British psychologist with an interest in cognitive testing. Published author, voiceover actor and classical scholar. Read more at: http://www.linkedin.com/in/drjohnharrison.
BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when prog... more BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer 's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.
Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcom... more Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.
Background and objectives: It is unclear to what extent cognitive outcome measures are sensitive ... more Background and objectives: It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups.
Methods: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years.
Results: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction.
Discussion: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.
Major depressive disorder (MDD) and other mental health issues pose a substantial burden on the w... more Major depressive disorder (MDD) and other mental health issues pose a substantial burden on the workforce. Approximately half a million Canadians will not be at work in any week because of a mental health disorder, and more than twice that number will work at a reduced level of productivity (presenteeism). Although it is important to determine whether work plays a role in a mental health condition, at initial presentation, patients should be diagnosed and treated per appropriate clinical guidelines. However, it is also important for patient care to determine the various causes or triggers including work-related factors. Clearly identifying the stressors associated with the mental health disorder can help clinicians to assess functional limitations, develop an appropriate care plan, and interact more effectively with worker’s compensation and disability programs, as well as employers. There is currently no widely accepted tool to definitively identify MDD as work-related, but the presence of certain patient and work characteristics may help. This paper seeks to review the evidence specific to depression in the workplace, and provide practical tips to help clinicians to identify and treat work- related MDD, as well as navigate disability issues.
Objective: We aimed to investigate whether item response theory (IRT)-based scoring allows for a ... more Objective: We aimed to investigate whether item response theory (IRT)-based scoring allows for a more accurate, responsive, and less biased assessment of everyday functioning than traditional classical test theory (CTT)-based scoring, as measured with the Amsterdam Instrumental Activities of Daily Living Questionnaire. Method: In this longitudinal multicenter study including cognitively normal and impaired individuals, we examined IRT-based and CTT-based score distributions and differences between diagnostic groups using linear regressions, and investigated scale attenuation. We compared change over time between scoring methods using linear mixed models with random intercepts and slopes for time. Results: Two thousand two hundred ninety-four participants were included (66.6 ± 7.7 years, 54% female): n = 2,032 (89%) with normal cognition, n = 93 (4%) with subjective cognitive decline, n = 79 (3%) with mild cognitive impairment, and n = 91 (4%) with dementia. At baseline, IRT-based and CTT-based scores were highly correlated (r = −0.92). IRT-based scores showed less scale attenuation than CTT-based scores. In a subsample of n = 1,145 (62%) who were followed for a mean of 1.3 (SD = 0.6) years, IRT-based scores declined significantly among cognitively normal individuals (unstandardized coefficient [B] = −0.15, 95% confidence interval, 95% CI [−0.28, −0.03], effect size = −0.02), whereas CTT-based scores did not (B = 0.20, 95% CI [−0.02, 0.41], effect size = 0.02). In the other diagnostic groups, effect sizes of change over time were similar. Conclusions: IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior suitability for use in preclinical populations.
Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, an... more 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.
Journal of autism and developmental disorders, Jan 11, 2016
15q13.3 microdeletion syndrome causes a spectrum of cognitive disorders, including intellectual d... more 15q13.3 microdeletion syndrome causes a spectrum of cognitive disorders, including intellectual disability and autism. We aimed to determine if any or all of three cognitive testing systems (the KiTAP, CogState, and Stanford-Binet) are suitable for assessment of cognitive function in affected individuals. These three tests were administered to ten individuals with 15q13.3 microdeletion syndrome (14-18 years of age), and the results were analyzed to determine feasibility of use, potential for improvement, and internal consistency. It was determined that the KiTAP, CogState, and Stanford-Binet are valid tests of cognitive function in 15q13.3 microdeletion patients. Therefore, these tests may be considered for use as objective outcome measures in future clinical trials, assessing change in cognitive function over a period of pharmacological treatment.
The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is des... more The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Compared to the...
Cognitive symptoms are core symptoms with an impact on functioning in depression. Remission is co... more Cognitive symptoms are core symptoms with an impact on functioning in depression. Remission is considered as the main objective of the management and treatment of depression. This study was aimed to compare cognitive performance between melancholic (MelD) and non-melancholic depression (NMelD) and to determine whether these cognitive alterations remain after clinical remission. We performed a 6 month follow-up study of 88 melancholic and non-melancholic depressive patients. Sociodemographic and clinical characteristics were recorded. Depression was examined using the Hamilton Depression Rating Scale and the CORE Index for Melancholia. Cognitive performance was assessed with the Trail Making Test (TMT), the Digit Span subtest of the WAIS-III, Stroop Colour Word Test (SCWT), the Tower of London (TOL DX), the Controlled Oral Word Association Test (FAS), Semantic Verbal Fluency and Finger Tapping Test (FTT). MelD patients show worse performance than N-MelD at baseline, with significant differences at Digit Span subtest of WAIS Part I and Part II, SCWT Part I and Part II, TOL DX, Total Problem Solving, Total Execution Time and FTT- Preferred hand. Cognitive impairment remains at six months follow-up after clinical remission in MelD. In the comparison between remitted and non-remitted patients, cognitive impairment in Trail Making Test Part B and Verbal and Semantic Fluency (Animals) remains after clinical remission in MelD group but not in non-melancholic patients. The use of psychopharmacological treatment and the small sample of melancholic patients. Patients with MelD do not improve cognitive performance despite clinical remission compared with remitted NMelD patients. The persistence of some cognitive dysfunctions in MelD remitted patients could represent a trait marker of a different depressive subtype and not be secondary to disease severity.
To report the psychometric properties of an alternative instrument to the cognitive subscale of t... more To report the psychometric properties of an alternative instrument to the cognitive subscale of the Alzheimer's Disease Assessment Scale, a neuropsychological test battery (NTB) for measuring drug efficacy in Alzheimer disease clinical trials. Design: The NTB was evaluated in a randomized, doubleblind, placebo-controlled trial of AN1792(QS-21) (synthetic -amyloid plus an adjuvant) (300 patients) and isotonic sodium chloride solution (72 patients). The testretest reliability of the NTB was examined, and the NTB was correlated with other cognitive (cognitive subscale of the Alzheimer's Disease Assessment Scale and Mini-Mental State Examination) and functional (Disability Assessment Scale for Dementia and Clinical Dementia Rating Sum of Boxes) measures. In addition, a factor analysis was performed on NTB components. Finally, the sensitivity of the NTB to change was assessed as a function of Mini-Mental State Examination performance. Results: The NTB had high test-retest reliability at 6 (Pearson product moment correlation [r] = 0.92) and 12 (r =0.88) months. Internal consistency was high (Cronbach ␣=0.84). The correlations between the NTB z score and scores on traditional measures of cognition and function were significantly different from 0 (PϽ.001). A factor analysis yielded "memory" and "executive function" factors. The NTB z score declined linearly over 1 year in patients receiving placebo and, in contrast to the Alzheimer's Disease Assessment Scale cognitive subscale, demonstrated similar declines in patients with high (21-26) and low (15-20) Mini-Mental State Examination scores at baseline. Conclusions: The NTB exhibits excellent psychometric properties and seems to be a reliable and sensitive measure of cognitive change in patients with mild to moderate Alzheimer disease. The psychometric properties of the NTB suggest that it may have particular utility in evaluating drug efficacy in clinical trials in which patients with mild Alzheimer disease are included.
PBO and 20 hours post-dose for MOX at the time points of pharmacokinetic sample collection. Stand... more PBO and 20 hours post-dose for MOX at the time points of pharmacokinetic sample collection. Standard safety monitoring was conducted throughout the study. Plasma EVP-6124 and metabolite concentrations were determined with a validated assay. Effects of EVP-6124 and MOX on ECG were assessed by central tendency (PBOand baseline-adjusted individual-corrected QT derived from triplicate means; QTcI), categorical, and morphologic analyses. Results: EVP-6124 was well-tolerated and 52 subjects completed the study. The majority of treatment-emergent adverse events were mild in severity and no apparent trends or clinically meaningful changes were observed from baseline in clinical laboratory tests results or vital signs measurements. MOX caused a QT prolongation with the lower bound of the one-sided 95%CI for QTcI change above 5 ms, thereby validating the study design and conduct. The maximum upper bound of the one-sided 95% CI for EVP-6124 change in QTcI was 3.4 ms. Similar results were observed with QTcF analysis. No EVP-6124 effect on categorical or morphologic analyses was observed. No relationship between EVP-6124 or metabolite exposure and QTcI change was observed. Conclusions: EVP-6124 was well-tolerated and did not delay cardiac repolarization in healthy subjects at supratherapeutic exposures.
The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to de... more The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 acti- vator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to- moderate dementia with Lewy bodies (DLB), a disease in which BFCN degen- eration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.
A crucial aspect of any clinical trial is using the right outcome measure to assess treatment eff... more A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi-step framework to advance the use of more effective COAs to assess clinically meaningful changes in This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
International Journal of Methods in Psychiatric Research, 2022
Introduction: We report further validation and normative data for the THINC-Integrated Tool (THIN... more Introduction: We report further validation and normative data for the THINC-Integrated Tool (THINC-it), a measure of cognitive function designed for use with individuals living with Major Depressive Disorder, but which is finding use in further psychiatric and neurological diseases. THINC-it comprises four objective computerised cognitive tests based on traditional psychological paradigms and a version of the Perceived Deficits Questionnaire assessment. Methods: Sample size of n = 10.019 typical control study participants were tested on one to two occasions to further validate the reliability of THINC-it. Temporal reliability was assessed across 120-180 days. Results: Test-retest reliability correlations varied between r = 0.50 and 0.72 for the component measures and r = 0.75 (95% confidence intervals 0.74, 0.76) for the THINC-it composite score. Normative data categorised by Age, Sex and Years of Education were calculated and the effect on task performance was reported. Discussion: Our analysis confirms previously reported levels of reliability and validates previously reported normative data values.
