ALSUntangled #73: Lion's Mane.

Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.

ALSUntangled # 69: astaxanthin.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review astaxanthin which has plausible mechanisms for slowing ALS progression including antioxidant, anti-inflammatory, and anti-apoptotic effects. While there are no ALS-specific pre-clinical studies, one verified "ALS reversal" occurred in a person using a combination of alternative therapies which included astaxanthin. There have been no trials of astaxanthin in people living with ALS. Natural astaxanthin appears to be safe and inexpensive. Based on the above information, we support further pre-clinical and/or clinical trials of astaxanthin in disease models and PALS, respectively, to further elucidate efficacy.

ALSUntangled #68: ozone therapy.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.

Actionable absolute risk prediction of atherosclerotic cardiovascular disease based on the UK Biobank.

Cardiovascular diseases (CVDs) are the primary cause of all death globally. Timely and accurate identification of people at risk of developing an atherosclerotic CVD and its sequelae is a central pillar of preventive cardiology. One widely used approach is risk prediction models; however, currently available models consider only a limited set of risk factors and outcomes, yield no actionable advice to individuals based on their holistic medical state and lifestyle, are often not interpretable, were built with small cohort sizes or are based on lifestyle data from the 1960s, e.g. the Framingham model. The risk of developing atherosclerotic CVDs is heavily lifestyle dependent, potentially making many occurrences preventable. Providing actionable and accurate risk prediction tools to the public could assist in atherosclerotic CVD prevention. Accordingly, we developed a benchmarking pipeline to find the best set of data preprocessing and algorithms to predict absolute 10-year atherosclerotic CVD risk. Based on the data of 464,547 UK Biobank participants without atherosclerotic CVD at baseline, we used a comprehensive set of 203 consolidated risk factors associated with atherosclerosis and its sequelae (e.g. heart failure). Our two best performing absolute atherosclerotic risk prediction models provided higher performance, (AUROC: 0.7573, 95% CI: 0.755-0.7595) and (AUROC: 0.7544, 95% CI: 0.7522-0.7567), than Framingham (AUROC: 0.680, 95% CI: 0.6775-0.6824) and QRisk3 (AUROC: 0.725, 95% CI: 0.7226-0.7273). Using a subset of 25 risk factors identified with feature selection, our reduced model achieves similar performance (AUROC 0.7415, 95% CI: 0.7392-0.7438) while being less complex. Further, it is interpretable, actionable and highly generalizable. The model could be incorporated into clinical practice and might allow continuous personalized predictions with automated intervention suggestions.

ALSUntangled #60: light therapy.

ALSUntangled reviews alternative and off-label treatments for people with ALS. Here we review light therapy. We show that it has theoretically plausible mechanisms, three flawed pre-clinical data, studies, and one incompletely documented case report supporting its use. We explain why further studies are needed to determine whether any specific light therapy protocol can help people with ALS.

ALSUntangled #62: vitamin C.

Vitamin C is one of the most common supplements taken by people with ALS. As an antioxidant, it has a plausible mechanism for slowing disease progression and there are some flawed pre-clinical studies and case reports suggesting benefit. However, a small human trial showed no benefit. Given this negative trial, we do not currently advise vitamin C as an ALS treatment.

Lunasin does not slow ALS progression: results of an open-label, single-center, hybrid-virtual 12-month trial.

Objective: Lunasin, a soy peptide that reportedly alters histone acetylation in vitro, was associated with a single ALS reversal in the media. Following an ALSUntangled report, we sought to determine whether Lunasin altered histone acetylation and improved progression in people with ALS, and whether patient-centric trial design features might improve enrollment and retention. Methods: This single-center, year-long trial (NCT02709330) featured broad inclusion criteria, historical controls, primarily virtual data collection, and real-time results. Participants measured their own ALSFRS-R score, weight and perceived efficacy, and recorded these monthly on PatientsLikeMe. Blood tests at screening and month 1 assessed alterations in histone H3 and H4 acetylation. The protocol was published online, empowering patients outside the study to self-experiment. Results: Fifty participants enrolled in 5.5 months. Although this population had more advanced disease compared to other trials, retention and adherence were very high. There was no significant effect of Lunasin treatment on histone acetylation or disease progression. A cohort following our protocol outside the trial reported similar side effects and perceived effectiveness; however, their compliance with data entry was markedly lower. Conclusions: While Lunasin's lack of efficacy is disappointing, our novel trial design had the highest ALS trial enrollment rate ever recorded, with excellent retention and adherence. Low data density from patients who are self-experimenting outside a formal protocol casts doubt on the possibility of gathering useful information from unsupervised expanded access programs or "right to try" initiatives.

