Study on the Effect of 40 Hz Non-Invasive Light Therapy System

Official title

ALZLIGHT Stage III - Study on the Effect of 40 Hz Non-Invasive Light Therapy System

Overview

The ALZLIGHT STAGE III Study is a continuation of the ALZLIGHT Pilot - Study on Safety, Feasibility and Neural Activation of Non-Invasive Light Therapy System. As with the first two stages, this study will examine whether entrainment of 40 Hz neural oscillation by novel 40 Hz Invisible Spectral Flicker is a potential therapy for Alzheimer's Disease. In order to examine this, 62 patients with mild to moderate Alzheimer's Disease will be recruited. The patients will be exposed to the Non-Invasive Light Therapy System for 1 hour a day for 6 months. The effect will be measured by a combination of electroencephalography, cognitive testing, functional magnetic resonance imaging, magnetic resonance spectroscopy and actigraphy.

Detailed description

Recent studies in mouse models of Alzhimer's Disease (AD) have shown that exposure to 40 Hz stroboscopic light therapy for one hour a day, resulted in slowing disease progression and lead to multiple neuroprotective effects such as cognition and memory recovery, and even scavenged both tau and Aβ protein species. Hence, the 40 Hz stroboscopic light therapy has a considerable potential for treatment of humans.

This study will utilize a novel way of masked light by alternating the spectral composition of a white light, rendering the flicker invisible to the conscience perception, while still entraining 40 Hz oscillations in the brain.

In the study, 62 patients with probable mild to moderate AD will be exposed to either invisible spectral flickering light through the Light Therapy System (LTS) (active setting) or continuous non-flickering white light (sham setting) for 1 hour each day. The sham setting is a high quality sham intervention as subjects will be blinded to the setting, both appear as white light.

The study participation will last 12 months for each participant and consist of 3 periods: An enrollment period, a randomized intervention period of 6 months, and 6 months of active intervention.

In order to test whether the LTS intervention is a potential treatment for AD, cognition will be measured by neuropsychological tests at baseline and at follow-ups. To get a better understanding of the potential effects, markers of efficacy based on MRI, MRS, EEG and blood samples will be tested.

The results from this study will increase the understanding of the impact of gamma oscillations in the human brain, and how it can be utilized as a novel and important tool for the treatment of neurodegenerative diseases.

Interventions

• Device Light Therapy System (LTS): Active Setting
  Exposure for 1 hour á day for consecutive days
• Device Light Therapy System (LTS): Sham Setting
  Exposure for 1 hour á day for consecutive days

Primary outcome measures

• Gamma oscillations assessment [Time frame: Change from Baseline to 6 months]
• Induction of 40 Hz Gamma oscillations [Time frame: Change from Baseline to 6 months]

Secondary outcome measures (12)

• Cognition and memory assessment [Time frame: Change from Baseline to 6 months and 12 months]
• Cognition and memory assessment [Time frame: Change from Baseline to 6 months and 12 months]
• Cognition and memory assessment [Time frame: Change from Baseline to 6 months and 12 months]
• Connectivity measures [Time frame: Change from Baseline to 6 months]
• Connectivity measures [Time frame: Change from Baseline to 6 months]
• MR Spectroscopy [Time frame: Change from Baseline to 6 months]
• Sleep Quality [Time frame: Change from Baseline to 6 months]
• Sleep Quality [Time frame: Change from Baseline to 6 months]
• Biomarkers of Alzheimer's Disease [Time frame: Change from Baseline to 6 months]
• Safety Assessment [Time frame: 12 months]
• Feasibility assessment [Time frame: Baseline to 6 months]
• Compliance assessment [Time frame: Baseline to 6 months]

Eligibility criteria

Inclusion criteria

• Adult competent person, able to understand the nature of the study and give written informed consent.
• Diagnosed with probable mild to moderate AD based on NIA-AA diagnostic criteria or in a prodromal stage of AD with at least one positive biomarker of AD.
• Age > 40 years. Females must be post-menopausal.
• Fluent in Danish.
• > 8 years of normal school education
• Pass a color-blindness test (Ishihara color test)
• Have visual and auditory capabilities, and language skills necessary for neuropsychological testing.
• Participants must have a designated caregiver, who is available to the participant and can provide the necessary assistance with using the LTS device and the Actigraph wearable at home and assist with clinical visits and other practical issues