As the focus of Alzheimer 's disease (AD) therapeutic development shifts to the early stages of t... more As the focus of Alzheimer 's disease (AD) therapeutic development shifts to the early stages of the disease, the clinical endpoints used in drug trials, and how these might translate into clinical practice, are of increasing importance. The clinical meaningfulness of trial outcome measures is often unclear, with a lack of conclusive evidence as to how these measures correlate to changes in disease progression and treatment response. Clarifying this would benefit all, including patients, care partners, primary care providers, regulators, and payers, and would enhance our understanding of the relationship between clinical trial endpoints and assessments used in everyday practice. At present, there is a wide range of assessment tools used in clinical trials for AD and substantial variability in measures selected as endpoints across these trials. The aim of this review is to summarize the most commonly used assessment tools for early stages of AD, describe their use in clinical trials and clinical practice, and discuss what might constitute clinically meaningful change in these measures in relation to disease progression and treatment response.
Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large ... more Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab. Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57-2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32-2.08). Rates of neurocognitive TEAEs were similar in patients receiving ali...
Journal of Alzheimer's disease : JAD, Jan 20, 2016
Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phosphol... more Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramér's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations. In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outc...
BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when prog... more BACKGROUND: Disease modifying therapies (DMTs) may be most beneficial in early disease, when progression is slow and changes small, with clinical relevance difficult to interpret. OBJECTIVES: Time component tests (TCTs) translate differences between treatments from mean change, vertical distance between longitudinal trajectories, into intuitively understood time saved, horizontal distance between trajectories, which can be readily combined across endpoints in a global TCT (gTCT). DESIGN: The value of composites, time savings estimates, and combination scores to optimize measurement and interpretation of DMTs are demonstrated, along with construction details and simulation studies. SETTING: TCT methods were applied to a randomized phase II clinical trial. PARTICIPANTS: Patients with early Alzheimer 's disease (N=332). INTERVENTION: Three treatment groups with AFFITOPE® AD02 and two control groups with aluminum oxyhydroxide, AD04. MEASUREMENTS: The co-primary efficacy outcomes were an adapted ADAS-Cog (aADAS) and adapted ADCS-ADL (aADL), which were optimized composite scales specific to cognitive and functional domains. A composite based on these two scores was the study's prespecified primary outcome. The CDR-sb and standard non-adapted ADCS-ADL and ADAS-Cog scales were prespecified secondary outcomes. RESULTS: The AD04 2 mg group showed some statistically significant effects compared with other study arms. It is unclear whether the observed 3.8-point difference on the composite is clinically meaningful. TCT results show a time savings of 11 months in an 18-month study with AD04 2 mg. CONCLUSION: The relevance of 11 months saved is more universally understood than a mean difference of 3.8 points in the composite outcome. These results suggest that a combination of a composite approach and a time savings interpretation offers a powerful approach for detecting and interpreting disease modifying effects.
Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcom... more Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.
Background and objectives: It is unclear to what extent cognitive outcome measures are sensitive ... more Background and objectives: It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups.
Methods: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years.
Results: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction.
Discussion: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.
Major depressive disorder (MDD) and other mental health issues pose a substantial burden on the w... more Major depressive disorder (MDD) and other mental health issues pose a substantial burden on the workforce. Approximately half a million Canadians will not be at work in any week because of a mental health disorder, and more than twice that number will work at a reduced level of productivity (presenteeism). Although it is important to determine whether work plays a role in a mental health condition, at initial presentation, patients should be diagnosed and treated per appropriate clinical guidelines. However, it is also important for patient care to determine the various causes or triggers including work-related factors. Clearly identifying the stressors associated with the mental health disorder can help clinicians to assess functional limitations, develop an appropriate care plan, and interact more effectively with worker’s compensation and disability programs, as well as employers. There is currently no widely accepted tool to definitively identify MDD as work-related, but the presence of certain patient and work characteristics may help. This paper seeks to review the evidence specific to depression in the workplace, and provide practical tips to help clinicians to identify and treat work- related MDD, as well as navigate disability issues.
Objective: We aimed to investigate whether item response theory (IRT)-based scoring allows for a ... more Objective: We aimed to investigate whether item response theory (IRT)-based scoring allows for a more accurate, responsive, and less biased assessment of everyday functioning than traditional classical test theory (CTT)-based scoring, as measured with the Amsterdam Instrumental Activities of Daily Living Questionnaire. Method: In this longitudinal multicenter study including cognitively normal and impaired individuals, we examined IRT-based and CTT-based score distributions and differences between diagnostic groups using linear regressions, and investigated scale attenuation. We compared change over time between scoring methods using linear mixed models with random intercepts and slopes for time. Results: Two thousand two hundred ninety-four participants were included (66.6 ± 7.7 years, 54% female): n = 2,032 (89%) with normal cognition, n = 93 (4%) with subjective cognitive decline, n = 79 (3%) with mild cognitive impairment, and n = 91 (4%) with dementia. At baseline, IRT-based and CTT-based scores were highly correlated (r = −0.92). IRT-based scores showed less scale attenuation than CTT-based scores. In a subsample of n = 1,145 (62%) who were followed for a mean of 1.3 (SD = 0.6) years, IRT-based scores declined significantly among cognitively normal individuals (unstandardized coefficient [B] = −0.15, 95% confidence interval, 95% CI [−0.28, −0.03], effect size = −0.02), whereas CTT-based scores did not (B = 0.20, 95% CI [−0.02, 0.41], effect size = 0.02). In the other diagnostic groups, effect sizes of change over time were similar. Conclusions: IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior suitability for use in preclinical populations.
Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, an... more 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.
Journal of autism and developmental disorders, Jan 11, 2016
15q13.3 microdeletion syndrome causes a spectrum of cognitive disorders, including intellectual d... more 15q13.3 microdeletion syndrome causes a spectrum of cognitive disorders, including intellectual disability and autism. We aimed to determine if any or all of three cognitive testing systems (the KiTAP, CogState, and Stanford-Binet) are suitable for assessment of cognitive function in affected individuals. These three tests were administered to ten individuals with 15q13.3 microdeletion syndrome (14-18 years of age), and the results were analyzed to determine feasibility of use, potential for improvement, and internal consistency. It was determined that the KiTAP, CogState, and Stanford-Binet are valid tests of cognitive function in 15q13.3 microdeletion patients. Therefore, these tests may be considered for use as objective outcome measures in future clinical trials, assessing change in cognitive function over a period of pharmacological treatment.
The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is des... more The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Compared to the...
Cognitive symptoms are core symptoms with an impact on functioning in depression. Remission is co... more Cognitive symptoms are core symptoms with an impact on functioning in depression. Remission is considered as the main objective of the management and treatment of depression. This study was aimed to compare cognitive performance between melancholic (MelD) and non-melancholic depression (NMelD) and to determine whether these cognitive alterations remain after clinical remission. We performed a 6 month follow-up study of 88 melancholic and non-melancholic depressive patients. Sociodemographic and clinical characteristics were recorded. Depression was examined using the Hamilton Depression Rating Scale and the CORE Index for Melancholia. Cognitive performance was assessed with the Trail Making Test (TMT), the Digit Span subtest of the WAIS-III, Stroop Colour Word Test (SCWT), the Tower of London (TOL DX), the Controlled Oral Word Association Test (FAS), Semantic Verbal Fluency and Finger Tapping Test (FTT). MelD patients show worse performance than N-MelD at baseline, with significant differences at Digit Span subtest of WAIS Part I and Part II, SCWT Part I and Part II, TOL DX, Total Problem Solving, Total Execution Time and FTT- Preferred hand. Cognitive impairment remains at six months follow-up after clinical remission in MelD. In the comparison between remitted and non-remitted patients, cognitive impairment in Trail Making Test Part B and Verbal and Semantic Fluency (Animals) remains after clinical remission in MelD group but not in non-melancholic patients. The use of psychopharmacological treatment and the small sample of melancholic patients. Patients with MelD do not improve cognitive performance despite clinical remission compared with remitted NMelD patients. The persistence of some cognitive dysfunctions in MelD remitted patients could represent a trait marker of a different depressive subtype and not be secondary to disease severity.
