CURRENT STATUS OF CHOLINERGIC

INTERVENTIONS IN COGNITIVE

IMPAIRMENT

Rachel SchroederSummer Research Institute at FMHI

University of South FloridaAugust 4 t h, 2015

Acetylcholine background

Current treatments for diseases of interestAlzheimer’sSchizophreniaParkinson’s

Problems faced by pharmaceutical companies

Future interventionsBiomarkers

OVERVIEW

It’s a neurotransmitter!

Throughout the BodyMuscle contractionExcretion of hormones

In the BrainAffects cognitionFocus of pharmacological

treatments

ACETYLCHOLINE

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COGNITIVE CHOLINERGIC NUCLEI

Basal ForebrainExecutive functionMemoryLanguageAttention

Medial SeptumSpatial & recognition memoryArousal/Stress

BrainstemSpatial memoryVisual attentionVerbal attentionLearning

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Progressive loss of cholinergic neurons in the NBM and the basal forebrain

Significant decrease in activity of enzyme synthesizing ACh (ChAT)

Presence of amyloid-beta plaques and tau tangles Loss of memory, visual and spatial recognition,

difficulty completing familiar tasks, and confusion

AChEIs may reduce cognitive impairment

ALZHEIMER’S DISEASE

Psychological impairments: delusions, hallucinations, organizational, and motivational impairments

Cognitive impairments: attention, executive function, spatial abilities, language function, and memory

Current Treatments: Antipsychotics nAChR stimulation and AChEIs should be incorporated

SCHIZOPHRENIA

Normally characterized by physical symptoms

Cognitive deficits include visuospatial orientation, working memory, episodic memory, attention, and procedural learning

Current treatments: Dopaminergic precursors for motor impairments nAChR stimulation and AChEIs should be incorporated

PARKINSON’S DISEASE

5.2m Americans with Alzheimer ’s Disease in 2014

More than 3.1m Americans with Schizophrenia in 2014

Almost 1m Americans with Parkinson’s Disease in 2014

COSTS

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PHARMACEUTICALHURDLES

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Longer development periods Regulatory approval: 1.9

years versus 1.2 Phases 2/3 approval: 8.1

years versus <6

Lowest chances of success Phase 3: 54% will fail in

Phase 3, compared to only 34% of non-CNS trials

Costly Loss of patent protection Higher rates of failure

TIME & MONEY CONSTRAINTS

Cognitive impairments are more likely to go unnoticed

Not viewed as life-threatening

Less likely to be made available for Priority Review and Fast Track designation

SALIENCE

High Risk

Low Priority

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Not truly representative: purely symptomatic Can we measure an animal’s

subjective experience?

Transgenic and brain lesion models Mice that enable the use of

cognitive measures used in humans

ANIMAL MODELS

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Placebo Effect: The belief of being treated can be as effective or more than effective than the drug treatment

Genetic and environmental factors Mice are genetically homogenous Generalizability due to environment

Diagnostic tools and methods for objectively measuring and assessing the effects of drugs in the brain

ADDITIONAL ISSUES

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FUTURE INTERVENTIONS

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Unlike definitions of heart disease, lymphoma, or AIDS, the DSM diagnoses are based on clinical symptom clusters

Diagnoses not based on any objective laboratory measure

Equivalent to creating diagnoses based on the nature of the chest pain or the quality of the fever

Thomas Insel, MD, Director of NIMH

NEURODIAGNOSTICS

Diagnostic tools using biological features to measure the presence and progress of disease Early detection of disease Distinction between closely-

related disorders

Move away from treating symptoms to treating the disease

BIOMARKERS

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SUMMARY

Acetylcholine is a neurotransmitter involved in cognition

Cognitive impairments: Promote cholinergic activity

Pharmaceutical companies struggle to develop successful interventions due to Time and money constraints Lack of saliency of mental health disorders Unrepresentative animal models

Biomarkers will improve our understanding of diseases and lead to more effective drug interventions

Drs. Rex Philpot and Lynn Wecker

SRI Mentors and Faculty

National Institute of Mental Health

Louis de la Parte Florida Mental Health Institute

Fellow Student Scholars

ACKNOWLEDGMENTS