The ambivalence toward neuropsychology in dementia research, diagnosis, and drug development: Myths and misconceptions.

Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, and conducting clinical research. Biomarkers hold promise for targeted therapeutic approaches, selection of participants in clinical trials, and direct physiological efficacy readouts. However, the anchoring of biomarker research to clinical symptomatology is often based on short and insensitive cognitive screening. This gives the impression that cognitive symptoms occur relatively late and that their progression in the early stages of the disease is slow. A thorough cognitive assessment is a powerful tool and has a key role in the accurate and early diagnosis of dementia. It is very different from the cognitive testing usually seen in biomarker research and drug development. Yet the distinction between these approaches is unclear to many. This paper highlights the misconceptions around cognitive research in dementia and suggests a way forward to facilitate biomarker and drug development through the improved utility of cognitive assessment tools.

Cortical responses to amphetamine exposure studied by pCASL MRI and pharmacokinetic/pharmacodynamic dose modeling.

INTRODUCTION: Perfusion measurement by arterial spin labeling (ASL) techniques is well suited for pharmaceutical magnetic resonance imaging (phMRI) studies to investigate how drugs change the cerebral perfusion status and further, neuronal activity. MATERIALS AND METHOD: Twelve healthy normal male volunteers participated in the study which was based on a double blinded design. Six subjects were randomly selected to receive a single oral dose of 20mg d-amphetamine and six were given placebo. Perfusion measurements by pseudo-continuous ASL (pCASL) technique were repeatedly performed at 10 different time points with a 3T clinical MRI scanner during a 10 hour period after dose together with physiologic data and blood sample collections. The dynamic changes in cerebral perfusion in response to the plasma concentration variations of d-amphetamine were analyzed at voxel-level and for regions of interest. RESULTS: Compared to the placebo group a 20% reduction in cerebral blood flow (CBF) was observed in gray matter for the subjects that received d-amphetamine. The most significant reduction of regional CBF (rCBF) was detected in the basal ganglia, frontal region and insular cortex using voxel based analysis. A relation between d-amphetamine exposure and CBF response was found using PK/PD modeling, which predicted on average a 15% decrease of the CBF in gray matter at a plasma concentration of 30 ng/ml. CONCLUSION: In this study we have demonstrated that repeated perfusion measurements by pCASL technique was sufficiently robust to differentiate the neurological response between the groups that received d-amphetamine and placebo. Quantitative and repetitive CBF measurements can be used for PK/PD modeling of CNS drug responses in humans.

Brief Memory and Executive Test: evaluation of a new screening test for cognitive impairment due to small vessel disease.

BACKGROUND: cerebral small vessel disease (SVD) is the most common cause of vascular cognitive impairment (VCI). Despite this, there is a paucity of rapid simple screening tools to identify cognitive impairment in SVD and differentiate it from other common dementia types. OBJECTIVE: to validate a new screening test for cognitive impairment in SVD, the Brief Memory and Executive Test (BMET) battery, and examine its ability to detect SVD and differentiate it from Alzheimer's disease (AD). SUBJECTS: 45 patients with SVD, 27 patients with AD and 80 normal controls. METHODS: the BMET includes brief tests of executive functioning and processing speed, with comparative tests of memory and orientation. Group discrimination was calculated using discriminant function analysis. RESULTS: the BMET took an average of 10 min to administer. It showed high sensitivity (91%) and specificity (85%) in differentiating SVD patients with cognitive impairment from AD patients. As a comparison the mini-mental state examination had lower sensitivity (63%) and specificity (62%). CONCLUSIONS: the BMET is a simple and quick to administer clinical tool for the detection of VCI in SVD and its differentiation from AD impairment. Further multicentre studies are required to evaluate and compare it with other existing screening tests.

Validation of the Icelandic version of the Neuropsychiatric Inventory with Caregiver Distress (NPI-D).

BACKGROUND: Dementia is a complex and often debilitating illness, presenting with not only wide-ranging cognitive impairment but also neuropsychiatric challenges, which can have diverse consequences in quality of life for both patient and caregiver. AIM: Studying the validity and reliability of an Icelandic translation of the Neuropsychiatric Inventory with Caregiver Distress (NPI-D). METHODS: NPI-D was administered to 38 primary caregivers of dementia patients. The concurrent validity was explored by statistically comparing the NPI-D to the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) and the Geriatric Depression Scale (GDS). Regarding caregiver distress, concurrent validity was established between NPI-D, BEHAVE-AD Global Rating and two other caregiver distress scales. RESULTS: Significant correlation was found when total score on the BEHAVE-AD was compared with total score on the NPI-D. All NPI-D subscales achieved significant correlation with the corresponding BEHAVE-AD subscales apart from the 'depression/dysphoria subscale'. This NPI-D subscale correlated however, significantly with the GDS depression scale, a frequent and well validated measure of depressive symptoms in the elderly population. Cronbach's alpha coefficient indicated a high degree of overall internal consistency among the items of the NPI-D. Interestingly, apathy was the most frequent neuropsychiatric disturbance and the only subscale that differed significantly between dementia severity levels. Finally, when studying caregiver distress, the NPI-D showed good concurrent validity with other measures of caregiver burden and distress. CONCLUSIONS: The results demonstrate an acceptable level of validity and reliability; therefore the Icelandic translation of the NPI-D is well suited for identifying neuropsychiatric symptoms in dementia and associated caregiver burden.

Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study: Protocol for an Exploratory, Cross-sectional Study.

BACKGROUND: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests. OBJECTIVE: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials. METHODS: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments. RESULTS: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic. CONCLUSIONS: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35442.

Remote monitoring technologies in Alzheimer's disease: design of the RADAR-AD study.

BACKGROUND: Functional decline in Alzheimer's disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales. METHODS: This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. The RMT assessments, performed over an 8-week period, include walk tests, financial management tasks, an augmented reality game, two activity trackers, and two smartphone applications installed on the participants' phone. In the first sub-study, fixed sensors will be installed in the homes of a representative sub-sample of 40 participants. In the second sub-study, 10 participants will stay in a smart home for 1 week. The primary outcome of this study is the difference in functional domain profiles assessed using RMTs between the four study groups. The four participant groups will be compared for each RMT outcome measure separately. Each RMT outcome will be compared to a standard clinical test which measures the same functional or cognitive domain. Finally, multivariate prediction models will be developed. Data collection and privacy are important aspects of the project, which will be managed using the RADAR-base data platform running on specifically designed biomedical research computing infrastructure. RESULTS: First results are expected to be disseminated in 2022. CONCLUSION: Our study is well placed to evaluate the clinical utility of RMT assessments. Leveraging modern-day technology may deliver new and improved methods for accurately monitoring functional decline in all stages of AD. It is greatly anticipated that these methods could lead to objective and real-life functional endpoints with increased sensitivity to pharmacological agent signal detection.

A Study of Novel Exploratory Tools, Digital Technologies, and Central Nervous System Biomarkers to Characterize Unipolar Depression.

Background: Digital technologies have the potential to provide objective and precise tools to detect depression-related symptoms. Deployment of digital technologies in clinical research can enable collection of large volumes of clinically relevant data that may not be captured using conventional psychometric questionnaires and patient-reported outcomes. Rigorous methodology studies to develop novel digital endpoints in depression are warranted. Objective: We conducted an exploratory, cross-sectional study to evaluate several digital technologies in subjects with major depressive disorder (MDD) and persistent depressive disorder (PDD), and healthy controls. The study aimed at assessing utility and accuracy of the digital technologies as potential diagnostic tools for unipolar depression, as well as correlating digital biomarkers to clinically validated psychometric questionnaires in depression. Methods: A cross-sectional, non-interventional study of 20 participants with unipolar depression (MDD and PDD/dysthymia) and 20 healthy controls was conducted at the Centre for Human Drug Research (CHDR), the Netherlands. Eligible participants attended three in-clinic visits (days 1, 7, and 14), at which they underwent a series of assessments, including conventional clinical psychometric questionnaires and digital technologies. Between the visits, there was at-home collection of data through mobile applications. In all, seven digital technologies were evaluated in this study. Three technologies were administered via mobile applications: an interactive tool for the self-assessment of mood, and a cognitive test; a passive behavioral monitor to assess social interactions and global mobility; and a platform to perform voice recordings and obtain vocal biomarkers. Four technologies were evaluated in the clinic: a neuropsychological test battery; an eye motor tracking system; a standard high-density electroencephalogram (EEG)-based technology to analyze the brain network activity during cognitive testing; and a task quantifying bias in emotion perception. Results: Our data analysis was organized by technology - to better understand individual features of various technologies. In many cases, we obtained simple, parsimonious models that have reasonably high diagnostic accuracy and potential to predict standard clinical outcome in depression. Conclusion: This study generated many useful insights for future methodology studies of digital technologies and proof-of-concept clinical trials in depression and possibly other indications.

Digital Therapeutics: An Integral Component of Digital Innovation in Drug Development.

Digital therapeutics represent a new treatment modality in which digital systems such as smartphone apps are used as regulatory-approved, prescribed therapeutic interventions to treat medical conditions. In this article we provide a critical overview of the rationale for investing in such novel modalities, including the unmet medical needs addressed by digital therapeutics and the potential for reducing current costs of medical care. We also discuss emerging pathways to regulatory approval and how innovative business models are enabling further growth in the development of digital therapeutics. We conclude by providing some recent examples of digital therapeutics that have gained regulatory approval and highlight opportunities for the near future.