To report the psychometric properties of an alternative instrument to the cognitive subscale of t... more To report the psychometric properties of an alternative instrument to the cognitive subscale of the Alzheimer's Disease Assessment Scale, a neuropsychological test battery (NTB) for measuring drug efficacy in Alzheimer disease clinical trials. Design: The NTB was evaluated in a randomized, doubleblind, placebo-controlled trial of AN1792(QS-21) (synthetic -amyloid plus an adjuvant) (300 patients) and isotonic sodium chloride solution (72 patients). The testretest reliability of the NTB was examined, and the NTB was correlated with other cognitive (cognitive subscale of the Alzheimer's Disease Assessment Scale and Mini-Mental State Examination) and functional (Disability Assessment Scale for Dementia and Clinical Dementia Rating Sum of Boxes) measures. In addition, a factor analysis was performed on NTB components. Finally, the sensitivity of the NTB to change was assessed as a function of Mini-Mental State Examination performance. Results: The NTB had high test-retest reliability at 6 (Pearson product moment correlation [r] = 0.92) and 12 (r =0.88) months. Internal consistency was high (Cronbach ␣=0.84). The correlations between the NTB z score and scores on traditional measures of cognition and function were significantly different from 0 (PϽ.001). A factor analysis yielded "memory" and "executive function" factors. The NTB z score declined linearly over 1 year in patients receiving placebo and, in contrast to the Alzheimer's Disease Assessment Scale cognitive subscale, demonstrated similar declines in patients with high (21-26) and low (15-20) Mini-Mental State Examination scores at baseline. Conclusions: The NTB exhibits excellent psychometric properties and seems to be a reliable and sensitive measure of cognitive change in patients with mild to moderate Alzheimer disease. The psychometric properties of the NTB suggest that it may have particular utility in evaluating drug efficacy in clinical trials in which patients with mild Alzheimer disease are included.
PBO and 20 hours post-dose for MOX at the time points of pharmacokinetic sample collection. Stand... more PBO and 20 hours post-dose for MOX at the time points of pharmacokinetic sample collection. Standard safety monitoring was conducted throughout the study. Plasma EVP-6124 and metabolite concentrations were determined with a validated assay. Effects of EVP-6124 and MOX on ECG were assessed by central tendency (PBOand baseline-adjusted individual-corrected QT derived from triplicate means; QTcI), categorical, and morphologic analyses. Results: EVP-6124 was well-tolerated and 52 subjects completed the study. The majority of treatment-emergent adverse events were mild in severity and no apparent trends or clinically meaningful changes were observed from baseline in clinical laboratory tests results or vital signs measurements. MOX caused a QT prolongation with the lower bound of the one-sided 95%CI for QTcI change above 5 ms, thereby validating the study design and conduct. The maximum upper bound of the one-sided 95% CI for EVP-6124 change in QTcI was 3.4 ms. Similar results were observed with QTcF analysis. No EVP-6124 effect on categorical or morphologic analyses was observed. No relationship between EVP-6124 or metabolite exposure and QTcI change was observed. Conclusions: EVP-6124 was well-tolerated and did not delay cardiac repolarization in healthy subjects at supratherapeutic exposures.
The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to de... more The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 acti- vator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to- moderate dementia with Lewy bodies (DLB), a disease in which BFCN degen- eration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.
A crucial aspect of any clinical trial is using the right outcome measure to assess treatment eff... more A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi-step framework to advance the use of more effective COAs to assess clinically meaningful changes in This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
International Journal of Methods in Psychiatric Research, 2022
Introduction: We report further validation and normative data for the THINC-Integrated Tool (THIN... more Introduction: We report further validation and normative data for the THINC-Integrated Tool (THINC-it), a measure of cognitive function designed for use with individuals living with Major Depressive Disorder, but which is finding use in further psychiatric and neurological diseases. THINC-it comprises four objective computerised cognitive tests based on traditional psychological paradigms and a version of the Perceived Deficits Questionnaire assessment. Methods: Sample size of n = 10.019 typical control study participants were tested on one to two occasions to further validate the reliability of THINC-it. Temporal reliability was assessed across 120-180 days. Results: Test-retest reliability correlations varied between r = 0.50 and 0.72 for the component measures and r = 0.75 (95% confidence intervals 0.74, 0.76) for the THINC-it composite score. Normative data categorised by Age, Sex and Years of Education were calculated and the effect on task performance was reported. Discussion: Our analysis confirms previously reported levels of reliability and validates previously reported normative data values.
As the focus of Alzheimer 's disease (AD) therapeutic development shifts to the early stages of t... more As the focus of Alzheimer 's disease (AD) therapeutic development shifts to the early stages of the disease, the clinical endpoints used in drug trials, and how these might translate into clinical practice, are of increasing importance. The clinical meaningfulness of trial outcome measures is often unclear, with a lack of conclusive evidence as to how these measures correlate to changes in disease progression and treatment response. Clarifying this would benefit all, including patients, care partners, primary care providers, regulators, and payers, and would enhance our understanding of the relationship between clinical trial endpoints and assessments used in everyday practice. At present, there is a wide range of assessment tools used in clinical trials for AD and substantial variability in measures selected as endpoints across these trials. The aim of this review is to summarize the most commonly used assessment tools for early stages of AD, describe their use in clinical trials and clinical practice, and discuss what might constitute clinically meaningful change in these measures in relation to disease progression and treatment response.
Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large ... more Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab. Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57-2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32-2.08). Rates of neurocognitive TEAEs were similar in patients receiving ali...
Journal of Alzheimer's disease : JAD, Jan 20, 2016
Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phosphol... more Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes. Effect size was determined by calculating Cohen's d statistic (or Cramér's V method for nominal data), number needed to treat and number needed to harm. Statistical calculations were performed for the intent-to-treat populations. In patients with mild AD, effect sizes were 0.21 (95% confidence intervals: -0.06, 0.49) for the primary outc...
The focus of my thesis is the reception of classical myth in Georgian Britain as exemplified by r... more The focus of my thesis is the reception of classical myth in Georgian Britain as exemplified by responses to the garden imagery at Stourhead, Wiltshire. Previous explanations have tended to the view that the gardens were designed to recapitulate Virgil’s Aeneid. However, the garden owner, Henry Hoare II, left no record to substantiate this, or any other theme, and it is not mentioned in the many extant visitor accounts from the eighteenth and early-nineteenth centuries. My approach to understanding the garden began with the systematic collection of information on the garden’s content and evolution. This endeavour yielded more than 20 further visitor reports, as well as visual and literary sources not considered in previous secondary accounts. This research has shown that the garden included a number of artefacts unknown to previous theorists. It has also shown that the true provenance and acquisition of extant garden elements is often different to that listed in the Stourhead secondary literature. I conclude that visitor reception of the gardens yields highly idiosyncratic interpretation, the emotional and cognitive content of which was largely determined by information obtained from published literature, garden guides and fellow visitors. A strong further influence on the interpretation of the gardens by some visitors was familiarity with the Roman and wider Italian influences on the garden content. I have especially considered visitor experience of the Grand Tour in this context. I propose that visits to Stourhead elicited emotional and cognitive responses from visitors. An effect of encountering the garden edifices and artefacts was to prompt memories, particularly of prior visits to the original Roman or Italian buildings and artefacts, but also of copies encountered in English landscape gardens and elsewhere.
音楽を聴くと色が見える! 共感覚というのは、音を聞くと色が見えたり、食事を味わうといろいろな形が見えたりなど、普通は別々に感じられる感覚が二つ、同時に分かちがたく知覚される現象を言います。こうい... more 音楽を聴くと色が見える! 共感覚というのは、音を聞くと色が見えたり、食事を味わうといろいろな形が見えたりなど、普通は別々に感じられる感覚が二つ、同時に分かちがたく知覚される現象を言います。こういう感覚を持つ人は稀ですが、画家のカンディンスキーや、作曲家のスクリャービンなども、この持ち主であったと言われています。大変興味深い現象のため、以前から心理学者に注目されてきましたが、最近の脳の活動を画像化して見る技術の発展によって、新しい探求が始まりました。本書は、この世にも不思議な心の現象に魅せられた心理学者の探求と思索を通して、共感覚とは何かだけでなく、心理学とはどういう学問なのかをも、私たちに分かりやすく語りかけてくれます
Synästhesie bezeichnet ein Zusammenwirken verschiedener Sinneskanäle, das etwa bei Musik zu Farbw... more Synästhesie bezeichnet ein Zusammenwirken verschiedener Sinneskanäle, das etwa bei Musik zu Farbwahrnehmungen führen kann. Durch dieses Zusammenwirken wird durch Stimulierung eines Sinnes gleichzeitig ein weiterer Sinn angeregt. Dadurch können manche Menschen auch Farben hören und Formen schmecken, oder umgekehrt bei Stimmen und Klängen Farben, Geschmack oder Geruch feststellen. Im Verlauf der Geschichte haben sich viele berühmte Künstler und Schriftsteller als Synästheten bekannt, darunter Arthur Rimbaud, Wassily Kandinsky und David Hockney. Früher oft romantisiert ist diese Fähigkeit heute ein wichtiger Gegenstand neurowissenschaftlicher Forschung. Denn sie ist immer noch voller Rätsel.
En El extraño fenómeno de la sinestesia se describe la misteriosa alteración sensoperceptiva en l... more En El extraño fenómeno de la sinestesia se describe la misteriosa alteración sensoperceptiva en la que la estimulación de un sentido produce, en la concienca de quien la sufre, una percepción en otro: oir colores, ver sonidos, saborear formas. Desde el siglo XIX, la neurología romántica, llamada así por el autor, realizó descripciones clínicas y estableció hipótesis que han sido muy útiles para las neurociencias contemporáneas. Una rigurosa selección de pacientes sometidos a estudios neuropsicológicos e imagenológicos muy cuidadosos permitió obtener conclusiones sorprendentes que el autor expone con gran claridad.
