Repetitive Transcranial Magnetic Stimulation for Apathy in Alzheimer's Dementia

Objective: Alzheimer's Dementia (AD) is a major public health problem. Apathy, a profound
loss of motivation, is seen in majority of patients with AD. Dysfunction of the front of the
brain and loss of dopamine, a type of neurochemical, in this part of brain results in apathy.
Presence of apathy is linked to deficits in planning sequential tasks such as keeping a
routine. Patients with apathy have poor physical function and their caregivers experience
extra burden. Unfortunately there are no good medications to treat apathy. FDA has approved
the use of brain stimulation by a magnet known as repetitive transcranial magnetic
stimulation (rTMS), for treatment of depression. rTMS increases dopamine when applied to
frontal lobe of brain so we propose that rTMS would be a good treatment option for apathy in
AD.

Specific Aims: To determine the efficacy of rTMS to the dorsolateral prefrontal cortex
(DLPFC) in treating apathy in mild AD in comparison to sham treatment.

• To compare the efficacy of rTMS to the DLPFC on executive function in mild AD in comparison
to sham treatment.

Research Plan: Current study is a prospective randomized sham controlled study of daily rTMS.

Methods: Up to 500 subjects will be pre-screened to enroll 100 subjects for screening and
randomizing up to 50 subjects to analyze 20 completers. Subjects with mild AD and apathy will
be randomly assigned to rTMS or sham treatment after consent. All subjects will be tested for
memory, behavioral problems, functioning and caregiver burden. Apathy will be assessed using
the Apathy Evaluation Scale. Memory, executive function, functional status and caregiver
burden will be assessed. Subjects will receive daily treatments for 4 weeks with either rTMS
or sham coil for a total of 20 treatments. Neither the subject nor the investigators will
know which treatment the subject is receiving. Testing will be repeated at the end of 4 weeks
and at 8 and 12 weeks after treatment.

Inclusion Criteria:

1. Subjects age ≥ 55 years,

2. Diagnosis of Alzheimer's dementia meeting the DSM-IV TR criteria,

3. Apathy Evaluation Scale-Clinician (AES-C) score of ≥ 30,

4. Mini Mental Status Examination (MMSE) ≥ 18,

5. Subjects who clear the TMS adult safety scale (TASS)

6. On stable dose of antidepressants or dementia medicines (if applicable) for at least
two months

Exclusion Criteria:

1. Subjects taking medications known to increase the risk of seizures from the 2012 Beers
criteria: Bupropion, chlorpromazine, clozapine, maprotiline, olanzapine, thioridazine,
thiothixene, and tramadol.

2. Subjects taking medications known to increase seizure threshold not listed in the
Beers criteria but in the opinion of PI increase seizure threshold: tricyclic
antidepressants, theophylline, methylphenidate, and high-dose thyroid supplementation.

3. Subjects taking ototoxic medications: Aminoglycosides, Cisplatin.

4. Subjects in current episode of major depression

5. History of bipolar disorder

6. Subjects with history of seizure or first degree relative with seizure disorder

7. Subjects with implanted device: wearable or implantable cardioverter defibrillators,
conductive, ferromagnetic, or other magnetic sensitive metals that are implanted or
are non-removable within 30 cm of the treatment coil or those with cochlear implants

8. Subjects with diagnosis of current alcohol related problems

9. Subjects with history of stroke , aneurysm, or cranial neurosurgery

10. Any condition that in the opinion of the study physician is likely to compromise their
ability to safely participate in the study