Safety, Feasibility, and Potential Clinical Efficacy of 40 Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study.

BACKGROUND: Recent studies suggested induction of 40 Hz neural activity as a potential treatment for Alzheimer's disease (AD). However, prolonged exposure to flickering light raises adherence and safety concerns, encouraging investigation of tolerable light stimulation protocols. OBJECTIVE: To investigate the safety, feasibility, and exploratory measures of efficacy. METHODS: This two-stage randomized placebo-controlled double-blinded clinical trial, recruited first cognitive healthy participants (n = 3/2 active/placebo), and subsequently patients with mild-to-moderate AD (n = 5/6, active/placebo). Participants were randomized 1:1 to receive either active intervention with 40 Hz Invisible Spectral Flicker (ISF) or placebo intervention with color and intensity matched non-flickering white light. RESULTS: Few and mild adverse events were observed. Adherence was above 86.1% of intended treatment days, with participants remaining in front of the device for >51.3 min (60 max) and directed gaze >34.9 min. Secondary outcomes of cognition indicate a tendency towards improvement in the active group compared to placebo (mean: -2.6/1.5, SD: 6.58/6.53, active/placebo) at week 6. Changes in hippocampal and ventricular volume also showed no tendency of improvement in the active group at week 6 compared to placebo. At week 12, a potential delayed effect of the intervention was seen on the volume of the hippocampus in the active group compared to placebo (mean: 0.34/-2.03, SD: 3.26/1.18, active/placebo), and the ventricular volume active group (mean: -0.36/2.50, SD: 1.89/2.05, active/placebo), compared to placebo. CONCLUSION: Treatment with 40 Hz ISF offers no significant safety or adherence concerns. Potential impact on secondary outcomes must be tested in larger scale clinical trials.

Study on the effect of 40 Hz non-invasive light therapy system. A protocol for a randomized, double-blinded, placebo-controlled clinical trial.

Introduction: With no cure or effective treatment, the prevalence of patients with Alzheimer's disease (AD) is expected to intensify, thereby increasing the social and financial burden on society. Light-based 40 Hz brain stimulation is considered a novel treatment strategy for patients with AD that may alleviate some of this burden. The clinical trial ALZLIGHT will utilize a novel Light Therapy System (LTS). The LTS uses Invisible Spectral Flicker for non-invasive induction of 40 Hz neural activity. This protocol describes a trial evaluating the efficacy and safety of a light-based 40 Hz brain stimulation in patients with mild-to-moderate AD. Methods: 62 patients with mild-to-moderate AD will participate in a randomized, double-blinded, placebo-controlled, parallel-group, and single-center trial. The participants will partake in an enrollment period of 1 month, an intervention period of 6 months, and a 1.5-month post-interventional follow-up period. Prior to the baseline measurement (week 0), the patients will be randomized to either active or placebo intervention from baseline (week 0) to post-intervention follow-up (week 26). Discussion: This protocol describes a randomized, double-blinded, placebo-controlled clinical trial that may increase the understanding of the effect of gamma oscillations in the human brain and how it could be utilized as a novel and important tool for the treatment of AD. The effect is measured through a large, multidisciplinary assessment battery.Clinical trial registration:www.ClinicalTrials.gov, (NCT05260177). Registered on March 2, 2022.

Intravenous immunoglobulin treatment in a patient with adrenomyeloneuropathy.

BACKGROUND: Adrenomyeloneuropathy (AMN) is one of several phenotypes of the adrenoleukodystrophy spectrum caused by mutations in the ABCD1 gene on the X chromosome. An inflammatory component is part of the disease complex ranging from severe childhood CNS demyelination to spinal cord and peripheral nerve degeneration. CASE PRESENTATION: We present a patient with clinical progressive AMN and severe lower limb pain. Longitudinal brain magnetic resonance spectroscopy showed a constant slightly elevated myoinositol/total creatine ratio during the five year treatment period, probably reflecting demyelination, microglial activation and gliosis, indicating an inflammatory response. The pain was refractory to conventional therapy but intravenous immunoglobulin (IVIG) treatment was highly efficient. CONCLUSION: IVIG may be considered as a last resort for treatment of refractory pain in AMN patients with indications of an inflammatory component.

