Olfactory Deficits and Donepezil Treatment in Cognitively Impaired Elderly
Condition: Alzheimer Disease; Mild Cognitive Impairment; Delirium, Dementia, Amnestic, Cognitive Disorders
MeSH terms: Alzheimer Disease; Cognitive Dysfunction; Cognition Disorders; Neurocognitive Disorders
Intervention: Donepezil
Intervention description: Donepezil 5mg will be given for 4 weeks and if tolerated, the dose will be increased to 10 mg per day. The dose range of 5 to 10 mg of donepezil per day will be continued for the study duration, and this is the recommended dose for donepezil in the treatment of mild to moderate Alzheimer's disease. For patients who do not tolerate donepezil or have a history of intolerance to donepezil or cannot take donepezil for other reasons, treatment with other cholinesterase inhibitors (galantamine or rivastigmine) is permitted at any stage of the protocol. Data will be analyzed in two ways: for donepezil alone, and for any cholinesterase inhibitor (donepezil or rivastigmine or galantamine) as the intervention.
Intervention MeSH terms: Donepezil
Phase: Phase 4
Study type: Interventional
Primary purpose: Prevention
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 121.0
Sex: All
Minimum age: 55 Years
Maximum age: 95 Years
Healthy volunteers: No
Keywords: Smell; Olfaction Disorders; Atropine; Donepezil; Cholinesterase Inhibitors; Cognition Disorders

Summary:

      Olfactory identification deficits occur in patients with Alzheimer's disease (AD), are
      associated with disease severity, predict conversion from mild cognitive impairment (MCI) to
      AD and are associated with healthy elderly subjects developing MCI. Odor (olfactory)
      identification deficits may reflect degeneration of cholinergic inputs to the olfactory bulb
      and other olfactory brain regions. Acetylcholinesterase inhibitors (ACheI) like donepezil
      show modest effects in improving cognition but can be associated with adverse effects and
      increased burden and costs because of the need for prolonged, often lifelong, treatment.
      Converging findings on odor identification test performance (UPSIT, scratch and sniff 40-item
      test) from four pilot studies, including two of our own, suggest that acute change in the
      UPSIT in response to an anticholinergic challenge (atropine nasal spray), incremental change
      over 8 weeks, and even the baseline UPSIT score by itself, may predict cognitive improvement
      with ACheI treatment in MCI and AD. If change in odor identification deficits can help to
      identify which patients should receive ACheI treatment, this simple inexpensive approach will
      advance the goal of improving personalized treatment, improve selection and monitoring of
      patients for ACheI treatment, reduce needless ACheI exposure with risk of side effects, and
      decrease health care costs.
    

Eligibility criteria:

        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.