18 million people
By 2025 ~ 34 million
71% in developing countries
In Europe
5 million people
In UK
775, 000 people
<65 years ~ 18, 000
By 2010 ~ 870, 000
By 2050 ~ 1.8 million
Financial cost ~ $5.5 billion a year in Canada (1994-1998)
3. Challenges
Early detection
Clinical history
Diagnostic tests
Understanding pathogenesis
Autopsy material
Animal models
in vitro systems
Development of effective therapeutic strategies
5. Biomarkers for
early disease detection
Genetic
Identifies “at risk” population
? if and when disease develops
Doesn’t detect pre-clinical or clinical manifestations
NB “sporadic” disease
Neuroimaging
In vivo neuropathology?
Clinical
“mild cognitive impairement” (MCI)
Distinction from normal ageing
Biochemical
Serum
CSF
6. Positron emission tomography (PET)
Cerebral blood flow
Energy metabolism
Neurotransmitter function
Imaging abnormal proteins
β-amyloid
Advances in imaging
Mathis et al. (2005) Arch Neurol, 62:196-200
8. Animal models – APP transgenics [Bloom et al (2005) Arc Neurol, 62:185-187]
9. Animal models – tau transgenics [Gotz et al. (2001) Brain Res Rev, 35:266-286]
10. Therapeutic strategies – Alzheimer’s
disease
Already available [Francis et al. (2005) TIPS 26(2):104-111]
FDA approved
Tacrine (1993)
Donepezil (1997)
Rivastigmine (2000)
Galanatamine (2001)
Trials completed, data not yet released
Phenserine
Trial in progress
TAK147
Huperzine A
Huperzine B
11. Therapeutic strategies –
Alzheimer’s disease
Decrease level of Aβ42 in brain
Small molecule inhibitors of β-secretase
β-secretase deletion few adverse effects
Small molecule inhibitors of γ-secretase
Has numerous substrates
Prevent aggregation of A-β
Anti-Aβ immunotherapy
Active vaccination with Aβ
Meningoencephalitis in 6% of treated patients – trial halted
Passive infusion of Aβ antibodies
Anti-inflammatory drugs
Inconclusive initial trials
Derivatives lacking cyclo-oxygenase inhibitory action , but retaining
ability to lower Aβ currently in trial
12. The future – Alzheimer’s disease
Selkoe (2005) Arch Neurol, 62:192-195
Risk assessment for AD
Family history
Neuropsychological assessment
Screening for known genetic risk factors
Measurement of plasma and/or CSF Ab (and tau)
Quantitative imaging assessment of amyloid load
Treatment plan….
How about other neurodegenerative diseases?
14. Protein aggregation
Taylor et al. (2002) Science 296:1991-1995
AD
• amyloid
• tangle
Pick’s disease
• tau
Prion disease
• PrPSc
amyloid
Parkinson’s
disease
• α-synuclein
15. Therapeutic strategies –
neurodegenerative diseases
Cause
Targets for prevention of protein accumulation
β-sheet breakers
Immunotherapy
Effect
Targets for prevention of neuronal loss
Prevention of excitotoxicity
Neurotrophic factors
Anti-oxidants
Anti-inflammatory drugs
Stem cell treatment
Scale of variant CJD and iatrogenic CJD diseas???…….
16. Farming Today reveals how beef
which could have been
contaminated with BSE reached
the UK food chain.
We ask how robust the system
designed to protect the public
from CJD really is.
And the Food Standards Agency
tells us why it failed to issue a
public health alert.
Radio 4 FARMING TODAY 17th
march 2005
www.bbc.co.uk/radio4/news/farmingtoday
17. BSE beef 'entered UK food chain'
17th
March 2005, http://news.bbc.co.uk
Beef which could have
been contaminated with
BSE or mad cow disease
has entered the UK food
chain.
The Food Standards Agency
told the BBC it did not alert
the public because the meat
had probably been already
eaten.
18. Wash helps stop “Mad cow”
transmission in surgery
25th
February 2005, http://today.reuters.co.uk
“British scientists said on Friday they had developed a cheap and
effective detergent wash that virtually eliminates the risk of spreading
variant Creutzfeld-Jakob disease, or “mad cow” disease, via surgical
instruments.
……..
‘It is not dissimilar from biological washing powder’, Jackson said.
‘It is easy to do and relatively cheap and fits in with existing hospital
sterilisation methods’.”
20. Francis PT et al. (2005) A preclinical view of cholinesterase
inhibitors in neuroprotection: do they provide more than
symptomatic benefits in Alzheimr’s disease? Trends in
Pharmacological Science 26(2):104-111
Youdim MBH et al. (2005) Mutlifunctional drugs for various CNS
targets in the treatment of neurodegenerative disorders. Trends
in Pharmacological Science 26(1):27-35
Migliore L et al. (2005) Searching for the role and the most
suitable biomarkers of oxidative stress in Alzheimer’s disease
and in other neurodegenerative diseases. Neurobiology of
Ageing, 26:587-595
Mathis CA et al. (2005) Imaging technology for
neurodegenerative diseases. Progress toward detection of
specific pathologies. Archives of Neurology, 62:196-200
References (for interest)
21. References (for interest)
DeKosky ST et al. (2003) Looking backward to move forward:
Early detection of neurodegenerative disorders. Science,
302:830-834
Mallucci et al. (2005) Rational targeting for prion therapeutics.
Nature Reviews Neuroscience, 6:23-34
Selkoe DJ (2005) Defining molecular targets to prevent
Alzheimer’s disease. Archives of Neurology, 62:192-195
Bloom FE et al. (2005) Mouse models of human
neurodegenerative disorders. Archives of Neruology, 62:185-
187
Farah MJ (2005) Neuroethics: the practical and the
philosophical. Trends in Cognitive Sciences, 9(1):34-40
Taylor JP (2002) Toxic proteins in neurodegenerative disease.
Science, 296:1991-1995