Increased liver fat associates with severe metabolic perturbations in low birth weight men.

Objective: Ectopic liver fat deposition, resulting from impaired subcutaneous adipose tissue expandability, may represent an age-dependent key feature linking low birth weight (LBW) with increased risk of type 2 diabetes (T2D). We examined whether presumably healthy early middle-aged, non-obese LBW subjects exhibit increased liver fat content, whether increased liver fat in LBW is associated with the severity of dysmetabolic traits and finally whether such associations may be confounded by genetic factors. Methods: Using 1H magnetic resonance spectroscopy, we measured hepatic fat content in 26 early middle-aged, non-obese LBW and 22 BMI-matched normal birth weight (NBW) males. Endogenous glucose production was measured by stable isotopes, and a range of plasma adipokine and gut hormone analytes were measured by multiplex ELISA. Genetic risk scores were calculated from genome-wide association study (GWAS) data for birth weight, height, T2D, plasma cholesterol and risk genotypes for non-alcoholic fatty liver disease (NAFLD). Results: The LBW subjects had significantly increased hepatic fat content compared with NBW controls (P= 0.014), and 20% of LBW vs no controls had overt NAFLD. LBW subjects with NAFLD displayed widespread metabolic changes compared with NBW and LBW individuals without NAFLD, including hepatic insulin resistance, plasma adipokine and gut hormone perturbations as well as dyslipidemia. As an exception, plasma adiponectin levels were lower in LBW subjects both with and without NAFLD as compared to NBW controls. Genetic risk for selected differential traits did not differ between groups. Conclusion: Increased liver fat content including overt NAFLD may be on the critical path linking LBW with increased risk of developing T2D in a non-genetic manner.

Ectopic Lipid Deposition Is Associated With Insulin Resistance in Postmenopausal Women.

Context: Menopause is associated with an increased incidence of insulin resistance and diabetes. Objective: The aim of this study was to explore the lipid deposition in liver and skeletal muscle and investigate the association with insulin sensitivity in postmenopausal and premenopausal women. Design and Setting: Single-center cross-sectional study of 55 healthy women between 45 and 60 years of age. We measured lipid deposition in the liver with magnetic resonance spectroscopy, intramuscular and intra-abdominal lipid deposition with MRI, body composition with a dual-energy X-ray absorptiometry scan, and insulin sensitivity with the composite Matsuda Index. Outcome Measures: We studied the association between fat distribution, ectopic lipid deposition, and insulin sensitivity in pre- and postmenopausal women. Results: Postmenopausal women had an increased lipid deposition in the liver [0.68% (0.44 to 0.99) vs 0.49% (0.38 to 0.64), P = 0.01] and skeletal muscle [3% (2 to 4) vs 2% (1 to 3), P = 0.001] and had a 28% lower Matsuda insulin sensitivity index during an oral glucose tolerance test (6.31 ± 3.48 vs 8.78 ± 4.67, P = 0.05) compared with premenopausal women. Total fat mass and leg fat mass were stronger predictors of ectopic lipid deposition, and visceral fat mass was a stronger predictor of both ectopic lipid deposition and insulin resistance in postmenopausal women compared with premenopausal women. Conclusions: For a given subcutaneous and visceral fat depot size, postmenopausal women show increased ectopic lipid deposition and insulin resistance compared with premenopausal women. It is suggested that lipid deposition in liver and skeletal muscle may represent important mechanistic links between the changes in fat depots and the increased incidence of insulin resistance seen after menopause.

Perfusion Pressure Cerebral Infarct (PPCI) trial - the importance of mean arterial pressure during cardiopulmonary bypass to prevent cerebral complications after cardiac surgery: study protocol for a randomised controlled trial.

