Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly

In this clinical trial, the investigators will evaluate, treat and follow two broad samples
of adult patients at New York State Psychiatric Institute/Columbia University Medical Center.
Study 1 will include 70 patients with amnestic Mild Cognitive Impairment (MCI). Study 2 will
include 100 patients with probable Alzheimer's Disease (AD). Recruitment will be from clinics
and/or advertisements. In the protocol, all 170 patients will receive baseline memory and
olfactory assessments and are treated 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 0, 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 MCI and AD for treatment
based on the evaluation of olfaction tests to predict response to donepezil. Since mild
cognitive impairment is widespread and Alzheimer's disease represents a major public health
problem, this study has considerable public purpose and significance.

Study 1

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-III 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

- Retains capacity to consent

Exclusion Criteria:

- 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 less than or
equal to 2 mg daily and narcotics will also not be permitted.

- Meets criteria for dementia by Diagnostic and Statistical Manual IV (DSM-IV) or
probable Alzheimer's disease by National Institute of Neurological and Communicative
Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association
(NINCDS-ADRDA)

- Meets Diagnostic and Statistical Manual IV Text Revision (DSM IV TR) 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

- Cystic Fibrosis

- 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. Patients already receiving one of these medications at
screening who undergo a 2-week washout before starting all study procedures will not
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.

- 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.

- Exclusion criteria for atropine nasal spray: presence of nasal deformity or disease
that makes it difficult to administer the nasal spray reliably. A patient who cannot
complete the atropine nasal spray procedure can still participate in the rest of the
study.

Study 2

Inclusion Criteria:

- Of either sex, age 55-95 years old

- Diagnosis of probable Alzheimer's disease (NINCDS-ADRDA criteria) and the diagnosis of
"Probable AD dementia: core clinical diagnosis with amnestic or nonamnestic initial
presentation".

- Folstein Mini Mental State (MMSE) score 18-27 out of 30

- Availability of informant

- Retains capacity to consent

Exclusion Criteria:

- 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 less than or
equal to 2 mg daily and narcotics will also not be permitted.

- Meets DSM IV TR 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

- Cystic Fibrosis

- 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. Patients already receiving one of these medications at
screening who undergo a 2-week washout before starting all study procedures will not
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.

- 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.

- Exclusion criteria for atropine nasal spray: presence of nasal deformity or disease
that makes it difficult to administer the nasal spray reliably. A patient who cannot
complete the atropine nasal spray procedure can still participate in the rest of the
study.