Cognition in (pre)symptomatic Dutch-type hereditary and sporadic cerebral amyloid angiopathy.

Introduction: Cerebral amyloid angiopathy (CAA) is a main cause of cognitive dysfunction in the elderly. We investigated specific cognitive profiles, cognitive function in the stage before intracerebral hemorrhage (ICH), and the association between magnetic resonance imaging (MRI) based cerebral small vessel disease (cSVD) burden in CAA because data on these topics are limited.

Methods: We included Dutch-type hereditary CAA (D-CAA) mutation carriers with and without ICH, patients with sporadic CAA (sCAA), and age-matched controls.

A cross-sectional study in healthy elderly subjects aimed at development of an algorithm to increase identification of Alzheimer pathology for the purpose of clinical trial participation.

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 (Aβ) 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.

Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study.

Background: The cholinergic system and M receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M 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.

First-in-man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M -receptor partial agonist for the treatment of dementias.

Aims: HTL0018318 is a selective M 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.

Brain Bio-Energetic State Does Not Correlate to Muscle Mitochondrial Function in Huntington's Disease.

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.

Safety, pharmacokinetics and pharmacodynamics of SBT-020 in patients with early stage Huntington's disease, a 2-part study.

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.

Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine.

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.

Quantification of tremor using consumer product accelerometry is feasible in patients with essential tremor and Parkinson's disease: a comparative study.

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).

A Computerized Test Battery to Study Pharmacodynamic Effects on the Central Nervous System of Cholinergic Drugs in Early Phase Drug Development.

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.

Predictors of simulated driving performance in Huntington's disease.

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.

Altered driving performance of symptomatic Huntington's disease gene carriers in simulated road conditions.

Objective: In clinical practice, patients with Huntington's disease (HD) often decide to solely drive in their own familiar neighborhoods and not on a motorway or in an unknown area. The aim of the study was to identify differences in driving performance between HD gene carriers and healthy individuals in simulated urban and motorway environments.

Methods: This cross-sectional study included 87 participants (28 premanifest HD, 30 manifest HD, 29 controls).

An EEG nicotinic acetylcholine index to assess the efficacy of pro-cognitive compounds.

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.

The visual cortex and visual cognition in Huntington's disease: An overview of current literature.

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.

Cognitive Performance and Apathy Predict Unemployment in Huntington's Disease Mutation Carriers.

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.

Reversal of mecamylamine-induced effects in healthy subjects by nicotine receptor agonists: Cognitive and (electro) physiological responses.

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).

Driving with a neurodegenerative disorder: an overview of the current literature.

Driving is important for employment, social activities, and for the feeling of independence. The decision to cease driving affects the quality of life and has been associated with reduced mobility, social isolation, and sadness. Patients with neurodegenerative disorders can experience difficulties while driving due to their cognitive, motor, and behavioral impairments.

Pharmacokinetics and pharmacodynamics of oral mecamylamine - development of a nicotinic acetylcholine receptor antagonist cognitive challenge test using modelling and simulation.

A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects. A one-compartment linear kinetic model best described the plasma concentrations of mecamylamine.

Participants at the Leiden Site of the REGISTRY Study: A Demographic Approach.

Background: REGISTRY is the largest European observational study of Huntington's disease (HD). The Leiden University Medical Center (LUMC) in The Netherlands is the largest recruiting site.

Objective: The aim of this paper is to give an overview of the baseline characteristics of all Leiden participants from the start of the study in 2005 until the close of REGISTRY at the LUMC in September 2014.

Reliability and factor structure of the Short Problem Behaviors Assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies.

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.

Longitudinal resting state fMRI analysis in healthy controls and premanifest Huntington's disease gene carriers: a three-year follow-up study.

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.

Motor dysfunction influence on executive functioning in manifest and premanifest Huntington's disease.

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.

Reduced functional brain connectivity prior to and after disease onset in Huntington's disease.

Background: Huntington's disease (HD) is characterised by both regional and generalised neuronal cell loss in the brain. Investigating functional brain connectivity patterns in rest in HD has the potential to broaden the understanding of brain functionality in relation to disease progression. This study aims to establish whether brain connectivity during rest is different in premanifest and manifest HD as compared to controls.

Longitudinal pilot-study of Sustained Attention to Response Task and P300 in manifest and pre-manifest Huntington's disease.

Background: Earlier research has found cross-sectional attentional control deficits in manifest Huntington's disease (HD) using neuropsychological testing combined with simultaneous P300 registration. In the current pilot-study, we investigate attentional control in pre-manifest and manifest HD over a 3-year follow-up period.

Method: Five manifest HD (MHD), 9 pre-manifest HD (PMHD), and 12 control subjects were included.

Better global and cognitive functioning in choreatic versus hypokinetic-rigid Huntington's disease.

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.