The early detection of Alzheimer’s disease (AD) offers the prospect of delivering current and pos... more The early detection of Alzheimer’s disease (AD) offers the prospect of delivering current and possible treatments, especially of drugs with disease modifying potential, as the point at which patients are most likely to benefit. Whilst we have met with very little success in developing new treatments, the extraordinary research effort of the past two decades has led to important advances in biomarker development. CSF and blood assays offer the prospect of identifying early-stage patients, and those at risk, by confirming the presence of pathological AD markers. However, the clinical measures of cognition still commonly employed in primary practice, and in clinical drug trials, has exhibited none of the innovation that has benefitted other areas of our AD research efforts. In spite of widespread criticism of tools such as the MMSE, CDR and ADAS-cog, these measures have remained the mainstay of cognitive assessment in clinical drug trials, and in the case of the MMSE, in primary practice. These scales have been rightly criticised for their poor psychometric qualities and this is especially the case with respect to content validity. Our understanding of the variety of cognitive deficits seen in individuals with AD has improved markedly in the more than 35 years since these measures were first published. We understand now that AD, even in in its earliest stages, whilst often apparent as difficulties with episodic memory, can commonly present as difficulties with attention, working memory and various executive skills. This variable presentation has been formally acknowledged in the proliferation of MCI variants.
In this lecture I will begin by describing the variety and nature of cognitive deficits seen in early AD. I will show that whilst digital testing offers an efficient means of assessing cognition, its measures rarely exceed the levels of sensitivity and specificity for AD achieved by reliable ‘paper-and-pencil’ tests, which still have a key role to play. I will then critically review the measures commonly employed to assess cognition in primary healthcare, specialist centres and clinical trials. I will conclude with a review of options and recommendations.
The creators of the eighteenth-century English landscape garden at Stourhead left few clues as to... more The creators of the eighteenth-century English landscape garden at Stourhead left few clues as to their design intentions. This void has been filled with various competing theories of Stourhead’s meaning, perhaps the best known of which is Woodbridge’s view that the circuit walk of the garden was intended to recapitulate the journey of Aeneas and the foundation of Rome. This paper will demonstrate that the evidence cited by Woodbridge and later theorists is based on incomplete information and erroneous interpretation of the edifices and artefacts at Stourhead. I will introduce new evidence which suggests that Ovid was a major influence in the garden design of Stourhead. My main example will be the content of the grotto at Stourhead and the references there to Ovid’s tale of Daphne and Peneus.
Building gardens provided socially aspirational eighteenth-century individuals, such as the banker and Stourhead owner Henry Hoare, with the opportunity to demonstrate knowledge of Roman myth as an illustration of their ‘Taste’. In eighteenth-century Britain ‘Taste’ was heavily influenced by Roman literature, and especially the writings of Ovid. Translations of Ovid were widely read in eighteenth-century Britain and published not just for a literary elite, but instead to meet ‘a consistent demand across the century for Ovidian writing’. I will show how the use of Ovid at Stourhead in the eighteenth century illustrates how his tale of gods and nymphs could invoke reflection on the legacy of Rome as expressed in the context of an English landscape garden.
Cognitive dysfunction is an important aspect of major depressive disorder (MDD) [1,2]. The domain... more Cognitive dysfunction is an important aspect of major depressive disorder (MDD) [1,2]. The domains of executive function, working memory, attention and episodic memory are amongst those commonly affected [3], with cognitive performance diminished in the range of small (0.2) to medium (0.5) effect sizes in even first-episode MDD patients [4]. A variety of objective tests have been used to detect cognitive deficits in MDD. However, few of these tests are appropriate for the screening of cognitive deficits, as they are often overly time-consuming and deficient with respect to their reliability, sensitivity and validity [5]. Working memory is often assessed using the n-back task, attention by the Choice Reaction Time task, executive function by the Trail Making Test-B and general cognition by the Digit Symbol Substitution Test. These objective tests can be usefully supplemented by subjective data obtained from self-report assessments such as the 5-item version of the Perceived Deficits Questionnaire (PDQ-5). The need for a simple, well-validated screening tool to evaluate cognitive dysfunction in patients with MDD has led to the THINC Task Force developing the ‘THINC-it’ assessment. THINC-it is comprised of executive function, memory, attention and working memory measures that have been ‘gamified’, and are augmented with an on-screen version of the PDQ-5. THINC-it can be used on desktop and tablet computers, requires non-expert administration and yields simple data reporting. The different elements of THINC-it will be demonstrated during the presentation.
Theorists of meaning at Stourhead gardens have tended to suppose that a 'grand plan' was intended... more Theorists of meaning at Stourhead gardens have tended to suppose that a 'grand plan' was intended. The best known theory is the one proposed by Kenneth Woodbridge, who suggested that the circuit walk at Stourhead was intended to recapitulate Aeneas' journey to found Rome. However, there is very little evidence to support this view. In my presentation I will critically review the Aeneid theory. I will instead propose that the designers' intention was to build a series of garden buildings, each of which was designed as an individual tableau. I will focus on the original statue selection and their juxtaposition at sites such as the Pantheon, the Grotto and the Temple of Apollo.
Prof John Harrison will explain the range of objective measures that are available for the assess... more Prof John Harrison will explain the range of objective measures that are available for the assessment of cognitive dysfunction in depression.
John will be discussing current medications and therapies, new drugs in development and practical... more John will be discussing current medications and therapies, new drugs in development and practical self-help.
For the past 40 years cognitivism has been amongst the dominant paradigms in psychology. Cogniti... more For the past 40 years cognitivism has been amongst the dominant paradigms in psychology. Cognitive psychologists have been concerned with how information is represented, and models of memory, concept representation and problem solving have been proposed to explain human behaviour. Cognitive psychology can be applied to visitor reception of classical iconography and yet to date this approach has been only rarely employed. In this paper I will demonstrate how this can be achieved.
Theorists of Stourhead’s meaning have tended to presume that Henry Hoare (1705-1785) had in mind a ‘Grand Design’ and they have focused on the proposition that he was heavily influenced by the Aeneid. These same theorists have proposed psychoanalytic explanations of Henry Hoare’s design intentions. My doctoral research indicates that much of this theorising has been based on incorrect information and interpretation based on an intentionalist fallacy.
Rather than assuming that a grand plan was envisaged, I have adopted the view that individual elements of the garden must also be considered for meaning. These elements might be objects (e.g. statues), or arrays of objects in the context of a single structure (e.g. a temple or grotto). I propose also that the question of meaning should be extended beyond the intentions of the designer to include the reception of Stourhead by 18 & 19th century visitors. Furthermore I propose that visitor experience can be helpfully interpreted using a cognitive psychological rather than psychoanalytic approach.
In seeking to understand visitor accounts I have employed cognitive psychological theory and especially schema theories of memory organisation. I have assumed that visitor reception can be understood through the application of theories of memory and knowledge representation. I have further assumed that prior knowledge and expectation are a function of written and oral sources of information. Many of the early poetic and published accounts of visits were available in periodicals and it seems likely that visitor experiences were mediated by these published records. However, other sources of influence, including formal schooling and information passed orally from visitor acquaintances, estate workers and local guides, have also been considered. The structures and objects at Stourhead have been influenced and inspired by classical Roman structures, many of which were publically accessible to visitors in the 18thcentury, and especially those who embarked on Grand Tour expeditions. This source of influence and information has also therefore been considered.
In my presentation I will provide a brief description of my research into the gardens at Stourhead since October 2012, with reference to the Temple of Ceres, the Pantheon and the Temple of Apollo. My specific focus will be on the Grotto, which at Stourhead houses statues of a river god and a nymph. This structure has been interpreted by those adopting a Virgilian perspective as symbolic of Aeneas’ descent into hell. I will argue that recently discovered primary sources, including an Italian visitor account from 1787 and a 1780 poem, suggest that a more likely source of inspiration is Ovid’s tale of Daphne and Peneus from the Metamorphoses.
The meeting will comprise state of the art plenary sessions, clinical perspectives presentations,... more The meeting will comprise state of the art plenary sessions, clinical perspectives presentations, Q&A panel discussions and break-out sessions, providing an engaging and interactive format to enable exchange of information and networking. In the clinical perspectives presentations, invited speakers will present their own latest research or interesting clinical cases.
A series of break-out sessions will also be held, in which the latest basic or clinical research in the field of cognitive dysfunction in depression will be showcased by a member of the THINC Task Force. These will cover topics such as the neural underpinnings of cognitive dysfunction and the impact of antidepressant therapy on patient functioning, and will be followed by workshop activities. There will be the opportunity to ask questions throughout the meeting, in addition to interactive Q&A panel discussions with the presenters and members of the THINC Task Force. Attendance at this meeting is by personal invitation only.
This is a copy of the presentation made at various hospital Grand Rounds, academic groups and psy... more This is a copy of the presentation made at various hospital Grand Rounds, academic groups and psychiatry meetings in Canada between 3rd & 7th November, 2014.
Henry Hoare, the creator of the landscape garden at Stourhead, is known to have travelled on Gran... more Henry Hoare, the creator of the landscape garden at Stourhead, is known to have travelled on Grand Tour between 1738 and 1741. Comparisons of the garden content with that of early 18th century Grand Tour guidebooks suggest that the former may have been profoundly influenced by the latter. For example, most of the garden statues at Stourhead were reproduced in Antiquarum Statuarum Urbis Romae. Roman quotations and architectural influences were also incorporated into the Stourhead estate.
The extant literature includes a number of visitor accounts to Stourhead though most have been relatively uninformative with respect to the content and evolution of the garden. This includes the garden buildings and their furnishings, but is particularly true of the statues that populated the various temples. A conspicuous exception to this was the record left by Horace Walpole after his visit in 1762, though his account is incomplete and contains factual errors.
