ABSTRACT
AIMS: HTL0009936 is a selective M1 muscarinic receptor agonist in development for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 administered by continuous IV infusion at steady state were investigated in elderly subjects with below average cognitive functioning (BACF). METHODS: Part A was a four-treatment open label sequential study in healthy elderly investigating 10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a five-treatment randomized, double-blind, placebo and physostigmine controlled cross-over study with IV HTL0009936 in elderly subjects with BACF. Pharmacodynamic assessments were performed using neurocognitive and electrophysiological tests. RESULTS: Pharmacokinetics of HTL0009936 showed dose-proportional increases in exposure with a mean half-life of 2.4 hours. HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at the highest dose in part B. Overall, there was suggestive, but no definitive, positive or negative pharmacodynamic effects. Statistically significant effects were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. CONCLUSIONS: HTL0009936 showed well-characterized pharmacokinetics and single doses were safe and generally well-tolerated in healthy elderly subjects. Due to physostigmine tolerability issues and subject burden, the study design was changed and some pharmacodynamic assessments (neurocognitive) were performed at suboptimal drug exposures. Therefore no clear conclusions can be made on pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive of central target engagement.
Subject(s)
Cholinergic Agents , Receptors, Cholinergic , Aged , Area Under Curve , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , HumansABSTRACT
AIMS: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT-020, a novel compound to improve mitochondrial function, in a 2-part study in early stage HD patients. METHODS: Part 1 consisted of 7-day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28-day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells. RESULTS: Treatment-emergent adverse events were mild and more present in the SBT-020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT-020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [∆Ψm < 3412 and τPCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction. CONCLUSION: SBT-020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT-020.
Subject(s)
Huntington Disease , Neurodegenerative Diseases , Humans , Huntington Disease/drug therapy , Leukocytes, Mononuclear , Magnetic Resonance ImagingABSTRACT
AIMS: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. METHODS: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects. RESULTS: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. CONCLUSION: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias.
Subject(s)
Alzheimer Disease , Adult , Aged , Alzheimer Disease/drug therapy , Area Under Curve , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , HumansABSTRACT
AIMS: Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor. METHODS: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine. RESULTS: Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy). Mecamylamine 30 mg induced significant disturbances of cognitive functions. Attention and execution of visual (fine) motor tasks was decreased, short- and long-term memory was impaired and the reaction velocity during the test was slower when compared to placebo. Mecamylamine 30 mg produced a decrease in posterior α and ß power in the surface electroencephalogram, effects that were reversed by nicotine coadministration. Memory and motor coordination tests could be partially reversed by the coadministration of nicotine. CONCLUSIONS: Mecamylamine administration induced slowing of the electroencephalogram and produced decrease in performance of tests evaluating motor coordination, sustained attention and short- and long-term memory. These effects could be partially reversed by the coadministration of nicotine, and to a lesser extent by galantamine.
Subject(s)
Cognition/drug effects , Electroencephalography/drug effects , Galantamine/pharmacology , Mecamylamine/antagonists & inhibitors , Nicotine/pharmacology , Adolescent , Adult , Cross-Over Studies , Double-Blind Method , Drug Interactions , Healthy Volunteers , Humans , Male , Mecamylamine/pharmacology , Middle Aged , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Reaction Time/drug effects , Young AdultABSTRACT
Unemployment is common for those with Huntington's disease (HD), a genetic neurodegenerative disorder, and affects patients' quality of life. HD is characterized by motor disturbances, cognitive dysfunction, and psychiatric symptoms. The purpose of this article was to determine which clinical signs of HD are predictive of unemployment. Data for employed (N=114) and unemployed (N=106) HD mutation carriers were used to investigate group differences. Univariate logistic regression analyses, adjusted for age and gender, were performed to determine individual predictors of unemployment. Subsequently, a multivariate logistic regression analysis was performed, entering all significant results from the univariate analyses into one fully adjusted model to determine the strongest predictors. HD mutation carriers with lower cognitive performances and higher apathy scores were more likely to be unemployed than were HD mutation carriers with higher cognitive scores and no signs of apathy. Motor functioning was an independent predictor of unemployment but was not associated with unemployment in the fully adjusted model. Cognitive impairments, especially in the executive domain, and apathy were independent determinants of unemployment in HD mutation carriers. Motor disturbances, the clinical hallmark of HD, did not appear to be the most important predictor for work cessation. These results should be taken into consideration in clinical practice when evaluating HD patients' ability to work.
