Mild Cognitive Impairment: Cerebrovascular Dysfunction and Exercise Training
Specific aim 1a: to determine whether baroreflex function is impaired, leading to enhanced blood pressure instability and thus hemodynamic challenges for brain perfusion in patients with MCI. Baroreflex function will be quantified using both non-pharmacological methods during changes in body position from sitting or squatting to upright standing and using vasoactive drugs (sodium nitroprusside and phenylephrine) to induce transient changes in blood pressure. Blood pressure variability will be quantified under resting conditions and using 24-h ambulatory blood pressure.
Specific aim 1b: To determine whether cerebral autoregulation and cerebral vasomotor reactivity to CO2 are impaired in patients with MCI and whether cerebrovascular dysfunction is associated with atherosclerosis and arterial stiffness. Static cerebral autoregulation will be quantified by measuring changes in cerebral blood flow (CBF) velocity using transcranial Doppler (TCD) during increases and decreases in arterial pressure induced by intravenous infusion of phenylephrine and nitroprusside. Dynamic autoregulation will be quantified during transient changes in arterial pressure using the transfer function methods. In addition, regional cerebral autoregulation and vasomotor reactivity to CO2 will be quantified using functional MRI during transient changes in arterial pressure induced by bolus injecting of nitroprusside and during 5% CO2 breathing. Finally, we will use ultrasound and tonometry technology to measure artery stiffness and carotid artery intima-media thickness (IMT).
Specific aim 2: To determine whether enhanced blood pressure instability in conjunction with cerebrovascular dysfunction leads to brain atrophy, white matter lesions and cognitive impairment. We will use structural magnetic resonance imaging (MRI) to measure the whole brain as well as regional brain tissue volume, brain white matter hyperintensities (WMH) and white matter micro-integrity using diffusion tensor imaging (DTI). We will measure cognitive function using a comprehensive battery of neuropsychological tests focused on memory and executive function.
Specific aim 3: To determine whether exercise training improves cerebrovascular function, brain perfusion and ameliorates brain atrophy, white matter lesions and cognitive decline in patients with MCI and whether exercise training upregulates brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF). We will apply a year-long exercise training program to patients with MCI. A control group of patients with MCI performing flexibility and balance training will be included. Patients will be assigned randomly either to the exercise or the control group. We will measure cerebrovascular function, brain structure and cognitive function as specified above before and after exercise training. Furthermore, we will measure brain derived neurotrophic factor (BDNF) in blood and cerebral spinal fluid (CSF) and measure Aβ and Tau protein in CSF using the standard ELISA method (R and amp;D; Minneapolis, MN). Brain perfusion will be measured non-invasively using both the transcranial Doppler and functional MRl (Arterial-Spin-Labeling) methods.
Specific aim 4: To determine whether exercise training reduces brain amyloid burden in patients with mild cognitive impairment (MCI).
1. Age 55 – 80, all races/ethnicities, and both genders are eligible.
2. For control subjects, absence of cognitive complaints and normal performance in Uniform Data Set (UDS) neuropsychological tests.
3. For patients, diagnosis of amnestic MCI (single and multiple domain) by Petersen’s criteria (as modified for ADNI-GO study).
4. Stable medical condition for > 6 months.
5. Stable medications for > 2 months (use of cholinesterase inhibitors, or prior use of antihypertensive medication or multivitamins are allowed).
6. Caregiver/informant available to accompany patient for scheduled visits.
7. Fluency of subjects or caregivers in English.
8. Ability to return to clinic or laboratory for additional visits over 12 months.
9. Greater than or equal to 10 years of education, or enough work history to exclude mental retardation.
10. Adequate visual and auditory acuity to allow neuropsychological testing.
11. Screening laboratory tests and ECG without significant abnormalities that might interfere with the study.
12. Physical ability to undergo endurance exercise training.