To compare quantitative EEG signal and test-retest reliability of medical grade and consumer EEG systems.
Resting state EEG was acquired by two medical grade (B-Alert, Enobio) and two consumer (Muse, ...Mindwave) EEG systems in five healthy subjects during two study visits. EEG patterns, power spectral densities (PSDs) and test/retest reliability in eyes closed and eyes open conditions were compared across the four systems, focusing on Fp1, the only common electrode. Fp1 PSDs were obtained using Welch's modified periodogram method and averaged for the five subjects for each visit. The test/retest results were calculated as a ratio of Visit 1/Visit 2 Fp1 channel PSD at each 1 s epoch.
B-Alert, Enobio, and Mindwave Fp1 power spectra were similar. Muse showed a broadband increase in power spectra and the highest relative variation across test-retest acquisitions. Consumer systems were more prone to artifact due to eye blinks and muscle movement in the frontal region.
EEG data can be successfully collected from all four systems tested. Although there was slightly more time required for application, medical systems offer clear advantages in data quality, reliability, and depth of analysis over the consumer systems.
This evaluation provides evidence for informed selection of EEG systemsappropriate for clinical trials.
Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS
) will provide key information for optimising clinical trials in this patient ...population.
To establish an updated natural history of ALS
.
Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.
Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1
), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1
) for analysis.
Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1
and SOD1
(p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1
. SOD1
survival probability (median survival 1.2 years) was significantly decreased compared with SOD1
(median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1
compared with SOD1
participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1
compared with SOD1
(p=0.02).
SOD1
is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALS
patient population.
AMPA receptors (AMPARs) are ionotropic glutamate receptors that play a major role in excitatory neurotransmission. AMPARs are located at both presynaptic and postsynaptic plasma membranes. A huge ...number of studies investigated the role of postsynaptic AMPARs in the normal and abnormal functioning of the mammalian central nervous system (CNS). These studies highlighted that changes in the functional properties or abundance of postsynaptic AMPARs are major mechanisms underlying synaptic plasticity phenomena, providing molecular explanations for the processes of learning and memory. Conversely, the role of AMPARs at presynaptic terminals is as yet poorly clarified. Accruing evidence demonstrates that presynaptic AMPARs can modulate the release of various neurotransmitters. Recent studies also suggest that presynaptic AMPARs may possess double ionotropic-metabotropic features and that they are involved in the local regulation of actin dynamics in both dendritic and axonal compartments. In addition, evidence suggests a key role of presynaptic AMPARs in axonal pathology, in regulation of pain transmission and in the physiology of the auditory system. Thus, it appears that presynaptic AMPARs play an important modulatory role in nerve terminal activity, making them attractive as novel pharmacological targets for a variety of pathological conditions.
The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to ...quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; Rρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; Rρ = -0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; Rρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two groups. However, mI/tNA was correlated with upper motor neuron burden (P = 0.004, Rρ = 0.74), which may reflect a relative increase of activated microglia around motor neurons. In summary, 7T 1H MRS is a powerful non-invasive imaging technique to study molecular changes related to neuronal injury and/or loss in people with ALS.
In Alzheimer's disease, the spread of aberrantly phosphorylated tau is an important criterion in the Braak staging of disease severity and correlates with disease symptomatology. Here, we report the ...results of TANGO ( NCT03352557 ), a randomized, double-blind, placebo-controlled, parallel-group and multiple-dose long-term trial of gosuranemab-a monoclonal antibody to N-terminal tau-in patients with early Alzheimer's disease. The primary objective was to assess the safety and tolerability of gosuranemab compared to placebo. The secondary objectives were to assess the efficacy of multiple doses of gosuranemab in slowing cognitive and functional impairment (using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores at week 78) and evaluate the immunogenicity of gosuranemab (using the incidence of anti-gosuranemab antibody responses). Participants were randomized (n = 654); received (n = 650) low-dose (125 mg once every 4 weeks (q4w), n = 58; 375 mg q12w, n = 58), intermediate-dose (600 mg q4w, n = 106) or high-dose (2,000 mg q4w, n = 214) gosuranemab or placebo (q4w, n = 214) intravenously for 78 weeks; and assigned to cerebrospinal fluid (n = 327) and/or tau positron emission tomography (n = 357) biomarker substudies. Gosuranemab had an acceptable safety profile and was generally well tolerated (incidence of serious adverse events: placebo, 12.1%; low dose, 10.3%; intermediate dose, 12.3%; high dose, 11.7%). The incidence of treatment-emergent gosuranemab antibody responses was low at all time points. No significant effects were identified in cognitive and functional tests as no dose resulted in a favorable change from the baseline CDR-SB score at week 78 compared to placebo control (adjusted mean change: placebo, 1.85; low dose, 2.20; intermediate dose, 2.24; high dose, 1.85). At week 76, all doses caused significant (P < 0.0001) reductions in the cerebrospinal fluid levels of unbound N-terminal tau compared to placebo.
