Olfactory Deficits in MCI as Predictor of Improved Cognition on Donepezil

New York State Psychiatric Institute

Status and phase: Completed; Phase 4

Conditions: Mild Cognitive Impairment

Treatments: Drug: Donepezil; Drug: Atropine

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT01845636

W81XWH-12-0142 (Other Grant/Funding Number)

6577

Details and patient eligibility

About

Odor identification deficits, which are a result of early Alzheimer's Disease (AD) pathology in the olfactory bulb and tract as well as olfactory projection areas in the medial temporal lobe (entorhinal and piriform cortex and hippocampus), lateral and central orbitofrontal cortex and several other regions, occur in AD and strongly predict mild cognitive impairment (MCI) conversion to AD. Our pilot data, along with converging findings in the literature, suggests that odor identification deficits, both incremental change over time and change in response to an anticholinergic challenge, may be clinically simple, relatively inexpensive, predictors of cognitive improvement with acetylcholinesterase inhibitor (ACheI) treatment with potential clinical implications for predicting improvement and monitoring ACheI therapy.

Full description

In this clinical trial, the investigators will evaluate, treat and follow a broad sample of 60 adult patients with amnestic MCI at New York State Psychiatric Institute/Columbia University Medical Center. Recruitment will be from clinics and/or advertisements. In the protocol, all 60 amnestic MCI patients will receive baseline memory and olfactory assessments and begin treatment with donepezil. Patients will be followed for a total of 1 year. During this time, patients will be monitored closely by the study physician and will receive memory and olfactory assessments at weeks 8, 26, and 52. In addition, an olfactory challenge test will be done at baseline.

This project will be of value in the selection of patients with mild cognitive impairment for treatment based on the evaluation of olfaction tests to predict response to donepezil and other ACheI. Since mild cognitive impairment is widespread and Alzheimer's disease represents a major public health problem, this study has considerable public purpose and significance.

Enrollment: 41 patients

Sex: All

Ages: 55 to 95 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Of either sex, age 55-95 years old

• Patients who meet criteria for amnestic mild cognitive impairment by meeting all of the following:

  (i) subjective memory complaints (ii) Wechsler Memory Scale-R Logical Memory combined Story A + B immediate recall score or combined Story A + B delayed recall score or Free and Cued Selective Reminding Test immediate recall or delayed recall score greater than 1.5 Standard Deviation (SD) below norms or Selective Reminding Test immediate recall or delayed recall score greater than 1.5 SD below norms iii) no functional impairment consistent with dementia

• Folstein Mini Mental State (MMSE) score ≥ 23 out of 30

• Clinical Dementia Rating (CDR) of 0.5 (questionable dementia)

• Availability of informant

Exclusion criteria

• Meets Criteria for dementia by Diagnostic and Statistical Manual IV (DSM-IV) criteria or probable Alzheimer's disease

• Meets DSM IV criteria for:

  (i)schizophrenia, schizoaffective disorder, other psychosis, or bipolar I disorder (ii)alcohol or substance dependence or abuse (current or within past 6 months)

• Current untreated major depression or suicidality

• Parkinson's disease, Lewy body disease, multiple sclerosis, central nervous system infection, Huntington's disease, amyotrophic lateral sclerosis, other major neurological disorder.

• Mental Retardation

• Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (small infarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion.

• Patients receiving cholinesterase inhibitors (donepezil, rivastigmine, galantamine) or memantine will be excluded.

• Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases will be excluded, but past history of successfully treated cancer will not lead to exclusion.

• Medical contraindication to donepezil treatment or prior history of intolerability to donepezil treatment.

• Medications with anticholinergic effects that have been shown to adversely impact cognition will not be permitted. Benzodiazepines in lorazepam equivalents greater than or equal to 2 mg daily and narcotics will also not be permitted.

• Exclusion criterion for olfaction: history of anosmia due to any cause (e.g. traumatic or congenital) verified by UPSIT score of <11 out of 40; head trauma with loss of consciousness; nasal sinus disease, current upper respiratory infection; severe allergies to odors; current smoker > 1 pack daily.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

---

41 participants in 1 patient group

Donepezil Treatment & Atropine Challenge

Experimental group

Description:

Atropine nasal spray is administered at baseline for the atropine challenge which involves administration of the 40-item University of Pennsylvania Smell Identification Test (UPSIT) immediately before and 45 minutes after atropine administration. Immediately after the atropine challenge, donepezil treatment is started and continues for 52 weeks.

Treatment:

Drug: Atropine

Drug: Donepezil