Subject(s)
Apathy , Cognition , Huntington Disease/psychology , Unemployment , Adult , Aged , Female , Heterozygote , Humans , Huntingtin Protein/genetics , Huntington Disease/diagnosis , Huntington Disease/genetics , Logistic Models , Male , Middle Aged , Mutation , Neuropsychological Tests , Prognosis , Unemployment/psychology , Young AdultABSTRACT
BACKGROUND: We previously demonstrated that in the premanifest stage of Huntington's disease (preHD), a reduced functional connectivity exists compared to healthy controls. In the current study, we look at possible changes in functional connectivity occurring longitudinally over a period of 3 years, with the aim of assessing the potential usefulness of this technique as a biomarker for disease progression in preHD. METHODS: Twenty-two preHD and 17 healthy control subjects completed resting state functional magnetic resonance imaging (fMRI) scans in two visits with 3 years in between. Differences in resting state connectivity were examined for eight networks of interest using FSL with three different analysis types: a dual regression method, region of interest approach, and an independent component analysis. To evaluate a possible combined effect of gray matter volume change and the change in blood oxygenation level dependent signal, the analysis was performed with and without voxel-wise correction for gray matter volume. To evaluate possible correlations between functional connectivity change and the predicted time to disease onset, the preHD group was classed as preHD-A if ≥10.9 years and preHD-B if <10.9 years from predicted disease onset. Possible correlations between burden of pathology score and functional connectivity change in preHD were also assessed. Finally, longitudinal change in whole brain and striatal volumetric measures was assessed in the studied cohort. RESULTS: Longitudinal analysis of the resting state-fMRI (RS-fMRI) data revealed no differences in the degree of connectivity change between the groups over a period of 3 years, though a significantly higher rate of striatal atrophy was found in the preHD group compared to controls in the same period. DISCUSSION: Based on the results found in this study, the provisional conclusion is that RS-fMRI lacks sensitivity in detecting changes in functional connectivity in HD gene carriers prior to disease manifestation over a 3-year follow-up period.
Subject(s)
Brain Mapping , Brain/blood supply , Huntington Disease/diagnosis , Magnetic Resonance Imaging , Rest , Adult , Brain/pathology , Disease Progression , Female , Humans , Huntington Disease/genetics , Image Processing, Computer-Assisted , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Oxygen/blood , Severity of Illness Index , Statistics, NonparametricABSTRACT
The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.
Subject(s)
Huntington Disease/complications , Mental Disorders/diagnosis , Mental Disorders/etiology , Psychiatric Status Rating Scales , Europe , Female , Humans , International Cooperation , Longitudinal Studies , Male , Registries , Reproducibility of Results , Severity of Illness Index , Statistics, Nonparametric , Video RecordingABSTRACT
Motor disturbances can be present in both manifest and premanifest Huntington's disease (HD). We aimed to investigate the role of motor functioning on executive functioning to better understand the progression of cognitive dysfunction in HD. Forty patients with manifest HD, 21 patients with premanifest HD, and a group of 28 controls were tested twice with a 1-year interval. For the Symbol Digit Modalities Test and the Figure Fluency Test, extra conditions were designed to measure motor involvement. Subtraction of this motor score from the original test score resulted in isolation of the cognitive component. Groups were compared on motor, cognitive, and original test scores using multilevel regression analysis. Manifest patients had lower baseline scores of 0.53 standard deviations (SD) on the original Symbol Digit Modalities Test (P = 0.03) and 0.71 SD on the motor isolation part (P = 0.006), and they showed a deterioration of 0.47 SD over 1 year of follow-up on the original Symbol Digit Modalities Test (P = 0.001) compared with controls. Premanifest patients had lower baseline scores of 0.67 SD on the Symbol Digit Modalities motor part (P = 0.008) and deterioration of 0.48 SD on the original (P = 0.001) and cognitive isolation (P = 0.02) parts. Secondary analyses revealed that the premanifest deterioration resulted from the close-to-predicted-onset group. Motor disturbances have a negative influence on performance on the Symbol Digit Modalities Test. Isolation of the cognitive component of this test revealed cognitive deterioration in the premanifest group only, caused by deteriorating scores for patients who were close to their predicted clinical disease onset. The Figure Fluency Test did not prove sensitive to cognitive change.
