Impact of Photobiomodulation (PBM) on Biomarkers of Alzheimer's Disease

Alzheimer Disease Clinical Trial

— PBMbiomarker  

Official title:

Examining the Impact of Photobiomodulation on Cognition, Behavior, and Biomarkers of Alzheimer's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03405662
• Other study ID #: OsherRAP
• Status: Completed
• Phase: N/A
• Start date: August 16, 2018
• Est. completion date: January 1, 2021

Study information

• Verified date: June 2022
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Photobiomodulation (PBM) describes the use of near-infrared light (which is not visible to the eye) to heal and protect tissue that has either been injured, is degenerating, or else is at risk of dying. Research suggests that the light delivered during PBM enhances the body's biochemical ability to store and use energy and increase blood flow, which triggers the body's natural healing processes. The primary goal of this study is to determine if PBM administered transcranially (through the scalp and skull) and intranasally (inside the nose) with a commercially available device is safe and tolerable for patients with mild-to-moderate Alzheimer's disease (AD). Secondary goals are to examine whether tPBM has an effect on cognitive function and behavioral symptoms in patients with AD and whether tPBM has an effect on fluid biomarkers of AD. A biomarker is a specific physical trait used to measure the progress of a disease or condition.

Description:

Alzheimer's disease (AD), the most common form of dementia, is characterized by the loss of higher brain function such as memory, problem-solving abilities, and language. Photobiomodulation (PBM) describes a kind of light therapy that uses red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. The pathological hallmarks of AD include senile plaques rich in β-amyloid (Aβ) peptide and neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). In animal models of AD, PBM reduces the size and number of brain Aβ plaques, p-tau, and neurofibrillary tangles. PBM also mitigates behavioral deficits in transgenic AD mouse models and humans with dementia. The goal of this sham-controlled pilot trial is to investigate the effects of PBM on the cognitive function, behavioral symptoms, and fluid (i.e., cerebrospinal fluid (CSF) and blood) biomarkers of AD pathology including amyloid burden, tangle pathology, axonal injury, microglia activation/inflammation, and neurotrophic factors in 16 patients with biomarkers-supported probable Alzheimer's dementia, according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.

The main goal of the study is to examine the safety and tolerability of home administered transcranial photobiomodulation (tPBM) with a commercially available device in patients with mild-to-moderate AD. Another goal of the study is to examine the effect PMB on cognitive function and behavioral symptoms in patients with probable AD. The study's final goal is to examine the effects of 16 weeks of PBM on fluid biomarkers of inflammation (i.e., monocyte chemoattractant protein 1 and 3 [MCP-1 and MCP-3] and macrophage inflammatory protein 1β [MIP-1β]), neurodegeneration (i.e., ubiquitin carboxyl-terminal hydrolase isozyme L1 [UCH-L1] and neurofilament light chain [NfL]) and neurotrophic factors (i.e., vascular endothelial growth factor [VEGF] and brain-derived neurotrophic factor [BDNF]). We will also explore the relationship between cognitive and behavioral changes after 16 weeks of PBM with changes in biomarkers of inflammation, neurotrophic factors, and neurodegeneration.

Sixteen patients with biomarkers-supported probable Alzheimer's dementia will be enrolled and randomly assigned to an active or sham PBM group. All patients will be asked to use the Vielight Neuro Gamma (real or sham) device for 20 minutes/day, every other day, for 16 weeks. Randomization with blind assignment will be determined by a computer-generated random allocation. We will assess safety and tolerability by comparing adverse events (AD) in each group. Cognition, behavioral symptoms, and biomarker measures will be assessed in all study participants at baseline and after 16 weeks of PBM. Biomarkers will be obtained through a blood draw and lumbar puncture. A lumbar puncture (also called a spinal tap) is a procedure to collect cerebrospinal fluid, or CSF), which surrounds the brain and spinal cord. During a lumbar puncture, a needle is carefully inserted into the spinal canal low in the back (lumbar area).