BACKGROUND: Debilitating brain injury occurs in 1.6-5 % of patients undergoing cardiac surgery with cardiopulmonary bypass. Diffusion-weighted magnetic resonance imaging studies have reported stroke-like lesions in up to 51 % of patients after cardiac surgery. The majority of the lesions seem to be caused by emboli, but inadequate blood flow caused by other mechanisms may increase ischaemia in the penumbra or cause watershed infarcts. During cardiopulmonary bypass, blood pressure can be below the lower limit of cerebral autoregulation. Although much debated, the constant blood flow provided by the cardiopulmonary bypass system is still considered by many as appropriate to avoid cerebral ischaemia despite the low blood pressure. METHODS/DESIGN: The Perfusion Pressure Cerebral Infarct trial is a single-centre superiority trial with a blinded outcome assessment. The trial is randomising 210 patients with coronary vessel and/or valve disease and who are undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients are stratified by age and surgical procedure and are randomised 1:1 to either an increased mean arterial pressure (70-80 mmHg) or 'usual practice' (40-50 mmHg) during cardiopulmonary bypass. The cardiopulmonary bypass pump flow is fixed and set at 2.4 L/minute/m(2) body surface area plus 10-20 % in both groups. The primary outcome measure is the volume of the new ischaemic cerebral lesions (in mL), expressed as the difference between a baseline, diffusion-weighted, magnetic resonance imaging scan and an equal scan conducted 3-6 days postoperatively. Secondary endpoints are the total number of new ischaemic cerebral lesions, postoperative cognitive dysfunction at discharge and 3 months postoperatively, diffuse cerebral injury evaluated by magnetic resonance spectroscopy and selected biochemical markers of cerebral injury. The sample size will enable us to detect a 50 % reduction in the primary outcome measure in the intervention compared to the control group at a significance level of 0.05 and with a power of 0.80. DISCUSSION: This is the first clinical randomised study to evaluate whether the mean arterial pressure level during cardiopulmonary bypass influences the development of brain injuries that are detected by diffusion-weighted magnetic resonance imaging. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02185885 . Registered on 7 July 2014.

[Prognostic value of PET and MRS in the assessment of cerebral status of children]. / Prognostisk vaerdi af PET og MRS ved evaluering af cerebral status hos børn.

We report a case of a 12-week-old previously normal infant with severe brain damage after an episode of asphyxia during an RS-virus infection. Sub-acute MRI was normal, but new functional techniques, PET (positron emission tomography) and MRS (magnetic resonance spectroscopy) were severely abnormal. At an outpatient clinic three months later, he had developed microencephaly and the MRI was now severely abnormal. The case shows the importance of using multimodality functional imaging techniques to assess the cerebral status of infants for prognosis and course of treatment.

Cerebral proton magnetic resonance spectroscopy demonstrates reversibility of N-acetylaspartate/creatine in gray matter after delayed encephalopathy due to carbon monoxide intoxication: a case report.

INTRODUCTION: Predictive markers for long-term outcome in carbon monoxide-intoxicated patients with late encephalopathy are desired. Here we present the first data demonstrating a full reversibility pattern of specific brain substances measured by cerebral proton magnetic resonance spectroscopy in a carbon monoxide-intoxicated victim. This may provide clinicians with important information when estimating patient outcome. CASE PRESENTATION: We report the case of a 40-year-old Caucasian woman with severe carbon monoxide poisoning who was treated with five repetitive sessions of hyperbaric oxygen therapy in a multiplace chamber (100 percent oxygen with a ventilator, 90 minutes exposure to 2.8 atmospheres absolute). Initially, our patient recovered completely after three days of hospitalization, but became encephalopathic after a lucid interval of four weeks. An examination of the brain with cerebral proton magnetic resonance spectroscopy showed a dramatically decrease in N-acetylaspartate to total creatine ratios and elevated lactate levels in the gray matter. Subsequently, our patient received six additional sessions of hyperbaric oxygen therapy with only minimal recovery. At six-month follow-up our patient showed significant improvement in cognition and neuromuscular coordination. Extraordinarily, the cerebral proton magnetic resonance spectroscopy measurements at relapse compared to measurements at follow-up (217 days post insult) revealed full reversal of the severe abnormalities in mid-occipital gray matter and partial reversal in white matter. CONCLUSIONS: The present case indicates that cerebral proton magnetic spectroscopy provides valuable information on brain metabolism in patients presenting with delayed encephalopathy after acute carbon monoxide intoxication. The full reversal of N-acetylaspartate to total creatine ratios in gray matter has, to our knowledge, never been described before and shows that severe, initial measurements may not predict poor long-term patient outcome.