Subject(s)
Executive Function/physiology , Huntington Disease/physiopathology , Motor Neuron Disease/physiopathology , Adult , Aged , Cognition/physiology , Disease Progression , Female , Humans , Huntington Disease/complications , Male , Middle Aged , Motor Neuron Disease/etiology , Neuropsychological TestsABSTRACT
BACKGROUND: Understanding the relation between predominantly choreatic and hypokinetic-rigid motor subtypes and cognitive and general functioning may contribute to knowledge about different motor phenotypes in Huntington's disease. METHODS: In the European Huntington's Disease Network Registry study, 1882 subjects were classified as being predominantly choreatic (n=528) or hypokinetic-rigid (n=432), according to their scores on items of the total motor score a priori labeled as choreatic or hypokinetic-rigid; the other 922 patients were of a mixed type. The relationship between motor type and cognitive (verbal fluency, symbol digit modalities, Stroop color, word and interference tests) and functional (total functional capacity) capacity was investigated using multiple linear regression. RESULTS: Motor subtype contributed significantly to the total functional capacity score (partial r(2) : 7.8%; P<.001) and to the 5 cognitive scores (partial r(2) ranged from 2.0% to 8.4%; all P<.001). CONCLUSIONS: Patients with a predominantly choreatic motor phenotype performing better in all areas than patients with a hypokinetic-rigid motor phenotype.
Subject(s)
Cognition Disorders/diagnosis , Cognition Disorders/etiology , Huntington Disease/complications , Hypokinesia/complications , Muscle Rigidity/complications , Adult , Disability Evaluation , Europe , Female , Humans , Male , Middle Aged , Neuropsychological Tests , Severity of Illness IndexABSTRACT
Increased iron in subcortical structures in patients with Huntington's Disease (HD) has been suggested as a causal factor of neuronal degeneration. The present study examines iron accumulation, measured using magnetic resonance imaging (MRI), in premanifest gene carriers and in early HD patients as compared to healthy controls. In total 27 early HD patients, 22 premanifest gene carriers and 25 healthy controls, from the Leiden site of the TRACK-HD study, underwent 3T MRI including high resolution 3D T(1)- and T(2)-weighted and asymmetric spin echo (ASE) sequences. Magnetic Field Correlation (MFC) maps of iron levels were constructed to assess magnetic field inhomogeneities and compared between groups in the caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, accumbens nucleus, and thalamus. Subsequently the relationship of MFC value to volumetric data and disease state was examined. Higher MFC values were found in the caudate nucleus (p<0.05) and putamen (p<0.005) of early HD compared to controls and premanifest gene carriers. No differences in MFC were found between premanifest gene carriers and controls. MFC in the caudate nucleus and putamen is a predictor of disease state in HD. No correlation was found between the MFC value and volume of these subcortical structures. We conclude that Huntington's disease patients in the early stages of the disease, but not premanifest gene carriers, have higher iron concentrations in the caudate nucleus and putamen. We have demonstrated that the iron content of these structures relates to disease state in gene carriers, independently of the measured volume of these structures.
Subject(s)
Brain Chemistry/physiology , Brain/pathology , Huntington Disease/metabolism , Huntington Disease/pathology , Iron/metabolism , Adult , Age of Onset , Aged , Aging/physiology , Atrophy , Caudate Nucleus/metabolism , Disease Progression , Educational Status , Electromagnetic Fields , Female , Heterozygote , Humans , Huntington Disease/genetics , Image Processing, Computer-Assisted , Logistic Models , Magnetic Resonance Imaging , Male , Middle Aged , Putamen/metabolism , Sex CharacteristicsABSTRACT
BACKGROUND: Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntington's disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials. METHODS: There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks. RESULTS: 10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls. CONCLUSIONS: The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.
