CogT BEEM Study (a tDCS Study)

Co-existing neuropsychiatric symptoms (NPS) in patients with mild cognitive impairment (MCI), especially those worsening over time, are associated with more rapid cognitive and functional decline and a greater risk of Alzheimer's disease (AD). Optimal NPS management, meaning effectively managing multiple NPS simultaneously, requires a solid understanding of the shared neural mechanism across NPS. The goal of this proof-of-concept mechanistic intervention study is to validate the causal relationship between a NPS-shared neural circuit the investigators previously discovered and various NPS. The investigators will modify a key region within the NPS-shared neural circuit \[i.e. left precentral gyrus (LPG), critical for regulating visual attention\] with anodal transcranial direct current stimulation (tDCS). Our central hypothesis is that an activation of LPG and a reorganization of NPS-shared neural circuit will link to improvement in multiple NPS. Using a Stage 0 pilot randomized control trial design the investigators will recruit n = 40 older adults with informant-rated NPS that has worsened in the past 2 years, which is considered the most detrimental type of NPS in MCI. The investigators will assign participants to 4-week active anodal vs. sham LPG online tDCS group. The investigators will assess resting-state and visual attention task-related functional MRI and informant-rated NPS at baseline, and the end of week 4 and week 8, and diffusion MRI at baseline. The two primary aims are to determine the effect of tDCS on NPS-shared neural circuit (Aim 1), as well as the relationship between NPS-shared neural circuit and informant-report NPS (Aim 2). The exploratory aim will be to examine the relationship between NPS and the coherence between structural and functional aspects of the NPS-shared neural circuit. Probing the LPG via anodal tDCS provides a way to experimentally test the causal relationship between our previously discovered NPS-shared neural circuit and informant-rated NPS. The proposed research is highly innovative, while scientifically grounded, for targeting one brain region that may affect multiple NPS. Validating the hypotheses has the potential for future R01 study that directly conducts a Stage 2 trial addressing NPS in MCI, and thus ultimately improves patient's quality of life and reducing caregiving burden.


Eligibility Criteria:
Inclusion Criteria:

1. Forty subjects with MCI and comorbid NPS, which have worsened in the past 2 years (as rated by their study-partner's responses to the NPI-Q):

1. In the past month, presence of \> 2 symptoms; and
2. Compared to two years ago, having \> 1 pre-exist symptom whose severity rating has worsened, or having \> 1 new symptom; 2. Consensus diagnosis of "mild cognitive impairment due to Alzheimer's disease" based on 2011 NIA-AA diagnostic criteria by the investigators based on screening information: i. Memory deficits at screening: 1 standard deviation (SD) below age- and/or education- corrected population norms for the Rey Auditory Verbal Learning Test (RAVLT, Lists C\&D); ii. Global memory deficits at screening: Montreal Cognitive Assessment (MoCA, Version 2) total score within the range 18 ≤ x ≤ 26, after educational adjustment; iii. Preserved activity of daily living: ADL-PI-self total score ≤ 30; iv. Absence of dementia. 3. Stable (same dosage, frequency, type) on memory medications for ≥ 3 months before screening; 4. Stable (same dosage, frequency, type) on any anti-depressants, antipsychotics, and/or anxiolytics for ≥ 7 days; 5. Community-dwelling: Subjects live in homes or independent- and assisted- living facilities (i.e. - not nursing home residents, due to the large cognitive variability in nursing home residents); 6. Aged 60-89 years at screening; 7. English-speaking; 8. Adequate visual and hearing acuity for testing; 9. Verified tDCS and MRI safety: Subject should not have any contraindications to either and pass safety screening questions for both (see exclusion section for more information); 10. Capacity to consent, based on responses and ratings to the UCSD Brief Assessment of Capacity to Consent (UBACC) form modified for this study 11. Availability of a study partner who spends at least several hours per week with the subject, supervises his/her care, and who is willing to accompany the subject to some study visits and participate in the study; 12. Informed consent for study participation obtained by both the subject and his/her study partner; 13. Agree to donate 20mL of blood at baseline, after fasting for at least 8 hours (only water and prescribed medicines)

Exclusion Criteria:

* Participants may be excluded from enrollment, or have their enrollment deferred until they are eligible, for the reasons listed below. Final decisions regarding enrollment will be determined by the PI on a case-by-case basis.

  1. Presence of any neurological or vascular disorders (e.g. - Multiple Sclerosis \[MS\], Traumatic Brain Injury \[TBI\], chronic heart failure \[CHF\], Parkinson's disease \[PD\]);
  2. Clinical diagnosis of dementia as defined by the most recent version of the DSM;
  3. Current enrollment in another study aimed at improving cognitive abilities and/or emotional well-being;
  4. MRI contraindications (e.g. - pacemaker, implantable cardioverter defibrillator \[ICD\], aneurysm clips, severe claustrophobia);
  5. tDCS contraindications (e.g. - scalp or skin condition, history of migraines, seizures or epilepsy, and/or strokes, TBI), metallic implants, history of adverse effects to previous tDCS or other brain stimulation techniques).