Cognitive Dysfunction In Parkinson's

Parkinson's disease (PD) is the second most common neurodegenerative illness (after
Alzheimer's disease) affecting 1-2% of people over age 65.3 Although PD is traditionally
characterized by its motor symptoms (e.g. tremor, stiffness, slowness), research demonstrates
that cognitive dysfunction has a greater impact on patient suffering and caregiver burden
despite being under-recognized. Cognitive dysfunction is a significant risk factor for
psychosis, dementia, nursing home placement and affects 20- 40% of PD patients even at the
time of initial diagnosis.4,5 In patients with PD surviving 20 years or longer, cognitive
dysfunction is the leading cause of nursing home placement and three fourths of PD patients
ultimately develop dementia.6

We know that neurons in the brain communicate with each other by firing at certain
frequencies. A growing literature shows that high frequency (30-50 Hz) brain activity called
gamma activity is particularly important for communication between distant brain areas and is
critical to normal cognition.7 Prior studies also show that gamma activity is reduced in PD.8
However, we do not know why gamma activity is reduced in PD or the relationship between
changes in gamma activity and cognitive dysfunction. We hypothesize that reductions in gamma
activity are a key mechanism underlying cognitive dysfunction in PD and that interventions to
increase gamma activity will improve cognition.

To test this hypothesis we propose to use a novel combination of research methods including
magnetoencephalography (MEG) and repetitive transcranial magnetic stimulation (rTMS). MEG
measures magnetic activity over the scalp to determine brain activity. We will use MEG to
determine whether reductions in gamma activity are related to cognitive dysfunction in PD.
TMS uses a magnetic coil placed over the scalp to stimulate brain activity. While there is
evidence that repetitive TMS (transcranial magnetic stimulation) increases gamma activity and
may improve cognition, it has not been studied for this purpose in PD. We will apply
repetitive TMS to PD patients to determine whether gamma activity and/or cognitive function
may be improved non-invasively.

Inclusion Criteria:

- We will recruit 60 PD patients through the University Colorado Hospital (UCH) Movement
Disorders Clinic diagnosed with probable PD using United Kingdom (UK) Brain Bank
Criteria.

- PD patients will be of mild to moderate severity based on the Hohn and Yahr scale
(score of 3 or less in on medication state) and be on a stable dose of PD medications.

- Clinical severity will also be assessed using the Unified Parkinson Disease Rating
Scale.

- We do not anticipate recruitment to be difficult as UCH Movement clinics see over 800
PD patients annually, the majority of whom are stage 3 or less.

- Controls will be approximately matched for age and gender as a group and recruited
through clinic (spouses) and advertisements in the community.

Exclusion Criteria:

- Subjects will be excluded if they have significant depression (Beck Depression
Inventory33 > 14)

- Dementia (Mini Mental State Examination34 < 26 or Frontal Assessment Battery35 < 14)

- Other neurological or psychiatric illness

- Significant history of head injury, significant systemic medical diseases (e.g. liver
failure, kidney failure, poorly controlled diabetes)

- Deep Brain Stimulation (DBS)

- Cognitive enhancing medications (e.g. stimulants or acetylcholinesterase inhibitors)
or contraindications to either TMS or MRI (pregnancy, pacemaker, unstable cardiac
disease, skull lesion, claustrophobia, history of epilepsy or on medications known to
lower seizure threshold).