Study partners (e.g., caregivers) will be asked to answer questions about the study participant's memory and daily functioning at baseline and after 16 weeks of PBM. Study partners will also be trained and ask to help the study partners administer PBM treatments with the Vielight Neuro Gamma device at home for 16 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: January 1, 2021
• Est. primary completion date: January 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria (for participants with AD):

• Diagnosis of AD supported by AD biomarkers (CSF or amyloid PET)

• Mini-Mental State Exam (MMSE) score > 13

• fluent in English

• has a reliable caregiver/study partner who can help administer and log PBM use

• no history of stroke or seizures

• willing to undergo 2 lumbar punctures approximately 4 months apart

• legally authorized representative consent

Exclusion Criteria: (for participants with AD)

• lack of assent to study procedures

• terminal illness (i.e., life expectancy < 1 year)

• started dementia medication (i.e., cholinesterase inhibitor or memantine) within the past 3 months or planning to start new dementia medication

• current participation in another research study that could potentially confound current study (e.g., medication or behavioral intervention)

• MMSE < 13

• history of structural brain lesions or stroke temporally related to the onset or worsening of cognitive impairment

• history of head trauma associated with injury-onset cognitive complaints or loss of consciousness for 10 minutes or longer.

Inclusion Criteria (for study partners):

• ability to answer questions about the primary participant's memory, behaviors, and activities of daily living

• willingness to help primary participant use and log the use of the Vielight Neuro Gamma device every other day for 16 weeks

• fluent in English

Exclusion Criteria (for study partners):

• major neurological or psychiatric condition

• terminal illness (i.e., life expectancy < 1 year)

• evidence of cognitive impairment

• inability to consent to study procedure

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Device:
• Vielight Neuro Gamma
The Vielight Neuro Gamma is headset that delivers transcranial (through the scalp and skull) and intranasal (through the nose) near infrared (NIR) light. The device is engineered for increased efficacy and easy domestic use for comprehensive brain photobiomodulation (PBM). The NIR lights are pulsed at a 40 Hz rate, which correlates with electroencephalogram (EEG) gamma brain wave entrainment.

Other:
• Sham Vielight Neuro Gamma
The Sham Vielight Neuro Gamma headset is identical to the active Vielight Neuro Gamma headset and intranasal light emitting diode (LED) except it has a power output of 0.

Locations

Country	Name	City	State
United States	UCSF Memory and Aging Center	San Francisco	California
United States	VA Health Care System	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (5)

Berman MH, Halper JP, Nichols TW, Jarrett H, Lundy A, Huang JH. Photobiomodulation with Near Infrared Light Helmet in a Pilot, Placebo Controlled Clinical Trial in Dementia Patients Testing Memory and Cognition. J Neurol Neurosci. 2017;8(1). pii: 176. doi: 10.21767/2171-6625.1000176. Epub 2017 Feb 28. — View Citation

De Taboada L, Yu J, El-Amouri S, Gattoni-Celli S, Richieri S, McCarthy T, Streeter J, Kindy MS. Transcranial laser therapy attenuates amyloid-ß peptide neuropathology in amyloid-ß protein precursor transgenic mice. J Alzheimers Dis. 2011;23(3):521-35. doi: 10.3233/JAD-2010-100894. — View Citation

Grillo SL, Duggett NA, Ennaceur A, Chazot PL. Non-invasive infra-red therapy (1072 nm) reduces ß-amyloid protein levels in the brain of an Alzheimer's disease mouse model, TASTPM. J Photochem Photobiol B. 2013 Jun 5;123:13-22. doi: 10.1016/j.jphotobiol.2013.02.015. Epub 2013 Mar 22. — View Citation

Purushothuman S, Johnstone DM, Nandasena C, Mitrofanis J, Stone J. Photobiomodulation with near infrared light mitigates Alzheimer's disease-related pathology in cerebral cortex - evidence from two transgenic mouse models. Alzheimers Res Ther. 2014 Jan 3;6(1):2. doi: 10.1186/alzrt232. eCollection 2014. — View Citation

