The purpose of this study is to evaluate the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a treatment for Alzheimer's disease (AD). The primary hypothesis is that rTMS applied to the dorsolateral prefrontal cortex will lead to improved memory, language and executive function compared to patients who receive a sham, control treatment. The improvement is defined as having higher performance on the California Verbal Learning Test (CVLT-II). Secondary Hypothesis are that 1)rTMS- will lead to higher performance on secondary cognitive measures relating to executive function and naming compared to performance by participants in the sham treatment group at the termination of treatment; and that 2) rTMS-induced memory improvement parallels changes in BDNF levels after treatment. Alzheimer's disease (AD) is extremely common among older adults, and is the most frequent cause of dementia in the general population (Kukull et al., 2002; National Institute of Health, 2010). Current treatments of AD are limited in their effectiveness and do not halt the progress of the disease. rTMS has been found to be effective in several conditions related to AD, and there is emerging evidence to suggest that it may be effective in treating AD (Bentwich et al., 2011; Ahmed et al., 2012, Rabey et al., 2013, Tezzon et al., 2014). Studies show that rTMS modifies the neuronal networking function (Hamidi et al., 2010; van der Werf et al., 2010). Although the exact mechanism by which rTMS causes improvement in cognitive function is unknown, it has been observed that rTMS reversed a decline in brain-derived neurotrophic factor (BDNF), lead to up-regulated NMDA-receptor expression in the hippocampus in mice (Tan et al., 2013) ), and caused increased level of BDNF in chronic pain patients (Dall'Agnol et al., 2014). This study aims to obtain better understanding how rTMS affect BDNF levels and how the change in BDNF level corresponds to cognitive improvement. The literature on rTMS and AD includes several studies, but all have significant limitations. First, studies have not involved comprehensive memory assessment (Bentwich et al., 2011; Cotelli et al., 2006, 2008, 2011), despite memory impairment being a primary deficit in AD (McKhann et al., 2011). Second, some studies have not included a control group or controlled for practice effects on cognitive testing. Third, studie have been limited by small sample sizes, limiting the power to detect effects of rTMS on cognitive functioning. Lastly, no studies have been completed with Veteran patients. This study will include 52 Veterans with a diagnosis of Mild Cognitive Impairment due to AD or Dementia due to AD over a period of two years. To account for an estimated 20% attrition rate, we will recruit an additional 10 participants to ensure a sufficient sample size and power to complete analyses (final sample n = 62). This double-blinded, randomized clinical trial will consist of two groups: Group 1) rTMS treatment group, two treatments applied to the dorsolateral prefrontal cortex 5 days a week for 2 weeks (similar to another ongoing protocol at this site) and Group 2) sham treatment (same frequency and duration). Participants will complete a battery of neuropsychological measures at three time points: initial baseline evaluation, immediately after treatment, and 4 months after cessation of treatment. Adverse effects of rTMS will be recorded carefully. The primary outcome measure will be the California Verbal Learning Test, second edition. Secondary outcome measures will include the Naming subtest of the Neuropsychological Assessment Battery and the NIH EXAMINER (Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research; Kramer et al., 2014). Serum and CSF levels of BDNF and choline acetyltransferase will be collected and analyzed. Apo-e and BDNF genotypes will be determined. Apo-E and BDNF genotypes will be used as moderator of the response. ANOVAs will be used to compare performance on the neuropsychological measures by the treatment and control group at and 4 months after the cessation of treatment.
The largest numbers of Veterans are between 65 and 69 years old and entering an age of increasing risk for developing Alzheimer's disease (AD). If this study finds repetitive transcrania magnetic stimulation (rTMS) to maintain or improve memory functioning in Veterans with AD, this will provide promise for an effective, non- invasive, non-pharmacological treatment for AD. This has the potential to improve the functioning of thousands of Veterans who have AD or who will have AD in the coming years. This may be found to be an efficacious treatment that can be provided at VA medical centers nationwide. If it is effective for AD, then it may also be effective for treating other causes of dementia (e.g., frontotemporal dementia). This study is also expected to improve our understanding how genetic difference affects the individual response to rTMS and increases cost-effectiveness of this potential treatment.