In the past two years I have found several previously unconsidered accounts of the garden at Stourhead. These include the accounts of both domestic and overseas visitors, as well as several poems. Amongst the overseas visitor accounts is one by Count Carlo Gastone della Rezzonico, who visited in 1787. Gastone, a highly educated Italian visitor, offers a descriptive and critical account of Stourhead gardens from the period shortly after Henry Hoare’s death and prior to the substantial changes made by Richard Colt Hoare. In my paper I will show how Gastone, visiting the garden 45 years after Henry's return from Grand Tour, offers us an educated, native Italian interpretation of the garden features. These features were inspired by Henry Hoare’s Grand Tour. I will further show how the insight Gastone offers us illuminates our understanding of the garden element selection and their possible meaning.
CLIN-011 study-a randomized, placebo-controlled, double-blind, crossover, study of the pharmacody... more CLIN-011 study-a randomized, placebo-controlled, double-blind, crossover, study of the pharmacodynamic effects of clenbuterol co-administered with nadolol on the CNS in subjects with neurodegenerative disorders.
Varoglutamstat (PQ912), a small molecule glutaminyl cyclase (QPCT) inhibitor, reduces the brain l... more Varoglutamstat (PQ912), a small molecule glutaminyl cyclase (QPCT) inhibitor, reduces the brain levels of pyroglutamate-3-Abeta (N3pE-Abeta), a toxic Abeta variant shown to play a pivotal role in the development and progression of Alzheimer's disease (AD). Varoglutamstat is in clinical development as oral disease-modifying therapy. A prior Phase 2a study (NCT02389413) reported encouraging first evidence of the disease-modifying activity of varoglutamstat, with statistically significant changes from baseline in working memory.
To examine the treatment benefit of high-dose aducanumab across individual items/domains in the p... more To examine the treatment benefit of high-dose aducanumab across individual items/domains in the primary, secondary, and tertiary clinical endpoints in EMERGE. ¤ The item level analyses are consistent with the results observed from the primary analysis of the clinical endpoints. ¤ The aducanumab high-dose group showed a consistent drug-placebo difference across 5 clinical efficacy endpoints, slowing clinical decline over 78 weeks. ¤ The results demonstrate the consistency of the aducanumab treatment effect in slowing decline across cognitive, functional, and behavioral domains in early Alzheimer's disease.
Establishing a Reliable Change Index for digital cognitive assessments may help in detecting clin... more Establishing a Reliable Change Index for digital cognitive assessments may help in detecting clinically significant changes in cognition.
Patients with Alzheimer's disease perform worse on Neurotrack's digital cognitive assessments tha... more Patients with Alzheimer's disease perform worse on Neurotrack's digital cognitive assessments than cognitively healthy controls.
Background • Sensitive instruments are required to detect subtle changes in everyday functioning ... more Background • Sensitive instruments are required to detect subtle changes in everyday functioning in early Alzheimer's disease (AD). The optimal detection of subtle changes may depend on instrument and psychometric properties of scoring
Psilocybin belongs to a class of drugs referred to as psychedelics (‘mind-manifesting’). Partial ... more Psilocybin belongs to a class of drugs referred to as psychedelics (‘mind-manifesting’). Partial agonism of 5-HT2A receptors is a key mechanism contributing to its biological effects. The effects of psilocybin on cognitive functioning have not been widely or systematically studied COMP360 is COMPASS Pathfinder Limited’s proprietary synthetic psilocybin formulation optimized for stability and purity, and is in clinical development for treatment-resistant depression following encouraging indications of psilocybin efficacy, with minimal adverse events (AEs), in pilot studies in depressive states. Previous studies in healthy participants have indicated acute improvements in social cognition following psilocybin administration (non COMP360 formulation); however, it remains unclear whether these benefits persist post-acutely and whether the potential beneficial effects of psilocybin are limited to improving social cognition or if psilocybin may also benefit general cognitive abilities. Here we report results on the effects of COMP360 on key domains of cognitive functioning from the largest randomized, placebo-controlled trial of psilocybin to date
Background
• In an attempt to improve the detection of clinically meaningful cognitive decline in... more Background • In an attempt to improve the detection of clinically meaningful cognitive decline in early Alzheimer’s disease (AD)1, we designed the Cognitive-Functional Composite (CFC).2-4 • We previously showed the CFC’s good reliability, feasibility of use and clinical relevance in mild cognitive impairment (MCI) and mild AD dementia.5,6 Aim - To investigate the CFC’s sensitivity to change over time, in comparison to traditional clinical endpoints.
Type 2 diabetes is a risk factor for Alzheimer disease (AD) and several studies have shown that i... more Type 2 diabetes is a risk factor for Alzheimer disease (AD) and several studies have shown that insulin signalling is impaired in AD brain. Progressive brain hypometabolism is a hallmark of AD and can be evaluated using [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). Peripheral insulin resistance (IR) also increases AD risk. Recent evidence suggests that peripheral IR is associated with significantly lower regional cerebral glucose metabolism in elderly individuals at risk for AD and also predicts medial temporal hypometabolism in AD patients
Clinical drug trials in preclinical AD populations will require novel approaches to participant i... more Clinical drug trials in preclinical AD populations will require novel approaches to participant identification, screening, and enrollment. Cognitive screening instruments must be straightforward, sensitive to disease-specific pathology, and allow for the interpretation of findings over time relative to demographically age-matched normative samples. Well-designed assessments of visuospatial working memory may serve as fruitful screening measures. Specific impairments in visuospatial working memory related to hippocampal-dependent binding of stimulus features have been suggested as a potential early marker AD neuropathology. Prior work in this area has shown that subjects with mild cognitive impairment may not differ from healthy controls in basic working memory tasks, but tasks that require encoding and maintenance of combined object features, such as identity and location, demonstrate increased sensitivity. The specificity of these deficits suggests a potential relationship between task performance and reduced integrity of the hippocampal, perirhinal and entorhinal cortices which are affected early in AD pathology. We describe results of a recent study utilizing a novel tablet-based visuospatial working memory (VSWM) task to examine differences between healthy older adults with and without subjective cognitive decline (SCD).
Background: Early phase clinical trials of disease modifying drugs must show that such compounds ... more Background: Early phase clinical trials of disease modifying drugs must show that such compounds are safe. one possible adverse event associated with some disease modifying drugs is encephalopathy. among other signs encephalopathy manifests as an acute decrease in cognitive function. Hence routine monitoring of cognitive function in clinical trials can provide the earliest signal of encephalopathy. Methods: Thirty-six patients received a single dose of novel disease modifying compound. They completed the brief CogState AD battery every week of the trial. Automatic statistic algorithms processed data in real time by comparing data from the current visit to that from the visit before. the rate of cases identified was computed and cases were validated on the basis of a full neurological workup. Results: Of the 36 patients 87% completed testing at all sessions. Five cases of encephalopathy were declared although four of these were due to data entry mistakes. no person without encephalopathy was classified as having undergone significant deterioration in cognitive function. Conclusions: Real time monitoring of cognitive function can provide both an early, objective and reliable detection system for encephalopathy in clinical trials of disease modifying agents.
Background - The Cognitive-Functional Composite (CFC) is designed to detect clinically relevant c... more Background - The Cognitive-Functional Composite (CFC) is designed to detect clinically relevant changes in early dementia. The CFC exhibits high test-retest reliability and feasibility of use. To further validate this measure, we investigated its factor structure and compared CFC scores with traditional measures of cognition and function. Methods - We used baseline data of the Capturing Changes in Cognition (Catch-Cog) study: an international, multicenter, observational, prospective cohort-study including subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), mild dementia due to Alzheimer’s disease (AD) and Lewy Bodies dementia (DLB) (MMSE ≥ 18). The CFC comprises seven existing cognitive tests focusing on memory and executive function, and an informant-based everyday functioning measure: the Amsterdam IADL Questionnaire (A-IADL-Q). The CFC’s factor structure was investigated using a principal component analyses (PCA) of all eight subtests. We calculated a weighted cognitive composite z-score (CC z-score) for the seven cognitive subtests, as well as a CFC z-score for all eight CFC subtests. We computed Pearson’s correlation coefficients between the CFC and traditional measures, including: 1) the CC z-score, MMSE and ADAS-Cog-13; 2) the A-IADL-Q, ADCS-ADL and CDR-SB; and 3) the CFC z-score and CDR-SB. To investigate range restrictions, we compared score distributions using histograms of the CFC and the traditional tests. Results - A total of 142 subjects completed our baseline assessment (mean age 71.7±8.4, 43% female, mean MMSE 25.3±2.9). Diagnoses included SCD (n=13), MCI (n=54), mild AD (n=60) and DLB (n=11). The PCA yielded two factors, one loading on memory tests, and one mainly on executive functioning tests and the A-IADL-Q. As expected, we found moderate-to-high correlations between the CFC and traditional measures, supporting the CFC’s concurrent and construct validity. Histograms showed expected floor and ceiling effects for the traditional measures as compared with the CFC. Conclusions - The CFC is a measure of early dementia relevant domains of cognition and function, yielding fewer range restrictions as compared to traditional tests. It is therefore better indicated for use to adequately and meaningfully evaluate cognition and function, in line with the recent FDA recommendations. We are currently assessing the CFC longitudinally in our Catch-Cog cohort.