Subject(s)
Cognition Disorders/etiology , Huntington Disease/complications , Adolescent , Adult , Age Factors , Aged , Disease Progression , Female , Humans , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Severity of Illness Index , Sex Factors , Time Factors , Young AdultABSTRACT
BACKGROUND: In the current study, we aimed to develop an algorithm based on biomarkers obtained through non- or minimally invasive procedures to identify healthy elderly subjects who have an increased risk of abnormal cerebrospinal fluid (CSF) amyloid beta42 (Aß) levels consistent with the presence of Alzheimer's disease (AD) pathology. The use of the algorithm may help to identify subjects with preclinical AD who are eligible for potential participation in trials with disease modifying compounds being developed for AD. Due to this pre-selection, fewer lumbar punctures will be needed, decreasing overall burden for study subjects and costs. METHODS: Healthy elderly subjects (n = 200; age 65-70 (N = 100) and age > 70 (N = 100)) with an MMSE > 24 were recruited. An automated central nervous system test battery was used for cognitive profiling. CSF Aß1-42 concentrations, plasma Aß1-40, Aß1-42, neurofilament light, and total Tau concentrations were measured. Aß1-42/1-40 ratio was calculated for plasma. The neuroinflammation biomarker YKL-40 and APOE ε4 status were determined in plasma. Different mathematical models were evaluated on their sensitivity, specificity, and positive predictive value. A logistic regression algorithm described the data best. Data were analyzed using a 5-fold cross validation logistic regression classifier. RESULTS: Two hundred healthy elderly subjects were enrolled in this study. Data of 154 subjects were used for the per protocol analysis. The average age of the 154 subjects was 72.1 (65-86) years. Twenty-four (27.3%) were Aß positive for AD (age 65-83). The results of the logistic regression classifier showed that predictive features for Aß positivity/negativity in CSF consist of sex, 7 CNS tests, and 1 plasma-based assay. The model achieved a sensitivity of 70.82% (± 4.35) and a specificity of 89.25% (± 4.35) with respect to identifying abnormal CSF in healthy elderly subjects. The receiver operating characteristic curve showed an AUC of 65% (± 0.10). CONCLUSION: This algorithm would allow for a 70% reduction of lumbar punctures needed to identify subjects with abnormal CSF Aß levels consistent with AD. The use of this algorithm can be expected to lower overall subject burden and costs of identifying subjects with preclinical AD and therefore of total study costs. TRIAL REGISTRATION: ISRCTN.org identifier: ISRCTN79036545 (retrospectively registered).
Subject(s)
Alzheimer Disease , Aged , Aged, 80 and over , Algorithms , Alzheimer Disease/diagnosis , Amyloid beta-Peptides , Biomarkers , Cross-Sectional Studies , Humans , Peptide Fragments , tau ProteinsABSTRACT
BACKGROUND: The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects. METHODS: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions. RESULTS: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes. CONCLUSION: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. TRIAL REGISTRATION: Netherlands Trial Register identifier NTR5781 . Registered on 22 March 2016.
Subject(s)
Alzheimer Disease , Adult , Aged , Area Under Curve , Cognition , Dose-Response Relationship, Drug , Double-Blind Method , Humans , NetherlandsABSTRACT
BACKGROUND: To quantify pharmacological effects on tremor in patients with essential tremor (ET) or Parkinson's Disease (PD), laboratory-grade accelerometers have previously been used. Over the last years, consumer products such as smartphones and smartwatches have been increasingly applied to measure tremor in an easy way. However, it is unknown how the technical performance of these consumer product accelerometers (CPAs) compares to laboratory-grade accelerometers (LGA). This study was performed to compare the technical performance of CPAs with LGA to measure tremor in patients with Parkinson's Disease (PD) and essential tremor (ET). METHODS: In ten patients with PD and ten with ET, tremor peak frequency and corresponding amplitude were measured with 7 different CPAs (Apple iPhone 7, Apple iPod Touch 5, Apple watch 2, Huawei Nexus 6P, Huawei watch, mbientlabMetaWear (MW) watch, mbientlab MW clip) and compared to a LGA (Biometrics ACL300) in resting and extended arm position. RESULTS: Both in PD and ET patients, the peak frequency of CPAs did not significantly differ from the LGA in terms of limits of agreement. For the amplitude at peak frequency, only the iPhone and MW watch performed comparable to the LGA in ET patients, while in PD patients all methods performed comparable except for the iPod Touch and Huawei Nexus. Amplitude was higher when measured with distally-located CPAs (Clip, iPhone, iPod) compared with proximally-located CPAs (all watches). The variability between subjects was higher than within subjects for frequency (25.1% vs. 13.4%) and amplitude measurement (331% vs. 53.6%). Resting arm position resulted in lower intra-individual variability for frequency and amplitude (13.4 and 53.5%) compared to extended arm position (17.8 and 58.1%). CONCLUSIONS: Peak frequencies of tremor could be measured with all tested CPAs, with similar performance as LGA. The amplitude measurements appeared to be driven by anatomical location of the device and can therefore not be compared. Our results show that the tested consumer products can be used for tremography, allowing at-home measurements, in particular in studies with a cross-over or intra-individual comparison design using the resting arm position. TRIAL REGISTRATION: This trial was registered in the Dutch Competent Authority (CCMO) database with number NL60672.058.17 on May 30th 2017.
