Effects of modulating gamma oscillations via 40Hz transcranial alternating current stimulation (tACS) on Tau PET imaging in mild to moderate Alzheimer’s Disease

340 Introduction: Alzheimer’s Disease (AD) is the leading cause of dementia. The therapeutic options are very limited, with some pharmacologic interventions that can temporarily improve memory and cognition but no available disease modifying treatments. AD is characterized by diffuse Aβ and p-Tau aggregates, as well as widespread neurodegeneration. Apart from protein deposition, a consistent finding in patients with AD is a relative attenuation of fast oscillatory activity of the brain in the 30-80 Hz range, known as “gamma” activity. Recently it has been demonstrated that exogenously-induced 40 Hz gamma oscillations can reduce Aβ deposition via microglia activation and may also reduce p-Tau levels in a mouse model of AD. The same authors have also determined that in presymptomatic AD mice, induction of gamma activity prevents subsequent neurodegeneration and behavioral impairments, suggesting that gamma induction may represent a novel and powerful therapeutic approach for AD. The purpose of this study was to determine the ability of Tau Positron emission tomography (PET) imaging to reveal the hypothesized impact of modulation of gamma oscillations in humans with AD. Methods: In this pilot study 5 amyloid-positive patients with mild-to-moderate AD over 65 years old underwent 4 weeks (20 sessions of one hour) of transcranial alternating current stimulation (tACS) at 40Hz to bilateral temporal lobes using a multichannel tCS stimulator (Starstim device, Neuroelectrics Barcelona). tACS uses low amplitude (max 2mA) alternating sinusoidal currents via scalp electrodes to modulate brain cortical rhythmic activity in a frequency-specific manner. Each participant underwent Aβ, p-Tau and Microglia PET imaging measured by [11C]-PiB, [18F]-AV-1451 and [11C]-PBR28 on a Discovery MI (GE Healthcare) PET/CT scanner. Fifty (50) minutes after the injection of a 15mCi (555MBq) intravenous bolus of [11C]-PiB, static data were acquired for 20 minutes. Seventy-five (75) minutes following a 10mCi (370 MBq) bolus injection of [18F]-AV-1451, static data were collected for 30 minutes. Sixty (60) minutes following a 15mCi (370 MBq) bolus injection of [11C]-PBR28, static data were collected for 30 minutes. An X-ray CT scan was performed right before each PET segment for attenuation correction and was obtained using standard acquisition parameters with the GE MI Discovery PET/CT scanner. Reference region-based analysis of [11C]-PiB and [18F]-AV-1451 uptake were performed using the cerebellum (no vermis) and white matter as reference tissues, respectively. Occipital cortex was used as a reference region for analysis of [11C]-PBR28 uptake. Structural Magnetic Resonance Imaging (MRI) was performed for anatomical mapping. PET and MRI scans were acquired before and after the tACS 4-week course. Results: [18F]-AV-1451 PET revealed a trend for a decrease of intracerebral Tau burden following the tACS treatment in 3/5 patients, especially in brain regions targeted by tACS. The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS. No clear effect on microglial activation as indexed by [11C]-PBR28 was noted, possibly due to the timing of post-tACS PET scanning. Conclusion: The study demonstrates preliminary evidence of the potential beneficial impact of gamma-induction tACS protocols in AD, also showing the utility of Tau PET tracers as [18F]-AV-1451 for the reliable detection/quantification of modification in p-Tau deposition in AD. Acknowledgements: DARPA project D17AP00080, RO1A6060981, P41EB022544