Background: Amnestic Mild Cognitive Impairment (MCIa) is a putative prodromal stage of Alzheimer'... more Background: Amnestic Mild Cognitive Impairment (MCIa) is a putative prodromal stage of Alzheimer's Disease (AD) characterized by focal deficits in episodic verbal memory. Relative deficits in visuospatial learning are not routinely considered to be a defining feature of MCIa, and yet ample human and animal evidence indicates both hippocampal involvement in visuospatial learning and both hippocampal degeneration and defective cholinergic neuro-transmission in early AD. Methods: This study sought to better characterize the components of spatial working memory dysfunction in MCIa participants (N 1⁄4 62), compared to healthy elderly adults (HE; N 1⁄4 94) using a hidden maze task. Results: Robust group differences were found (controlling for age and simple visuomotor speed) [F(1)1⁄44.9, p1⁄4.028] on the measure of spatial learning efficiency (exploratory errors), but both groups performed similarly on measures of spatial problem solving and reasoning. The learning curve between the first two learning trials was four times as steep for HE compared with MCIa (slope 1⁄4 4.9 vs. 1.24, respectively), indicating that MCIa participants exhibited relative difficulties in creating and making immediate effective use of an internal spatial map. Conclusions: MCIa patients demonstrated clear focal deficits in visuospatial working memory, with relative preservation of functioning on task measures of visuospatial reasoning and problem-solving.
Background: The acute response of cognitive function to treatment with cholinesterase inhibitors ... more Background: The acute response of cognitive function to treatment with cholinesterase inhibitors is not well described. The aim of the current study was to measure the magnitude of change in memory, attention and executive function in response to a single acute 5mg dose of donepezil. Methods: 16 patients with mild Alzheimer's disease (AD) were enrolled in a double-blind placebo controlled two arm crossover trial of 5mg donepezil and placebo. The Detection, Identification, verbal learning and paired associate learning tests from the CogState AD battery were used to measure cognitive function. Assessments were made before and then at 1,2,4,6,9 hours after dosing. Results: Significant benefits over placebo were observed for all cognitive measures with the effect becoming greatest 6 hours after dosing. Effects were greatest for measures of simple and choice reaction time and then visual paired associate learning. Conclusions: Cognitive function does improve in mild AD immediately after initiation of treatment with cholinesterase inhibitor. The magnitude of this improvement is moderate. These data suggest that a single day study with a cholinesterase inhibitor may provide a good challenge model for new drugs that are designed to alleviate cognitive symptoms in AD.
Background: The Brief Assessment of Cognition in Schizophrenia (BACS) is a pen-and-paper cognitiv... more Background: The Brief Assessment of Cognition in Schizophrenia (BACS) is a pen-and-paper cognitive assessment used in hundreds of research studies and clinical trials. A tablet-based version of the BACS, the BAC App, has been developed to allow standardized presentation of task instructions and stimuli, audio-recording of responses, and automatized scoring and data management. To extend use of the BAC App for assessment of cognition in aging and early detection of Mild Cognitive Impairment due to Alzheimer's disease (MCI-AD), additional tests of episodic verbal memory and visuospatial working memory were developed and incorporated. Collection of census- matched normative data in 750 healthy individuals is currently under- way. We describe preliminary findings comparing performance of young (<55) and older (≥55) healthy adults, as well as performance of individuals with subjective cognitive complaints. Methods: Tasks were designed in compliance with guidance for objective psychometric tests (Ferris et al., 1997) and to enable tablet-assisted administration, automatic scoring, and data management in compliance with 21 CRF Part 11 requirements. Data currently includes 143 participants, including 63 healthy young adults (YA, <55 years), 76 healthy older adults (OA, ≥55 years), and 4 individuals with cognitive complaints. Participants with cognitive complaints were classified as such based on total scores of ≥ 4 on the Mail-In Function Cognitive Screening Instrument (MCSFI). Results: Means and standard deviations are presented for YAs, OAs and cognitive complainers. OAs underperformed YAs on BAC App endpoints including verbal learning, verbal fluency, symbol coding, and token motor test (p<.01 for all). Although delayed recall did not reliably differ between healthy YAs (mean1⁄49.01, SD1⁄43.02) and OAs (mean1⁄48.38, SD1⁄43.26), cognitive complainers performed well below their normative counterparts (mean1⁄44.25, SD1⁄42.99). Visuospatial working memory performance showed significant decline in OAs as compared to YAs (p<.01), and preliminary data suggest increased decline in cognitive complainers. Conclusions: Preliminary findings suggest the BAC App is sensitive to age-related changes in cognition and show potential sensitivity to differences between healthy OAs and those with subjective cognitive complaints. Enhancement of the BAC App with additional measures of episodic memory and visuospatial working memory shows potential for increasing the utility of the measure in early MCI-AD.
The need to maximize data quality in Alzheimer's disease clinical trials is essential given the f... more The need to maximize data quality in Alzheimer's disease clinical trials is essential given the failures of so many disease-modifying compounds. The use of enhanced eCOA 4.0 scales such as the eADAS-Cog and eMMSE are significantly more effective at reducing rater errors when compared to the original eCOA 3.0 scales and paper/pencil scales. These enhanced eCOA 4.0 scales coupled with an in-study ratings surveillance program to identify errors in scoring, can significantly improve data quality by reducing rater error, enhancing standardized administration/scoring of the scale and minimizing rater drift over the course of a trial.
Background - There is an urgent need for a psychometrically sound measure that is capable of capt... more Background - There is an urgent need for a psychometrically sound measure that is capable of capturing clinically relevant changes in the early stages of dementia. To this end, we designed a novel Cognitive-Functional Composite (CFC) combining seven cognitive tests focusing on episodic memory and executive functioning. The Amsterdam IADL Questionnaire (A-IADL-Q). Methods - Multicenter, prospective, test-retest study with 2-3 weeks between assessments. We included 48 memory-clinic subjects with MCI or mild dementia due to AD (MMSE ≥ 18, age ≥ 50) and 30 healthy volunteers (age ≥ 50). All subjects underwent the cognitive tests (+/- 25 min) whilst a study partner completed the A-IADL-Q (+/- 20 min). We computed intraclass correlation coefficients (ICCs) using a two-factor random model and type absolute agreement and Cohen’s d effect sizes. Feasibility was evaluated by interviewing a subsample of patients (n=15). Results A total of 43 patients (40% female, aged 69.9 (SD=7.4), MMSE 25.2 (SD=3.2), years of education 14.3 (SD=5.1)) and 30 controls (50% female, age 65 (SD=7.1), years of education 16.9 (SD=4.0)) completed both study visits. Overall, patients were older (p=.006) and received less education (p=. 022) than controls. Cognitive subtest ICCs were all >0.70, indicating high test-retest reliability (Table 1). We found very high test-retest reliability for the A-IADL-Q (ICC = .96). For the cognitive subtests, we found a statistical significant change on the DSST in patients and controls, and on the COWAT in controls (Figure 1). However, effect sizes for change scores indicated limited practice effects, especially in patients (Table 1). Feasibility interviews indicated that the patients’ general impression of the CFC was mainly positive. In general, its total duration (20-25 minutes) was experienced as acceptable. Test materials were described as clear and very readable. Conclusions -Our results demonstrate that the CFC meets important quality metrics for clinically meaningful outcome measures. The next step in our validation plan is to determine its sensitivity to change over time.
In the early 1980’s a computerised set of cognitive tests was developed to
facilitate the definit... more In the early 1980’s a computerised set of cognitive tests was developed to facilitate the definitive evaluation of the cognitive effects of novel compounds in drug development. Since then this system (the Cognitive Drug Research computersied assessment system) has been used in hundreds of clinical trials worldwide and data from the system has been widely disseminated including over 150 peered reviewed papers and chapters. A huge normative database has been established over the age range 20 to 90 years. The system has also been used widely in different types of dementia as well as in trials of AAMI, ARCD and MCI. The tests have also been extensively validated and correlated widely with functional everyday scales. This presentation will critically review the information which can be gained from screening with this instrument, and describe the extent to which such data can be used to support the identification and diagnoses of various cognitive disorders associated with aging.