ABSTRACT
INTRODUCTION: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine. METHODS: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine. RESULTS: Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median Tmax of 0.5 hour [range 0.5-1.0]). Cmax and AUC0-last increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279, P = 0.0055) compared to placebo after correction for individual baseline performance. DISCUSSION: Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.
ABSTRACT
BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. Improving mitochondrial function has been proposed as an opportunity to treat HD, but it is not known how mitochondrial function in different tissues relates. OBJECTIVE: We explored associations between central and peripheral mitochondrial function in a group of mild to moderate staged HD patients. METHODS: We used phosphorous magnetic resonance spectroscopy (31P-MRS) to measure mitochondrial function in vivo in the calf muscle (peripheral) and the bio-energetic state in the visual cortex (central). Mitochondrial function was also assessed ex vivo in circulating peripheral blood mononuclear cells (PBMCs). Clinical function was determined by the Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Pearson correlation coefficients were computed to assess the correlation between the different variables. RESULTS: We included 23 manifest HD patients for analysis. There was no significant correlation between central bio-energetics and peripheral mitochondrial function. Central mitochondrial function at rest correlated significantly to the UHDRS total motor score (Râ=â-0.45 and -0.48), which increased in a subgroup with the largest number of CAG repeats. DISCUSSION: We did not observe a correlation between peripheral and central mitochondrial function. Central, but not peripheral, mitochondrial function correlated to clinical function. Muscle mitochondrial function is a promising biomarker to evaluate disease-modifying compounds that improve mitochondrial function, but Huntington researchers should use central mitochondrial function to demonstrate proof-of-pharmacology of disease-modifying compounds.
Subject(s)
Energy Metabolism , Huntington Disease/metabolism , Mitochondria, Muscle/metabolism , Mitochondria/metabolism , Visual Cortex/metabolism , Adult , Brain/metabolism , Female , Humans , Huntington Disease/physiopathology , Leg , Leukocytes, Mononuclear/metabolism , Magnetic Resonance Spectroscopy , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: As the disease progresses, patients with Huntington's disease (HD), an inherited neurodegenerative disorder, become less independent in their daily life activities and have to consider if they can still drive a car. For most patients, the decision to quit driving is difficult and affects their independence and social activities. OBJECTIVE: To investigate if cognitive, motor, or psychiatric symptoms can predict driving performance in HD gene carriers using a simulator situation. METHODS: Twenty-nine controls, 28 premanifest HD, and 30 manifest HD participated in this observational, cross-sectional study and underwent neuropsychological, motor, and psychiatric evaluations. All participants drove a motorway scenario in a driving simulator to evaluate driving performance. Group differences were analyzed using Analysis of Covariance and stepwise forward linear regression analysis was used to investigate which clinical assessments were predictors of driving simulator outcomes. RESULTS: Manifest HD drove slower and had less vehicle control in the driving simulator compared to controls and premanifest HD. They also performed worse on all clinical assessments compared to controls. Postural sway and slower speed of information processing were predictors of the driving simulator outcome measures. Psychiatric symptoms were unrelated to simulated driving. There were no significant differences between premanifest HD and controls. CONCLUSIONS: Increased postural sway and slower speed of processing are predictive of driving simulator performance in manifest HD. Worse performance on these clinical tasks might be useful as a first screening and could assist clinicians in their referral for an official on-road driving test.
Subject(s)
Automobile Driving , Cognitive Dysfunction/physiopathology , Huntington Disease/physiopathology , Postural Balance/physiology , Psychomotor Performance/physiology , Adult , Cognitive Dysfunction/etiology , Cross-Sectional Studies , Female , Heterozygote , Humans , Huntington Disease/complications , Huntington Disease/genetics , Male , Middle AgedABSTRACT
Investigating potential pharmacodynamic effects in an early phase of central nervous system (CNS) drug research can provide valuable information for further development of new compounds. A computerized and thoroughly validated battery of neuropsychological and neurophysiological tests has been shown to be sensitive to detect drug-induced effects of multiple new and existing compounds. The test battery covers the main CNS domains, which have been shown to respond to drug effects and can be repeatedly administered following drug administration to characterize the concentration-effect profile of a drug. The standard tests in the battery are saccadic eye movement, smooth pursuit eye movement, the Bowdle visual analog scale (VAS), the Bond and Lader VAS, body sway, adaptive tracking, visual verbal learning, and quantitative electroencephalography (qEEG). However, the test battery is adaptive in nature, meaning that it can be composed and adjusted with tests fit to investigate specific drug classes, or even specific receptors. Showing effects of new cholinergic drugs designed to have a pro-cognitive outcome has been difficult. The pharmacological challenge model is a tool for early proof-of-pharmacology. Here, a marketed drug is used to induce temporary and reversible disease-like symptoms in healthy subjects, via a pharmacological mechanism related to the disease that is targeted as indication for the new compound. The test battery was implemented to investigate the potential of the nicotinic receptor antagonist mecamylamine to be used as a challenge model for cholinergic dysfunction, as seen in neurodegenerative disorders. A worsening of scores in a dose dependent manner on the visual verbal learning test (VVLT; a test for learning and memory abilities) and the adaptive tracking test (a measure of visuomotor control and arousal), in particular, showed that the test battery is sensitive to showing acute pharmacodynamic effect after administration of anti-cholinergic drugs.
