A phase 2, open-label study of anti-inflammatory NE3107 in patients with dementias.

BACKGROUND: Alzheimer's disease (AD) is a progressive, multifactorial, neurodegenerative disorder affecting >6 million Americans. Chronic, low-grade neuroinflammation, and insulin resistance may drive AD pathogenesis. We explored the neurophysiological and neuropsychological effects of NE3107, an oral, anti-inflammatory, insulin-sensitizing molecule, in AD. METHODS: In this phase 2, open-label study, 23 patients with mild cognitive impairment or mild dementia received 20-mg oral NE3107 twice daily for 3 months. Primary endpoints assessed changes from baseline in neurophysiological health and oxidative stress (glutathione level) using advanced neuroimaging analyses. Secondary endpoints evaluated changes from baseline in neuropsychological health using cognitive assessments, including the 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, Clinical Dementia Rating, Quick Dementia Rating Scale, Alzheimer's Disease Composite Score, and Global Rating of Change (GRC). Exploratory endpoints assessed changes from baseline in neuroinflammation biomarkers (tumor necrosis factor alpha, TNF-α) and AD (amyloid beta and phosphorylated tau [P-tau]). RESULTS: NE3107 was associated with clinician-rated improvements in cerebral blood flow and functional connectivity within the brain. In patients with MMSE ≥ 20 (mild cognitive impairment to mild AD; n = 17), NE3107 was associated with directional, but statistically nonsignificant, changes in brain glutathione levels, along with statistically significant improvements in ADAS-Cog11 (P = .017), Clinical Dementia Rating (P = .042), Quick Dementia Rating Scale (P = .002), Alzheimer's Disease Composite Score (P = .0094), and clinician-rated GRC (P < .001), as well as in cerebrospinal fluid P-tau levels (P = .034) and P-tau:amyloid beta 42 ratio (P = .04). Biomarker analyses also demonstrated directional, but statistically non-significant, changes in plasma TNF-α, consistent with the expected mechanism of NE3107. Importantly, we observed a statistically significant correlation (r = 0.59) between improvements in TNF-α levels and ADAS-Cog11 scores (P = .026) in patients with baseline MMSE ≥ 20. CONCLUSION: Our results indicate that in this study NE3107 was associated with what appear to be positive neurophysiological and neuropsychological findings, as well as evidence of improvement in biomarkers associated with neuroinflammation and AD in patients diagnosed with dementia. Our findings are consistent with previous preclinical and clinical observations and highlight a central role of neuroinflammation in AD pathogenesis.

Functional MRI Lateralization [M1] of dlPFC and Implications for Transcranial Magnetic Stimulation (TMS) Targeting.

The present study investigates a potential method of optimizing effective strategies for the functional lateralization of the dorsolateral prefrontal cortex (dlPFC) while in a scanner. Effective hemisphere lateralization of the dlPFC is crucial for lowering the functional risks connected to specific interventions (such as neurosurgery and transcranial magnetic stimulation (TMS), as well as increasing the effectiveness of a given intervention by figuring out the optimal location. This task combines elements of creative problem solving, executive decision making based on an internal rule set, and working memory. A retrospective analysis was performed on a total of 58 unique participants (34 males, 24 females, Mage = 42.93 years, SDage = 16.38). Of these participants, 47 were classified as right-handed, 7 were classified as left-handed, and 4 were classified as ambidextrous, according to the Edinburgh Handedness Inventory. The imaging data were qualitatively judged by two trained, blinded investigators (neurologist and neuropsychologist) for dominant handedness (primary motor cortex) and dominant dorsolateral prefrontal cortex (dlPFC). The results demonstrated that 21.4% of right-handed individuals showed a dominant dlPFC localized to the right hemisphere rather than the assumed left, and 16.7% of left-handers were dominant in their left hemisphere. The task completed in the scanner might be an efficient method for localizing a potential dlPFC target for the purpose of brain stimulation (e.g., TMS), though further study replications are needed to extend and validate these findings.

Transcranial Infrared Laser Stimulation for the Treatment of Traumatic Brain Injury: A Case Series.

Introduction: This study intended to evaluate the safety and possible therapeutic effect of transcranial infrared laser stimulation (TILS) based on photobiomodulation (PBM) among patients with traumatic brain injury (TBI). Methods: Eleven participants who were diagnosed with TBI after full neurological examination and MRI evaluation by a board-certified neurologist completed five to eight 20-minute TILS sessions using the Cytonsys CytonPro-5000 apparatus (pilot laser control, focused wavelength of 1064 nm, maximum output power of 10W, maximum optical power density of 500 mW/cm2, effective area 4.5 cm2 in diameter). Per TILS session, participants underwent a laser dose of 250 mW/cm2 continuous laser wave to each hemisphere using predetermined patient-specific coordinates. Structural imaging was used to neuronavigate individual treatment targets in the frontal cortex (Brodmann area 10). The primary safety measure for this study was the occurrence of adverse events (AEs) or serious adverse events (SAEs). The primary efficacy outcome measure was the participant-rated global rating of change (GRC) post-intervention. Secondary outcome measures included a battery of neuropsychological testing and mood questionnaires done both pre- and post-intervention. Results: All patients enrolled in this study protocol were able to tolerate the study procedures without any AEs or SAEs. Nine out of eleven participants had clinically significant improvements in GRC score (≥ +2). Neuropsychological testing and mood questionnaire outcomes also suggested a positive therapeutic effect. Conclusion: This study provides preliminary evidence supporting the safety and potential efficacy of TILS as a non-invasive clinical intervention for individuals with TBI.