Retinal oxygen metabolism in patients with mild cognitive impairment.

INTRODUCTION: We have previously reported that retinal vessel oxygen saturation is increased in mild-to-moderate dementia of Alzheimer's type when compared with healthy individuals. Mild cognitive impairment (MCI) is the predementia stage of the disease. The main purpose was to investigate if these changes are seen in MCI. METHODS: Retinal vessel oxygen saturation was measured in 42 patients with MCI and 42 healthy individuals with a noninvasive retinal oximeter, Oxymap T1. The groups were paired according to age. RESULTS: Arteriolar and venular oxygen saturation was increased in MCI patients compared to healthy individuals (arterioles: 93.1 ± 3.7% vs. 91.1 ± 3.4%, P = .01; venules: 59.6 ± 6.1% vs. 54.9 ± 6.4%, P = .001). Arteriovenous difference was decreased in MCI compared to healthy individuals (33.5 ± 4.5% vs. 36.2 ± 5.2%, P = .01). DISCUSSION: Increased retinal vessel oxygen saturation and decreased arteriovenous difference in MCI could reflect less oxygen extraction by retinal tissue. This indicates that retinal oxygen metabolism may be affected in patients with MCI.

Primary and secondary anosognosia for memory impairment in patients with Alzheimer's disease.

The neuropsychology of anosognosia for memory impairment in Alzheimer's disease (AD) was examined in 92 AD patients and 92 case matched individuals for comparison, using three quantitative methods of assessment: Experimenter Rating Scale (ERS), Objective Judgement Discrepancy (OJD) and Subjective-Rating Discrepancy (SRD). The OJD showed significant domain specific correlations with memory functioning as well as a significant correlation with susceptibility to intrusional errors. Memory or executive dysfunction may affect the immediate ability to judge cognitive performance in a domain specific manner (secondary anosognosia). Longer-term awareness of cognitive deficit appears less influenced by impaired basic cognitive functions, than by the decline of metacognitive function (primary anosognosia).

Clinically Meaningful Outcomes in Early Alzheimer Disease: A Consortia-Driven Approach to Identifying What Matters to Patients.

BACKGROUND: Numerous statistically derived composite measures have recently been proposed as clinical outcome assessments (COAs) for clinical trials in the early stages of Alzheimer disease. Critical Path Institute's Coalition Against Major Diseases (CAMD) advanced a proposed statistically derived composite measure to regulatory agencies with the goal of qualifying it as a COA for pre-dementia trials. In response to FDA's requirement to demonstrate that proposed COAs are meaningful to patients, this project aimed to identify the most important cognition-related concerns patients and informants report early in the disease and determine how this information maps to what is assessed by several statistically derived composite measures. METHODS: Leveraging qualitative research completed by Critical Path Institute's Patient-Reported Outcome Consortium, CAMD utilized a summary report that included frequency grids of reported concerns of amnestic mild cognitive impairment patients and their informants, as well as the narrative transcripts from focus groups. Transcripts were reviewed and analyzed to identify which cognitive domains the patient- and informant-reported concerns mapped onto. The results were then compared to see how well these cognitive domains were represented in various statistically derived composite measures. RESULTS: The patient- and informant-reported concerns primarily mapped to the cognitive domains of episodic memory and, secondarily, orientation and language. Depending on the specified composite, there were varying levels of alignment between their subcomponents and these cognitive domains. CONCLUSION: Through secondary analyses of existing qualitative data, this study examined several statistically derived composite measures and found that they generally capture cognitive domains that reflect aspects of day-to-day functioning that patients and informants consider meaningful.

Executive dysfunction, awareness deficits and quality of life in patients with cerebral small vessel disease: a structural equation model.

OBJECTIVE: To investigate the relationships between executive dysfunction, awareness deficits and perceptions of quality of life (QOL) in patients with cerebral small vessel disease (SVD). METHOD: We tested neuropsychological function with simultaneous measurement of awareness performance in 125 participants. Forty-five were carefully phenotyped patients with SVD, defined as a lacunar stroke with corresponding infarct on neuroimaging; and 80 were age-matched controls, providing a normal comparison for neuropsychological measures. Patients also completed the Stroke-Specific Quality of Life Scale. In patients with SVD, the impact of executive dysfunction on awareness and QOL was examined simultaneously using structural equation modeling. RESULTS: A simple regression indicated a positive relationship between awareness and QOL. However, when executive function was added to the model, the results showed strong relationships between executive function and awareness, and executive function and QOL, but no direct relationship between awareness and QOL. CONCLUSION: Our results show that the main neuropsychological symptom associated with SVD, namely, executive dysfunction, may predict both reductions in awareness and QOL. However, there is no direct impact of awareness deficits on QOL in patients with SVD, when executive function is included in the model.