Introduction - Alirocumab is a fully human antibody to proprotein convertase subtilisin kexin typ... more Introduction - Alirocumab is a fully human antibody to proprotein convertase subtilisin kexin type 9 (PCSK9) which has demonstrated large reductions in low-density lipoprotein cholesterol (LDL-C) in Phase 3 clinical trials. Subjective neurocognitive complaints have been reported by patients taking statins and other lipid-lowering therapies (LLTs)and some research has reported an increase in neurocognitive treatment-emergent adverse events (TEAEs) during clinical trials of LLTs. However, several clinical trials found no association between neurocognitive problems and either use of LLTs or low LDL-C levels. The objective of this analysis was to provide a comprehensive overview of neurocognitive TEAEs reported in clinical trials of alirocumab. Methods - Data were included from 14 trials (four Phase 2 and 10 Phase 3). Double- blind treatment periods were 8–12 weeks for Phase 2 and 24–104 weeks for Phase 3. In most studies, patients with hypercholesterolemia received maximally tolerated statin; other LLTs were also permitted in the majority of studies. Alirocumab was administered at a dose of 75 or 150 mg every 2 weeks (Q2W). All Phase 2 and five Phase 3 studies compared alirocumab with placebo; five Phase 3 studies compared alirocumab with ezetimibe. Neurocognitive TEAEs were self-reported by patients. In the current analysis, they were defined using a broad company custom Medical Dictionary of Regulatory Activities (MedDRA) query proposed by the sponsor. An analysis was performed to examine the rate of neurocognitive TEAEs in different age groups (<65 years, 65–74 years, and ≥75 years). Results - Data were available for 5234 patients (n=3340 alirocumab, n=1276 placebo, n=618 ezetimibe). Exposure to alirocumab was 4029 patient-years. The mean age across all treatment groups was 58.5–62.1 years. In the placebo-controlled pool, 22 patients (0.9%) receiving alirocumab and nine patients (0.7%) receiving placebo had a neurocognitive TEAE (HR 1.24; 95% CI 0.57–2.68); corresponding values in the ezetimibe-controlled pool were 10 (1.2%) and eight (1.3%) for alirocumab and ezetimibe, respectively (HR 0.81; 95% CI 0.32–2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with two consecutive values of LDL-C <25 mg/dL (n=5/839; 0.6%;0.5/100 patient-years) versus patients receiving alirocumab with levels≥25 mg/dL (n=26/2501; 1.0%; 0.8/100 patient-years) and patients in control groups (n=17/1894; 0.9%; 0.7/100 patient-years) (Figure 2). No patients in the control groups achieved LDL-C <25 mg/dL. One (0.1%) patient receiving alirocumab, two (0.2%) receiving placebo,and three (0.4%) receiving ezetimibe had neurocognitive TEAEs leading to treatment discontinuation. Most neurocognitive TEAEs were mild or moderate. One patient receiving placebo had a severe neurocognitive TEAE, compared with none receiving alirocumab or ezetimibe. Across groups, neurocognitive TEAE rates were highest in patients aged ≥75 years (3.9–6.9%) and lowest for patients aged <65 years (0.3–0.8%), with no significant difference between treatment groups in any age bracket. Conclusions - In four Phase 2 and 10 Phase 3 trials involving 5200 patients for up to 104 weeks, there was no apparent increase in neurocognitive TEAEs with alirocumab treatment overall or in different age groups. Based on the analyzed Phase 2 and 3 trials, LDL-C levels <25 mg/dL were not associated with a higher frequency of neurocognitive TEAEs. Further evaluation in longer-term studies is planned, with more detailed neurocognitive assessment and evaluation of potential contributing factors such as age, comorbidities and concomitant medication. A study on the neurocognitive effects of longer-term alirocumab treatment has begun (NCT XXX), using formal neurocognitive testing.
Neuropsychological testing is essential for monitoring disease progression and treatment evaluati... more Neuropsychological testing is essential for monitoring disease progression and treatment evaluation in dementia. ‘Capturing Changes in Cognition’ is a research project designed to improve the measurement of disease progression in mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). We inventoried the needs and wishes of dementia researchers and clinicians for instruments targeted at disease progression.
This certificate acknowledges that John Harrison has successfully completed a one hour training a... more This certificate acknowledges that John Harrison has successfully completed a one hour training and certification to administer and score the Montreal Cognitive Assessment, MoCA. Only health professionals with expertise in cognition can interpret test results.
Alzheimer's disease Drug Development: Research and Development Ecosystem, 2022
Many disorders of the central nervous system can cause a decline in cognitive function. The type ... more Many disorders of the central nervous system can cause a decline in cognitive function. The type and magnitude of the observed deficits is understood to be a function of the physiological systems that subserve specific cognitive skills. In the case of Alzheimer’s disease (AD) there is good evidence to show that amongst the structures most susceptible to early pathological damage are those subserving an individual’s ability to encode and recall new information. These episodic memory deficits are often the presenting sign for individuals who have developed AD. It is perhaps therefore unsurprising that the traditional measures of cognitive function used in AD are heavily weighted toward memory assessment. This is particularly true of instruments commonly employed in clinical drug trials of putative new therapies such as the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog) and the Mini-Mental State Examination (MMSE) [1, 2]. In these two scales more than half of the possible score tally is derived from measures of episodic memory, with the remaining subtests providing indices of language and praxis function. However, AD research in the past decade has repeatedly highlighted that cognitive functions either not well or not at all indexed by the ADAS-cog and MMSE can also be impaired early in the disease process. There is now good evidence of early impairments of attention, executive function, and working memory, deficits often manifested in individuals living with AD, as well as deficits of concentration, problem-solving, and navigation. This variable presentation of early AD is well understood by specialist centres, expert groups, and third-party stakeholders, such as advocacy groups and drug-approval regulators.
Cognitive Dimensions of Major Depressive Disorder, 2019
Accurately capturing an individual’s cognitive status is a key requirement for identifying levels... more Accurately capturing an individual’s cognitive status is a key requirement for identifying levels of impairment in patients with CNS indications, including in those with diagnoses of Major Depressive Disorders (MDD). This requirement extends to the determination of whether a therapeutic intervention has impacted cognition and if so, the extent to which this has occurred. In this chapter we will consider these issues with respect to the assessment of cognition in patients with MDD. We begin with a review of performance on measures reported in recent meta-analyses and with a particular focus on their sensitivity to treatment effects. We proceed to a consideration of how best we might accurately capture levels of cognitive performance and the precautions required to reduce sources of measurement error. These methods will then be considered in the context of a recent case study of a treatment (vortioxetine) development programme. The issues explored in the context of assessing cognition in the vortioxetine programme are then considered in the context of screening for deficits in patients with MDD. We close the chapter with a summary, and recommendations for the accurate assessment of cognition, as well as a brief consideration of how technological developments might aid this process.
Handbook of Behavioral Neuroscience: Translational Medicine in CNS Drug Development, 2019
The assessment of cognition in clinical drug trials of potential new therapies for Alzheimer’s di... more The assessment of cognition in clinical drug trials of potential new therapies for Alzheimer’s disease (AD) has traditionally been conducted using the Mini-Mental State Examination (MMSE—Folstein, Folstein, & McHugh, 1975) and variants of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog—Rosen, Mohs, & Davis, 1984). The MMSE is a portmanteau measure of very brief tests of memory, attention, praxis, and language, originally designed as a brief, bedside measure of general cognition. In AD trials, it has traditionally been employed as a means of both selecting and stratifying patient cohorts. The earliest trials of AD therapies were designed to assess treatment effects in patients labeled as having “mild-to-moderate” disease severity, typically a range of 14–26 on the MMSE. The MMSE is ranged from 0 to 30 with higher scores indicating superior performance. An informal scheme has evolved by which patients with scores in the 0–12 range are classified as “severe,” 13–20 as “moderate,” and 21–26 as “mild.” The ADAS-cog has for the past 20 years near universally been employed as the primary cognitive efficacy measure in AD trials (Hobart et al., 2013; Wesnes & Harrison, 2003). Like the MMSE, it is also a portmanteau measure and is similarly composed of memory, language, and praxis subtests. A major limitation of the ADAS-cog is the omission of working memory, attention and execu- tive function (EF) tests, and a deficiency highlighted by Mohs et al. (1997). In an attempt to remedy these deficien- cies, Mohs et al. (1997) recommended the inclusion of maze and number cancellation tests, as well as a delayed recall version of the original Word Recall measure. These additional measures are referred to as ADAS-cog+ tests and on occasion have been augmented by the “concentration/distractibility” element of the ADAS- noncog. These additional measures have been variously added to the original 11 ADAS-cog subtests to create new configurations, the most common of which is the ADAS-cog13.
Henry Hoare, the creator of the landscape garden at Stourhead, is known to have travelled on Gran... more Henry Hoare, the creator of the landscape garden at Stourhead, is known to have travelled on Grand Tour between 1738 and 1741. Comparisons of the garden content with eighteenth-century Grand Tour guidebooks suggest that the former may have been profoundly influenced by the latter. The extant literature includes a number of Stourhead visitor accounts, though most have been relatively uninformative with respect to the content and evolution of the garden. Conspicuous exceptions to this are the 1762 record left by Horace Walpole and a recently discovered 1787 account from Count Carlo Gastone della Torre di Rezzonico. These accounts have informed our understanding of the possible meaning of Stourhead garden elements and thrown substantial doubt on the veracity of established theories of meaning at Stourhead based on Aeneas’ journey to and foundation of Rome. The English landscape garden was copied throughout Europe in the eighteenth century, including at locations in Italy. Aesthetic, cognitive and political reasons for this phenomenon are discussed in the final section of the chapter.
McIntyre RS & Cha D (Eds.) Cognitive Impairment in Major Depressive Disorder
The focus of this chapter will be the measurement of cognitive change and the detection of cognit... more The focus of this chapter will be the measurement of cognitive change and the detection of cognitive deficits in patients with major depressive disorder (MDD). Whilst this chapter deals specifically with the measurement of cognition in MDD, the principles outlined are equally applicable to other neurological and psychiatric conditions and are offered as guidance for the measurement of cognitive efficacy and safety when testing a variety of putative therapies, including pharmacological, psychotherapeutic and training/remedial interventions. A full review of the literature dealing with cognitive deficits in patients with MDD is beyond the scope of this chapter, but before progressing to a discussion of detecting deficits and measuring cognitive change we will briefly review the evidence for deficits with reference to recent meta-analyses. An advantage of this focus is that the coinage we will deal in is effect size, a convenient common vocabulary for comparing performance with other diseases and disorders, as well as between cognitive domains and when comparing therapeutic interventions. Later in the chapter we shall employ effect size in our discussion of clinical relevance. We begin with a consideration of human cognition with a focus on its division into various domains, their measurement and the challenges of obtaining pure measurements of specific domains. For the purposes of clarity we will define cognitive testing as a subset of neuropsychological testing, as this latter category includes the assessment of mood, handedness, etc. Note that we will not employ the term 'neurocognitive' which we regard as an unnecessary tautology.