A 6-month rodent toxicology and pharmacokinetic (PK) study was performed to provide supportive safety data for long-term use of intravenous ceftriaxone in a clinical trial in patients with ...amyotrophic lateral sclerosis (ALS). Ceftriaxone was administered by subcutaneous injection at up to 2 g/kg/day to Sprague-Dawley Crl:CD (SD) rats. Ceftriaxone was found to be safe and well tolerated. Specifically, no significant differences in body weight and food consumption were observed between the treatment and control groups. With the exception of in red cell parameters decrease, there were no ceftriaxone-related changes in hematology, coagulation, clinical chemistry and urinalysis parameters. Injection site trauma and associated reversible anemia, likely due to chronic blood loss at the injection site, were all attributable to subcutaneous route of administration. Cecum dilatation and some skin changes were reversible after recovery period, while bile duct dilatation, observed only in a few animals, persisted. Changes in the non-glandular stomach do not have a human correlate. The no-observed-adverse-effect dose level (NOAEL) was 0.5 g/kg/day ceftriaxone in both sexes. Ceftriaxone showed rapid absorption with half-life values ranging between 1 and 1.5 hours. Additionally, there was no evidence of accumulation and a virtually complete elimination by 16 hours after the last dose. Overall there were no toxicologically meaningful drug-related animal findings associated with the long-term administration (6 months) of ceftriaxone. These results support safety of long-term use of ceftriaxone in human clinical trials.
Background
Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by progressive, profound behavioral changes plus loss of insight and independence, leading ...to significant burden for affected families both in daily life and clinical research participation. FORWARD study aimed to estimate disease‐related decline in patients with early‐stage bvFTD (NCT03088956) over 1 year (consisting of 6 in‐clinic and at least 4 at home study visits), using a battery of cognitive tests, functional, behavioral, and quality of life assessments. Participants were asked to complete an end‐of‐study questionnaire with the purpose to identify aspects of the study considered as potentially burdensome, challenging and/or positive.
Method
The one‐time end‐of‐study questionnaire consisting of 10 questions was completed by 29 bvFTD subjects and their 29 caregivers at their last study visit (Month 13 or Early Termination).
Result
Majority of participants were very satisfied in taking part in the study (66% bvFTD; 72% caregivers). The top motivators to participation included contributing to dementia research (79% bvFTD; 93% caregivers) while the main drivers to complete the study included their commitment to be in the study (83% bvFTD; 86% caregivers) as well as the amount of care and attention received from the study doctor and staff (76% bvFTD; 79% caregivers). In terms of study design, home visits were considered useful (76% bvFTD; 83% caregivers) and not burdensome (79% bvFTD; 86% caregivers) by the majority of participants. Most participants did not find every 3‐months clinic visits (55% bvFTD; 62% caregivers), clinic visit length (62% bvFTD; 76% caregivers), and study duration (59% bvFTD; 72% caregivers) as burdensome. However, bvFTD patients considered burdensome cognitive assessments done either in paper forms (55%) or on iPAD (55%). Use of iPAD was considered useful (48% bvFTD; 64% caregivers) and not burdensome (69% bvFTD; 93% caregivers) mainly by caregivers and less so by patients. Financial travel support was deemed useful (69% bvFTD; 66% caregivers) and 62% of caregivers found the overall study experience not burdensome for bvFTD patients.
Conclusion
These insights are useful to minimize the degree of burden for participants with improved clinical trial design in the bvFTD indication with limited drug development precedence.
Abstract
Background
Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by progressive, profound behavioral changes plus loss of insight and independence, ...leading to significant burden for affected families both in daily life and clinical research participation. FORWARD study aimed to estimate disease‐related decline in patients with early‐stage bvFTD (NCT03088956) over 1 year (consisting of 6 in‐clinic and at least 4 at home study visits), using a battery of cognitive tests, functional, behavioral, and quality of life assessments. Participants were asked to complete an end‐of‐study questionnaire with the purpose to identify aspects of the study considered as potentially burdensome, challenging and/or positive.
Method
The one‐time end‐of‐study questionnaire consisting of 10 questions was completed by 29 bvFTD subjects and their 29 caregivers at their last study visit (Month 13 or Early Termination).
Result
Majority of participants were very satisfied in taking part in the study (66% bvFTD; 72% caregivers). The top motivators to participation included contributing to dementia research (79% bvFTD; 93% caregivers) while the main drivers to complete the study included their commitment to be in the study (83% bvFTD; 86% caregivers) as well as the amount of care and attention received from the study doctor and staff (76% bvFTD; 79% caregivers). In terms of study design, home visits were considered useful (76% bvFTD; 83% caregivers) and not burdensome (79% bvFTD; 86% caregivers) by the majority of participants. Most participants did not find every 3‐months clinic visits (55% bvFTD; 62% caregivers), clinic visit length (62% bvFTD; 76% caregivers), and study duration (59% bvFTD; 72% caregivers) as burdensome. However, bvFTD patients considered burdensome cognitive assessments done either in paper forms (55%) or on iPAD (55%). Use of iPAD was considered useful (48% bvFTD; 64% caregivers) and not burdensome (69% bvFTD; 93% caregivers) mainly by caregivers and less so by patients. Financial travel support was deemed useful (69% bvFTD; 66% caregivers) and 62% of caregivers found the overall study experience not burdensome for bvFTD patients.
Conclusion
These insights are useful to minimize the degree of burden for participants with improved clinical trial design in the bvFTD indication with limited drug development precedence.
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