Brian S. Appleby, M.D. Associate Professor Department of Neurology Update on Clinical Research in Dementia
May 25, 2015
Brian S. Appleby, M.D.Associate Professor
Department of Neurology
Update on Clinical Research in Dementia
Dementia (Symptom not Diagnosis)
Chest Pain• Heart attack• Pneumonia• Muscle strain
Dementia• Reversible causes
– Vitamin deficiency– Depression
• Progressive brain diseases– Alzheimer’s disease– Frontotemporal dementia– Dementia with Lewy bodies
Neurodegenerative Dementias
Protein Misfolding Disorders (PMD)Disease ProteinAlzheimer’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
PMD Origins and PathophysiologyRoot 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
Jack CR, Lancet Neurology 2013
Progression of Alzheimer’s disease
What We Have Now
Cholinesterase Inhibitors
Medication Mechanism of Action
Donepezil AChE-Inh
Galantamine AChE-Inh
Tacrine AChE-Inh
Rivastigmine
AChE-Inh + Butyl-ChE-Inh
Adverse effects=GI upset & bradycardia
Nucleus Basalis of Meynert
Ach
Ach
AD AnticholinergicScopolamine
Cholinesterase Inhibition
Ach
Ach Ach
Ach
Ach
Ach
Ach
Ach
Ach
AchAch
AchE
Benefits
• Possibly decrease neuropsychiatric symptoms• Helps maintenance of daily functional ability• Treatment effect of about 3 years• Approved for use in mild-moderate AD• NO effect on survival time
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
Immunization Strategy
Holmes C, Lancet 2008
No Clinicopathologic Correlation
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”
Ashburn TT, Nat Rev Drug Discov 2004
The Power of Repositioning
Ashburn TT, Nat Rev Drug Discov 2004
Proteinopathies are “prionoid”
Morales R, CNSND-DT 2009
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
• 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
University Hospitals Studies