A randomized, double-blind, placebo-controlled crossover study of α4ß 2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder.

RATIONALE: Stimulation of nicotinic cholinergic systems has been shown to alleviate ADHD symptoms and to improve cognitive performance. AZD1446 is a selective α4ß2* nicotinic acetylcholine receptor agonist with potential effect on the symptoms of ADHD. OBJECTIVES: The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AZD1446 in adults with ADHD treated for 2 weeks. METHOD: This was a randomized, double-blind, placebo-controlled crossover trial. Participants were 79 adults with ADHD, grouped according to their use of nicotine-containing products. Nicotine non-users received placebo and two of three AZD1446 treatment regimens (80 mg tid, 80 mg qd, 10 mg tid). Nicotine users received placebo, AZD1446 80 mg tid and 80 mg qd. Efficacy measures included the Conners' Adult ADHD Rating Scale and cognitive measures of immediate and delayed verbal episodic memory, learning, attention, working memory, executive functioning, and spatial problem solving (CogState computerized test battery). RESULTS: There was no significant effect of AZD1446 on any of the clinical scores irrespective of dose, schedule, or concomitant use of nicotine products. A statistically significant improvement was seen on the Groton Maze Learning Task, a measure of executive functioning, in nicotine non-users after treatment with AZD1446 80 mg qd. CONCLUSIONS: AZD1446 was well tolerated, but did not significantly improve ADHD symptoms after 2 weeks of treatment compared to placebo. While the present study does not support the therapeutic utility of AZD1446 in ADHD, its potential pro-cognitive effects remain to be explored in other neuropsychiatric disorders.

Lack of awareness of neuropsychological deficit in cerebral small vessel disease: the relationship with executive and episodic memory functions.

A common cause of neuropsychological impairment in older adults is cerebral small vessel disease (SVD), but little is known as to whether lack of awareness of neuropsychological impairment is a feature of this clinical condition. In this study, we investigated awareness deficits in a well-phenotyped population of patients with SVD (n= 45; 21 with defined concomitant neuropsychological impairment) and made comparisons with 24 Alzheimer's disease (AD) patients and a further 80 control participants. Awareness of performance on a range of neuropsychological measures was examined based on the Brief Memory and Executive Test Battery (BMET) (Brookes, Hannesdottir, Lawrence, Morris, & Markus, 2012), exploring the relationship between awareness and memory and executive function. The results revealed significant awareness deficits in both the SVD and AD groups. When splitting the SVD group into those with or without concomitant neuropsychological impairment, only those with neuropsychological impairment showed reduced awareness. For the SVD group, executive function was significantly correlated with awareness but memory was not. By comparison, memory was significantly correlated with awareness in the AD group, with executive function showing a trend but remaining non-significant. The results show that lack of awareness of deficit is a clinical feature of SVD and indicate that there are distinct neuropsychological associations with awareness deficit for SVD and AD.

A study of the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) in an Icelandic elderly population.

The Alzheimer's Disease Assessment Scale (ADAS) is designed for screening of cognitive and non-cognitive dysfunctions characteristic of persons with probable Alzheimer's disease (AD). The cognitive part of the scale (ADAS-Cog) is both convenient for screening of probable AD and as a measure of cognitive functioning during drug intervention. The aim of this study was to translate the ADAS-Cognitive sub-test (ADAS-Cog) into Icelandic and to study its application in an elderly Icelandic population. The Mini-Mental State Examination (MMSE) and the ADAS-Cog were administered to 20 AD patients and 20 controls. Each patient was also rated on the Global Deterioration Scale (GDS). The probable AD patients were divided into two groups based on their GDS: 3-4 and 5-6 points. The patients were also divided into two groups based on their MMSE score: very mild to mild (23-30 points) and mild to moderate (15-22 points). Furthermore, the subjects were divided into two age groups: 65-76 and 77-92 years. Results revealed a highly significant difference on MMSE (22.3 +/- 3.4; 26.8 +/- 1.6; P < 0.05) and ADAS-Cog (18.4 +/- 7.7; 7.3 +/- 3.5; P < 0.05) scores for patients and controls respectively. AD patients also performed significantly worse than the elderly control group on eight of the 11 sub-tests. Thus, the present findings are mainly in line with those of previous studies. The scale exceeds other screening tests such as the MMSE in that it addresses in more detail the symptoms of AD and is valuable for early detection of the illness and staging. ADAS-Cog plays an important role in the diagnostic makeup of AD along with other detailed investigations, such as neuropsychological assessment.