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

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AD AnticholinergicScopolamine

Cholinesterase Inhibition

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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