Transcranial Magnetic Stimulation for Apathy in Mild Cognitive Impairment

Apathy, a profound loss of initiative and motivation, is often seen in older Veterans with memory problems. Apathy leads to serious health problems, increases dependency, and caregiver burden. If untreated, apathy hastens the progression to frank dementia. In a pilot study, the investigators found that apathy, working memory, and function can be restored using magnetic stimulation in some but not all older Veterans. The reason for this variation is unknown. The investigators propose a three-phase study in 125 older Veterans with mild memory problems. Their motivation, memory, and function will be measured periodically. Veterans with apathy that are eligible for treatment will receive either real or sham magnetic stimulation to the front part of their brain over 20 sessions. Genetic testing and biomarkers will be used to differentiate those who respond to magnetic stimulation from those who do not. Impact on function, quality of life, and rates of progression to dementia will also be studied.

A project modification was obtained to conduct a cross-sectional study, the COVID Dementia study. The cross-sectional study will examine the effect of the pandemic on MCI and AD patients and their caregivers ("individual COVID-related factors" such as, personally infected, death of a friend/family member, economic hardship, disruption in care, isolation), barriers to telehealth, caregiver distress, NPS, cognition (including onset of delirium), and function. Our goal is to develop a multi-pronged, remotely deliverable intervention to address consequences of healthcare disruptions in older Veterans with cognitive impairment.

Aim 1. To explore the association between COVID-related factors and neuropsychiatric symptoms in individuals with MCI and AD. Hypothesis: The number of COVID-related factors endorsed by caregivers will be positively correlated with the severity of NPI-Q in individuals with MCI and AD.

Aim 2. To assess cognition (telephonic version of the Montreal Cognitive Assessment; tMoCA12, and daily function (Functional Activities Questionnaire; FAQ13). Hypothesis: The number of COVID-related factors will be positively correlated with the severity of cognitive and functional deficits in individuals with MCI and AD.

Aim 3. To explore the associations among COVID-related factors and caregiver distress. Hypothesis: Caregiver resilience and perceived social support will modify the association between COVID-related factors and severity of distress in caregivers.

Apathy, a profound loss of initiative and motivation, is often seen in older Veterans with memory problems. Apathy leads to serious health problems, increases dependency, and caregiver burden. If untreated, apathy hastens the progression to frank dementia. In a pilot study, the investigators found that apathy, working memory, and function can be restored using magnetic stimulation in some but not all older Veterans. The reason for this variation is unknown. The investigators propose a three-phase study in 125 older Veterans with mild cognitive impairment. Their motivation, other behavioral problems, memory, and function will be measured periodically. Veterans with apathy that are eligible for treatment will receive either real or sham magnetic stimulation to the dorsolateral prefrontal cortex over 20 daily sessions on consecutive week days. Genetic testing and biomarkers will be used to differentiate those who respond to magnetic stimulation from those who do not. Impact on function, quality of life, and rates of progression to dementia will also be studied.

A project modification was obtained to conduct a cross-sectional study, the COVID Dementia study. The cross-sectional study will examine the effect of the pandemic on MCI and AD patients and their caregivers ("individual COVID-related factors" such as, personally infected, death of a friend/family member, economic hardship, disruption in care, isolation), barriers to telehealth, caregiver distress, NPS, cognition (including onset of delirium), and function. Our goal is to develop a multi-pronged, remotely deliverable intervention to address consequences of healthcare disruptions in older Veterans with cognitive impairment.

Aim 1. To explore the association between COVID-related factors and neuropsychiatric symptoms in individuals with MCI and AD. Hypothesis: The number of COVID-related factors endorsed by caregivers will be positively correlated with the severity of NPI-Q in individuals with MCI and AD.

Aim 2. To assess cognition (telephonic version of the Montreal Cognitive Assessment; tMoCA12, and daily function (Functional Activities Questionnaire; FAQ13). Hypothesis: The number of COVID-related factors will be positively correlated with the severity of cognitive and functional deficits in individuals with MCI and AD.

Aim 3. To explore the associations among COVID-related factors and caregiver distress. Hypothesis: Caregiver resilience and perceived social support will modify the association between COVID-related factors and severity of distress in caregivers.

Eligibility Criteria:
Inclusion Criteria:

* meeting the modified Mayo Clinic criteria for MCI
* Having caregivers
* apathy threshold (NPI)
* MMSE 23
* On stable dose of antidepressants for at least a month (if applicable)

Exclusion Criteria:

PHASE I

* Uncontrolled diabetes mellitus (Fasting BS\>200mg/dl, HbA1c\>10)
* Renal disease requiring dialysis
* Uncontrolled blood pressure (\>160/100, \<100 systolic)
* Metastatic cancer or undergoing chemotherapy
* Deep venous thrombosis or myocardial infarction in past 3 months
* Uncontrolled malignant cardiac arrhythmia
* Cerebral aneurysm or intracranial bleed in past year
* Unstable angina in past month
* Unstable abdominal or thoracic aortic aneurysm (\>4cm)
* End-stage congestive heart failure

EXCLUSIONARY DUE TO rTMS: ALL PHASE II AND SUBSET OF PHASE I THAT RECEIVE SINGLE SESSION rTMS

* Taking medications known to increase risk of seizures from 2012 Beers criteria such as bupropion, chlorpromazine, clozapine.
* Taking other medications known to increase risk of seizures such as tricyclic antidepressants.
* Taking ototoxic medications: Aminoglycosides, Cisplatin
* History of seizures/ seizures in first degree relatives
* Those with implanted device
* History of stroke, aneurysm, or cranial neurosurgery
* History of bipolar disorder
* Current alcohol related disorder needing medical treatment
* History of Tourette's syndrome or presence of motor tics
* History of abnormal electroencephalogram (EEG)

EXCLUSIONARY DUE TO CONFOUNDING WITH APATHY: PHASE II

* Current episode of Major Depressive Disorder
* Current use of stimulants
* Change in dose of dementia medications within 30 days
* Change in dose of antidepressants within 30 days