1. Advances in Neuroscience - dementia
Dr Betmouni
Department of Neuropathology
Bristol

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

4. Science (2003) 302:830-834

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

7. Genetics
Environment
Symptoms
Signs
Patient
Diagnosis
Prevention
Treatment
??
Understanding pathogenesis
Normal Disease

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?

13. Understanding pathogenesis-
accumulation of abnormal proteins
Taylor et al. (2002) Science 296:1991-1995

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’.”

19. Advances in neuroscience?

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