This document summarizes recent research in dementia. It discusses that dementia has reversible and progressive causes, with progressive causes including Alzheimer's, frontotemporal dementia, and dementia with Lewy bodies. These progressive dementias are protein misfolding disorders associated with the abnormal accumulation of proteins like amyloid-beta, tau, alpha-synuclein, and prions. Current treatments only provide mild symptomatic benefits and do not treat the underlying causes. Researchers are exploring new targets and compounds, as well as repositioning existing drugs, to develop more effective disease-modifying therapies for Alzheimer's and other dementias.
3. Neurodegenerative Dementias
Protein Misfolding Disorders (PMD)
Disease
Protein
Alzheimer’s disease
A-beta (plaques)
Phosphorylated tau (tangles)
Parkinson’s disease
Alpha-synuclein (Lewy bodies)
Prion disease
Prion protein
Frontotemporal dementias
Various
- Phosphorylated tau
- Ubiquinated inclusions
4. PMD Origins and Pathophysiology
Root Causes
Example
Overproduction of proteins
Trisomy 21, AD
Inefficient protein metabolism
Presenilin mutations in AD
Impaired protein clearance
Tauopathies-impaired transport
Neurotoxicity
Protein oligomers in most PMD
Exictotoxicity
“Working overtime”-glutamate toxicity
Unfolded protein response
Stop making the normal proteins
AD=Alzheimer’s disease; PMD=protein misfolding disorders
11. Memantine
• NMDA antagonist
• Approved for use of moderate-severe AD
• Mild benefits in cognition and clinician’s global
assessment of change
• Not efficacious in mild AD
• NO effect on survival time
14. Immunotherapy Summary
• Early serious adverse effects of cerebral
edema
• Works from a pathophysiologic perspective
• No effect clinically
• ? Need to treat earlier?
• ? Are plaques protective “sinks”
18. Summary
• Pathophysiologic associations are well known;
direct neurotoxic mechanisms are becoming
better understood
• Only symptomatic treatments currently
• Many different targets for future treatments
and many compounds already studied in AD
models
19. University Hospitals Studies
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SNIFF (intranasal insulin for MCI and AD)
A4 (treatment in asymptomatic AD)
Isotretinoin (AD)
ADNI (Neuroimaging in AD)
TauRx (frontotemporal dementia)
FDA diagnostic study for sCJD (sCJD, AD, FTD)
FDG-PET neuroimaging in prion disease
Art therapy in prion disease
Cataracts in dementia