Sommer AP, Bieschke J, Friedrich RP, Zhu D, Wanker EE, Fecht HJ, Mereles D, Hunstein W. 670 nm laser light and EGCG complementarily reduce amyloid-ß aggregates in human neuroblastoma cells: basis for treatment of Alzheimer's disease? Photomed Laser Surg. 2012 Jan;30(1):54-60. doi: 10.1089/pho.2011.3073. Epub 2011 Oct 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog)	The ADAS-cog is the most popular cognitive testing instrument used in clinical trials of nootropics. It consists of 11 tasks measuring the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD. Higher ADAS-cog scores indicate greater cognitive impairment.; The changes score was determined by calculating the ratio of the ADAS-cog score at week 16 over the ADAS-cog score at baseline. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in ADAS-cog score compared to baseline.	Baseline to 16 weeks
Secondary	Change in Performance on Color Trails Test (CTT2/CTT1 Index)	CTT is a non-verbal test of visual attention, graphomotor sequencing, and effortful executive processing abilities (i.e., sustained attention and set shifting). A higher index score indicates less cognitive flexibility, a lower ability to shift attention.	Baseline to 16 weeks
Secondary	Change on the Neuropsychiatriac Inventory (NPI)	NPI is a well-validated, reliable, multi-item instrument to assess psychopathology (e.g., behavioral symptoms) in AD based on a questionnaire completed by the participants' study partners. Higher scores indicate more symptoms and/or more severe symptoms.; The changes score was determined by calculating the ratio of the week 16 NPI score over the baseline NPI score. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in NPI compared to baseline.	Baseline to 16 weeks
Secondary	Change on the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL)	ADCS-ADL assesses the competence of patients with AD in basic and instrumental activities of daily living (ADLs). It can be completed by a caregiver in questionnaire format, or administered by a clinician/researcher as a structured interview with a caregiver. ADCS-ADL scores range from 0-53, with higher scores indicating greater independence. The changes score was determined by calculating the ratio of the week 16 ADCS-ADL score over the baseline ADCS-ADL score. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in ADCS-ADL compared to baseline.	Baseline to 16 weeks
Secondary	Change in Plasma Levels of Aß42	Although Aß42 is present in plasma, it is unclear whether it originates from peripheral sources or from the brain. Because Aß can be transported bidirectionally across the blood-brain barrier, it has been hypothesized that there may be an equilibrium between CSF and plasma pools of Aß. Decreased levels of Aß42 in CSF occurs in conjunction with cognitive decline. However, patients with mutations in chromosome 21 that cause early-onset familial AD and patients with trisomy 21 have increased levels of plasma Aß42 before the onset of the symptoms of dementia. Therefore, it is possible that plasma Aß42 levels increase with cognitive decline. The change score was determined by calculating the ratio of plasma Aß42 at week 16 over the ADAS-cog score at baseline.	Baseline to 16 weeks
Secondary	Change in CSF Levels of Aß42.	Aß42 is a biomarker of AD pathology. CSF levels of Aß42 decrease in conjunction with the cognitive decline. The change score was determined by calculating the ratio of CSF Aß42 at week 16 over the ADAS-cog score at baseline. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in CSF levels of Aß42 compared to baseline.	Baseline to 16 weeks
Secondary	Change in Plasma Levels of Tau.	Tau, the microtubule-associated protein, forms insoluble filaments that accumulate as neurofibrillary tangles in Alzheimer's disease (AD). Research suggests that plasma tau levels increased with AD severity. The change score was determined by calculating the ratio of the week 16 plasma tau over the baseline plasma tau levels. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in plasma tau compared to baseline.	Baseline to 16 weeks
Secondary	Change in CSF Levels of Tau	Tau forms insoluble filaments that accumulate as neurofibrillary tangles in AD. Increased levels of tau in CSF is a key characteristic of AD and is considered to result from neurodegeneration. The change score was determined by calculating the ratio of week 16 CSF tau over baseline CSF tau. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in CSF tau compared to baseline.	Baseline to 16 weeks
Secondary	Change in Plasma Levels of Neurofilament Light Chain (NfL)	Neurofilament light chain (NfL) is a marker of axonal degeneration and is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. The change score was determined by calculating the ratio of week 16 plasma levels of NfL over the baseline levels of plasma NfL. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in plasma levels of NfL compared to baseline.	Baseline to 16 weeks
Secondary	Change in CSF Levels of NfL	Neurofilament light chain (NfL) is a marker of axonal degeneration and is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. There is a strong relationship with cerebrospinal fluid (CSF) NfL, suggesting that these biomarker modalities reflect the same pathological process. The change score was determined by calculating the ratio of week CSF NfL over baseline CSF NfL. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in CSF NfL compared to baseline.	Baseline to 16 weeks