Deep Brain Stimulation With LIFUP for Mild Cognitive Impairment and Mild Alzheimer's Disease

Alzheimer disease (AD) is a neurodegenerative condition and the most common cause of dementia
or a functional impairment in memory and other cognitive abilities. Prior to developing the
functional impairment of dementia, patients develop mild cognitive impairment (MCI), which
increases the risk for developing the functional impairment of dementia. Deep brain
stimulation (DBS) is of interest as a potential therapeutic option for MCI and AD because it
can directly target and modulate the activity of brain structures implicated in memory
functioning.

Recently there have been multiple reports that DBS of different locations within the brain
may be effective in improving symptoms characteristic of dementia (e.g., Heschman et al.,
2013). For example, Laxton et al. (2010) performed DBS in the fornix/hypothalamus of six
persons with AD in a phase I clinical trial. The investigators hypothesized that stimulation
of the fornix would alter the activity of the medial temporal memory circuits, and thus delay
and/or reverse memory loss. After 6-12 months, the investigators noted improvement or slowing
in the progression of AD in some of the research participants, as measured by two
commonly-used assessments of global cognitive function. In a recent literature review, Laxton
et al. (2013) also described several additional studies demonstrating that DBS of the fornix
or nucleus of Meynert or subthalamic nucleus influences the pathologic neurological circuits
involved in AD.

Four separate groups recently have published reports concluding that ultrasound improves
amyloid-β clearance in mouse models and restores memory (e.g., Leinenga & Götz, 2015). This
finding raises the question of whether one method of DBS, Low Intensity Focused Ultrasound
Pulse (LIFUP), could improve cognition in patients with AD, which is characterized by
abnormal deposition of amyloid plaques in brain regions controlling memory and thinking. The
use of LIFUP in animal models is well described (Bystritsky et al., 2014). LIFUP is able to
penetrate the human skull and reach deep structures within the temporal therapeutic window.
The structures that are reachable by LIFUP include the temporal cortices, hippocampus,
thalamus, and subthalamic nuclei, all of which are implicated in the pathophysiology of AD.
The Food and Drug Administration (FDA) recently approved an investigational device exemption
(IDE) to begin a feasibility and safety trial of LIFUP for persons with refractory seizures.

Although symptomatic treatments are available for AD, their modest effects are temporary and
there is a need for more effective interventions. In the current project, the investigators
propose to use the FDA-approved protocol to:

1. Determine the feasibility of a brief LIFUP intervention (four stimulations of 30 seconds
each, with 2-minute intervals between each treatment) for persons with MCI or mild
(early-stage) AD.

2. As a secondary aim, the investigators will explore whether this brief LIFUP intervention
is associated with improvements on neuropsychological measures of cognitive functioning
immediately following the intervention.

To investigate these aims, subjects with MCI or mild AD will be enrolled. Subjects will be
randomized using a single-blind design, to one of two LIFUP pulsing paradigms in which
activity of neurons in a certain part of the brain are either increased. Subjects will then
be administered four successive LIFUP treatments while the subjects are in a functional
magnetic resonance imaging (MRI). Neuropsychological assessments will be performed at
baseline, immediately after LIFUP is administered, and one week following the conclusion of
the visit.

Inclusion Criteria:

- Mild cognitive impairment or mild (early-stage) AD diagnosis through medical record
review

- Agreement to participate in a clinical and brain imaging study.

- Age 55 years or older.

- No significant cerebrovascular disease as determined by a modified Ischemic Score of ≤
4.

- Availability of a study partner (next of kin, family member) to attend all visits and
to provide surrogate consent should it be determined that the participant does not
have capacity.

- Adequate visual and auditory acuity to allow neuropsychological testing.

- Screening laboratory tests and ECG without significant abnormalities that might
interfere with the study.

- Use of cholinesterase inhibitors for AD (Aricept, Namenda, etc.) will be allowed as
long as the participant has been on a stable dose for at least two months.

- There must be a family member or caregiver available to make sure the participant
gives informed consent, and in case the participant develops cognitive impairment that
interferes with independent study participation.

Exclusion Criteria:

- Evidence of any other major neurologic or other physical illness that could produce
cognitive deterioration, except for mild cognitive impairment (MCI) and any history of
stroke or diabetes.

- History of myocardial infarction within the previous year or unstable cardiac disease.

- Uncontrolled hypertension (systolic BP > 170 or diastolic BP > 100), history of
significant liver disease, clinically significant pulmonary disease, diabetes, or
cancer.

- Major psychiatric disorders, such as bipolar disorder or schizophrenia, or persons
with current untreated major depression

- Current diagnosis or significant history of alcoholism or drug dependence.

- Participants taking medications known to influence cognitive functioning will be
excluded. Medications that will be excluded include: centrally active beta-blockers,
narcotics, clonidine, anti-Parkinsonian medications, benzodiazepines, systemic
corticosteroids, and medications with significant anticholinergic effects,
anti-convulsants, or warfarin. During the screening visit, physicians will review all
medications and determine whether the type, dose, and interaction of medications are
likely to impact cognition and determine exclusion based on these factors.

- Use of any investigational drugs within the previous month or longer, depending on the
drug's half-life.

- Contraindication for fMRI scan (e.g. metal in body, claustrophobia).