Subject(s)
Central Nervous System/drug effects , Cholinergic Agents/therapeutic use , Drug Development/methods , Adult , Cholinergic Agents/pharmacology , Female , Humans , MaleABSTRACT
OBJECTIVES: Cognitive impairment models are used in clinical studies aimed at proving pharmacology of drugs being developed for Alzheimer's disease and other cognitive disorders. Due to rising interest in nicotinic agonists, we aimed to establish a method to monitor neurophysiological effects of modulating the nicotinic cholinergic system. METHODS: In a four-way cross-over study, eyes-closed rest EEG was recorded in 28 healthy subjects receiving mecamylamine-a nicotinic acetylcholine receptor (nAChR) antagonist, which induces temporary cognitive dysfunction in healthy subjects-with co-administration of placebo, nicotine or galantamine. RESULTS: Using machine learning to optimally contrast the effects of 30â¯mg of mecamylamine and placebo on the brain, we developed a nAChR index that consists of 10 EEG biomarkers and shows high classification accuracy (â¼95% non-cross-validated, â¼70% cross-validated). Importantly, using the nAChR index, we demonstrate reversal of mecamylamine-induced neurophysiological effects due to 16â¯mg of galantamine as well as administering 21â¯mg of nicotine transdermally. CONCLUSIONS: Our findings indicate that the mecamylamine challenge model jointly with the nAChR index-a measure of the nicotinic EEG profile-could aid future proof-of-pharmacology studies to demonstrate effects of nicotinic cholinergic compounds. SIGNIFICANCE: This novel measure for quantifying nicotinic cholinergic effects on the EEG could serve as a useful tool in drug development of pro-cognitive compounds.
Subject(s)
Brain Waves/drug effects , Drug Evaluation/methods , Mecamylamine/pharmacology , Nicotinic Antagonists/pharmacology , Nootropic Agents/pharmacology , Adolescent , Adult , Cholinesterase Inhibitors/pharmacology , Cognition/drug effects , Drug Evaluation/standards , Galantamine/pharmacology , Humans , Machine Learning , Male , Mecamylamine/administration & dosage , Mecamylamine/adverse effects , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/administration & dosage , Nicotinic Antagonists/adverse effects , Nootropic Agents/administration & dosage , Nootropic Agents/adverse effectsABSTRACT
The processing of visual stimuli from retina to higher cortical areas has been extensively studied in the human brain. In Huntington's disease (HD), an inherited neurodegenerative disorder, it is suggested that visual processing deficits are present in addition to more characteristic signs such as motor disturbances, cognitive dysfunction, and behavioral changes. Visual deficits are clinically important because they influence overall cognitive performance and have implications for daily functioning. The aim of this review is to summarize current literature on clinical visual deficits, visual cognitive impairment, and underlying visual cortical changes in HD patients. A literature search was conducted using the electronic database of PubMed/Medline. This review shows that changes of the visual system in patients with HD were not the primary focus of currently published studies. Still, early atrophy and alterations of the posterior cerebral cortex was frequently observed, primarily in the associative visual cortical areas such as the lingual and fusiform gyri, and lateral occipital cortex. Changes were even present in the premanifest phase, before clinical onset of motor symptoms, suggesting a primary region for cortical degeneration in HD. Although impairments in visuospatial processing and visual perception were reported in early disease stages, heterogeneous cognitive batteries were used, making a direct comparison between studies difficult. The use of a standardized battery of visual cognitive tasks might therefore provide more detailed information regarding the extent of impairments in specific visual domains. Further research could provide more insight into clinical, functional, and pathophysiological changes of the visual pathway in HD.