PatientsLikeMe® Online Epilepsy Community: Patient characteristics and predictors of poor health-related quality of life.

OBJECTIVE: The online PatientsLikeMe® Epilepsy Community allows patients with epilepsy to record, monitor, and share their demographic, disease, and treatment characteristics, providing valuable insights into patient perceptions and understanding of epilepsy. The objective of this retrospective analysis was to characterize the profile of users and their disease and identify factors predictive of poor health-related quality of life (HRQoL), while assessing the platform's potential in providing patient-reported data for research purposes. METHODS: Data recorded (January 2010-November 2011) by Epilepsy Community members, with an epilepsy diagnosis and who reported >1 seizure, included the following: sociodemographic and disease characteristics, treatments, symptoms, side effects perceived as medication-related, seizure occurrence, and standardized questionnaires (Quality of Life in Epilepsy Inventory [QOLIE-31/P], EuroQoL 5-Dimensions Scale, 3 Levels [EQ-5D-3L], and Hospital Anxiety and Depression Scale [HADS]). Univariate and multivariate logistic regressions were conducted to identify predictors of poor HRQoL. RESULTS: During the study period, the Epilepsy Community comprised 3073 patients, of whom 71.5% were female, had a mean age of 37.8years, and had a mean epilepsy duration of 17.7years. The most frequently reported moderate/severe symptoms (n=2135) included memory problems (60.2%), problems concentrating (53.8%), and fatigue (50.0%). Medication-related side effects (n=639) included somnolence (23.2%), fatigue (17.2%), and memory impairment (13.8%). The QOLIE-31/P scores (n=1121) were significantly worse in patients who experienced a recent seizure. For QOLIE-31/P, highly predictive factors for poor HRQoL included the following: mild/moderate problems concentrating, depression, memory problems, treatment side effects, occurrence of tonic-clonic seizures, and epilepsy duration ≤1year. For EQ-5D-3L, highly predictive factors for poor HRQoL included the following: pain, depression, and comorbidities. Patients on newer AEDs were less likely to report poor HRQoL (QOLIE-31/P). SIGNIFICANCE: These findings move further towards supporting the feasibility and usefulness of collecting real-world, anonymized data recorded by patients online. The data provide insights into factors impacting HRQoL, suggesting that a holistic treatment approach beyond seizure control should be considered in epilepsy.

Could digital patient communities be the launch pad for patient-centric trial design?

The system of medical discovery does not revolve around patients as unique individuals with preferences, needs, and desires. Rather it revolves around scientific scrutiny, the needs of the sponsor, and the desires for regulatory approval. The patient is only a subject. Is it any wonder, then, that some patients have rejected the current medical paradigm and sought to find their own path?

Perceived benefits of sharing health data between people with epilepsy on an online platform.

An epilepsy community was developed on PatientsLikeMe.com to share data between patients to improve their outcomes by finding other patients like them. In a 14-day response period, 221 patients with epilepsy (mean age: 40 years, SD: 12, range: 17-72, 66% female) completed a survey about benefits they perceived. Prior to using the site, a third of respondents (30%) did not know anyone else with epilepsy with whom they could talk; of these, 63% now had at least one other patient with whom they could connect. Perceived benefits included: finding another patient experiencing the same symptoms (59%), gaining a better understanding of seizures (58%), and learning more about symptoms or treatments (55%). Number of benefits was associated with number of relationships with other patients, F(4,216)=8.173, P<0.001). Patients with epilepsy reported an array of perceived benefits similar to those reported by populations with other diseases. Controlled sharing of health data may have the potential to improve disease self-management of people with epilepsy.