Exclusion criteria

• Profound visual impairment (visual acuity > 0.5) provided correction with spectacles, if needed
• Significant abnormalities related to important parts of the brain, e.g., the visual system, prefrontal cortex, or hippocampus, or relevant lesions detected by pre-trial imaging.
• Prior history of significant diseases related to the visual system or the brain.
• Medication: Use of any antiepileptic drugs, neuromodulating drugs or high dose of sedatives will be excluded.
• Prior history of substance abuse within the past 2 years.
• Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the PI)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Denmark · 1 center

• Zealand University Hospital — Roskilde

Publications

• Kasteleijn-Nolst Trenite D, Rubboli G, Hirsch E, Martins da Silva A, Seri S, Wilkins A, Parra J, Covanis A, Elia M, Capovilla G, Stephani U, Harding G. Methodology of photic stimulation revisited: updated European algorithm for visual stimulation in the EEG laboratory. Epilepsia. 2012 Jan;53(1):16-24. doi: 10.1111/j.1528-1167.2011.03319.x. Epub 2011 Nov 16. PMID 22091642
• Herrmann CS. Human EEG responses to 1-100 Hz flicker: resonance phenomena in visual cortex and their potential correlation to cognitive phenomena. Exp Brain Res. 2001 Apr;137(3-4):346-53. doi: 10.1007/s002210100682. PMID 11355381
• Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, Young JZ, Kim DN, Kritskiy O, Barker SJ, Mangena V, Prince SM, Brown EN, Chung K, Boyden ES, Singer AC, Tsai LH. Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition. Cell. 2019 Apr 4;177(2):256-271.e22. doi: 10.1016/j.cell.2019.02.014. Epub 2019 Mar 14. PMID 30879788
• Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O, Abdurrob F, Adaikkan C, Canter RG, Rueda R, Brown EN, Boyden ES, Tsai LH. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016 Dec 7;540(7632):230-235. doi: 10.1038/nature20587. PMID 27929004
• Adaikkan C, Tsai LH. Gamma Entrainment: Impact on Neurocircuits, Glia, and Therapeutic Opportunities. Trends Neurosci. 2020 Jan;43(1):24-41. doi: 10.1016/j.tins.2019.11.001. Epub 2019 Dec 10. PMID 31836315
• Adaikkan C, Middleton SJ, Marco A, Pao PC, Mathys H, Kim DN, Gao F, Young JZ, Suk HJ, Boyden ES, McHugh TJ, Tsai LH. Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron. 2019 Jun 5;102(5):929-943.e8. doi: 10.1016/j.neuron.2019.04.011. Epub 2019 May 7. PMID 31076275
• Alawode DOT, Heslegrave AJ, Ashton NJ, Karikari TK, Simren J, Montoliu-Gaya L, Pannee J, O Connor A, Weston PSJ, Lantero-Rodriguez J, Keshavan A, Snellman A, Gobom J, Paterson RW, Schott JM, Blennow K, Fox NC, Zetterberg H. Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease. J Intern Med. 2021 Sep;290(3):583-601. doi: 10.1111 PMID 34021943
• Benedet AL, Mila-Aloma M, Vrillon A, Ashton NJ, Pascoal TA, Lussier F, Karikari TK, Hourregue C, Cognat E, Dumurgier J, Stevenson J, Rahmouni N, Pallen V, Poltronetti NM, Salvado G, Shekari M, Operto G, Gispert JD, Minguillon C, Fauria K, Kollmorgen G, Suridjan I, Zimmer ER, Zetterberg H, Molinuevo JL, Paquet C, Rosa-Neto P, Blennow K, Suarez-Calvet M; Translational Biomarkers in Aging and Dementi PMID 34661615

Identifiers

NCT: NCT05260177 · ASIII

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