Wenn Töne Farben haben oder geometrische Formen nack etwas schmecken, dan ist Synästhesie am Werk... more Wenn Töne Farben haben oder geometrische Formen nack etwas schmecken, dan ist Synästhesie am Werk. Manche Menschen können in ihrem Gehirn ganz offenbar die Sinneseiondrucke mischen: Bilder mit Tönen, Geschmacksempfindungen mit Bildern, Zahlen mit Farben.
The Neurological Boundaries of Reality, Sep 1, 1994
Ludwig, the "brain-in-a-vat" thought experiment (see chapter 10) requires the student to consider... more Ludwig, the "brain-in-a-vat" thought experiment (see chapter 10) requires the student to consider the frailty of the epistemological status of our outside world, in recognition of the fact that the fundamental coinage of the nervous system is electrochemical in nature, but more importantly one in which the component units communicate in binary code. This gedankenexperiment is designed to illustrate the questionable status of knowledge gleaned from the world via the senses and achieves this by suggesting that we may all be brains in vats and that we are stimulated to believe in the existence of tables, sunsets and experiments by receiving the appropriate stimulation to our nerve fibres.
The gardens at Stourhead feature a number of elements influenced by the legacy of classical Rome.... more The gardens at Stourhead feature a number of elements influenced by the legacy of classical Rome. Henry Hoare, the owner of Stourhead from 1741-1783, travelled to Rome as part of his own Grand Tour and his chief architect, Henry Flitcroft, was part of Lord Burlington’s circle. On Day 1 of this event we will explore classical influences on the eighteenth-century English country garden. On Day 2 we will consider classical influences solely in the context of the garden and wider estate at Stourhead. We invite papers on all aspects of classical influences on the eighteenth-century English garden and particularly the following topics:
• The influence of classical Roman literature on the eighteenth-century English country garden
• Greek influences in eighteenth-century English country gardens
• The influence of the Grand Tour on eighteenth-century English country gardens
• Visitor accounts of Stourhead and other eighteenth-century English country gardens
• Eighteenth-century English country garden designers
• The picturesque and the design and reception of the eighteenth-century English country garden
• Depiction of the eighteenth-century English country garden in the fine arts
• The country garden and publishing: newspapers, periodicals, guidebooks and journals
• Topographical poetry
• Theories of meaning in the eighteenth-century English country garden
• Relationships between houses, gardens and wider estates
• Lord Burlington and his circle
Hello, I am John Harrison, honorary senior lecturer, Department of Medicine, Imperial College, Lo... more Hello, I am John Harrison, honorary senior lecturer, Department of Medicine, Imperial College, London. I would like to welcome you to this program titled, "Measuring Cognitive Dysfunction in Major Depressive Disorder: Update on Scales, Outcomes, and Treatment." On our panel today we represent various disciplines. We have a psychologist, two psychiatrists, and a primary care physician. I am pleased to be here with Guy Goodwin, from the Department of Psychiatry, University of Oxford in the United Kingdom; Raymond Lam, professor and associate head for research, Department of Psychiatry, University of British Columbia, Vancouver, Canada; and Larry Culpepper, a professor of family medicine at Boston University School of Medicine and a staff physician at Boston Medical Center in the United States. In this program, we will be discussing some of the scales and neuropsychological tests used to measure depression and cognitive function in patients with major depressive disorder (MDD) and their relevance in interpreting patient outcomes and clinical data on treatments.
This webcast was presented at the invitation of CRF Health and concerns the measurement of cognit... more This webcast was presented at the invitation of CRF Health and concerns the measurement of cognition in patients with Major Depressive Disorder. The presentation contains information on the domains of cognition that can be compromised in MDD, as well as tools for measuring cognition in this indication.
This presentation includes descriptions of the cognitive outcome measures often employed in Alzhe... more This presentation includes descriptions of the cognitive outcome measures often employed in Alzheimer's disease clinical drug trials, particularly the ADAS-cog & MMSE. As well as describing the content of these two tests, I discuss also using baselines MMSE performance as a predictor of performance on elements of the ADAS-cog. This information can be used to calculate likely values for ADAS-cog subtest performance and provide an automatic validity check for recorded values.
This is an annotated version of the presentation given on 18th October 2016 to Stourhead National... more This is an annotated version of the presentation given on 18th October 2016 to Stourhead National Trust garden guides. In this presentation I explore the topic of Stourhead garden building name changes, what they mean, and who proposed them.
This is the presentation I gave on 6th September 2016 to a meeting of psychiatrists. The premise ... more This is the presentation I gave on 6th September 2016 to a meeting of psychiatrists. The premise of my presentation is that investigating human cognition requires the use of reliable, valid and sensitive measures. Traditionally employed measures such as the MMSE do not meet acceptable standards and newer tools such as THINC-it (http://thinc.progress.im/en) represent a superior means of detecting cognitive impairment and measuring cognitive change.
Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid parad... more Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. Objectives We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. Methods We used scopolamine to model cognitive dysfunc-tion similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopol-amine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. Results Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopol-amine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. Conclusions In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for
Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid parad... more Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. Objectives We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. Methods We used scopolamine to model cognitive dysfunc-tion similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopol-amine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. Results Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopol-amine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. Conclusions In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for
Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid parad... more Rationale Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. Objectives We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. Methods We used scopolamine to model cognitive dysfunc-tion similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopol-amine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. Results Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopol-amine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. Conclusions In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for
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Papers by John Harrison
guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available
to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.
Methods: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years.
Results: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction.
Discussion: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.
guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available
to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.
Methods: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.5 ± 3.1 years, range 0.6-18.9 years). Based on common inclusion criteria for clinical trials, we defined groups (amyloid, phosphorylated tau [p-tau], APOE ε4). Linear mixed models, adjusted for age, sex, and education, were used to estimate change over time in neuropsychological tests, a functional outcome, and 2 cognitive composite measures. Standardized regression coefficients of time in years (βtime) were reported as outcome of interest. We analyzed change over time with full follow-up, as well as with follow-up limited to 1.5 and 3 years.
Results: We included 387 individuals (aged 61.7 ± 8.6 years; 44% female) in the following (partly overlapping) biomarker groups: APOE ε4 carriers (n = 212), amyloid-positive individuals (n = 109), amyloid-positive APOE ε4 carriers (n = 66), CSF p-tau-positive individuals (n = 127), plasma p-tau-positive individuals (n = 71), and amyloid and CSF p-tau-positive individuals (n = 50), or in a control group (normal biomarkers; n = 65). An executive functioning task showed most decline in all biomarker groups (βtime range -0.30 to -0.71), followed by delayed word list recognition (βtime range -0.18 to -0.50). Functional decline (βtime range -0.17 to -0.63) was observed in all, except the CSF and plasma tau-positive groups. Both composites showed comparable amounts of change (βtime range -0.12 to -0.62) in all groups, except plasma p-tau-positive individuals. When limiting original follow-up duration, many effects disappeared or even flipped direction.
Discussion: In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD pathology. AD prevention trials should use sufficiently long follow-up duration and/or more sensitive outcome measures to optimally capture subtle cognitive changes over time.
In this lecture I will begin by describing the variety and nature of cognitive deficits seen in early AD. I will show that whilst digital testing offers an efficient means of assessing cognition, its measures rarely exceed the levels of sensitivity and specificity for AD achieved by reliable ‘paper-and-pencil’ tests, which still have a key role to play. I will then critically review the measures commonly employed to assess cognition in primary healthcare, specialist centres and clinical trials. I will conclude with a review of options and recommendations.
Building gardens provided socially aspirational eighteenth-century individuals, such as the banker and Stourhead owner Henry Hoare, with the opportunity to demonstrate knowledge of Roman myth as an illustration of their ‘Taste’. In eighteenth-century Britain ‘Taste’ was heavily influenced by Roman literature, and especially the writings of Ovid. Translations of Ovid were widely read in eighteenth-century Britain and published not just for a literary elite, but instead to meet ‘a consistent demand across the century for Ovidian writing’. I will show how the use of Ovid at Stourhead in the eighteenth century illustrates how his tale of gods and nymphs could invoke reflection on the legacy of Rome as expressed in the context of an English landscape garden.
Theorists of Stourhead’s meaning have tended to presume that Henry Hoare (1705-1785) had in mind a ‘Grand Design’ and they have focused on the proposition that he was heavily influenced by the Aeneid. These same theorists have proposed psychoanalytic explanations of Henry Hoare’s design intentions. My doctoral research indicates that much of this theorising has been based on incorrect information and interpretation based on an intentionalist fallacy.
Rather than assuming that a grand plan was envisaged, I have adopted the view that individual elements of the garden must also be considered for meaning. These elements might be objects (e.g. statues), or arrays of objects in the context of a single structure (e.g. a temple or grotto). I propose also that the question of meaning should be extended beyond the intentions of the designer to include the reception of Stourhead by 18 & 19th century visitors. Furthermore I propose that visitor experience can be helpfully interpreted using a cognitive psychological rather than psychoanalytic approach.
In seeking to understand visitor accounts I have employed cognitive psychological theory and especially schema theories of memory organisation. I have assumed that visitor reception can be understood through the application of theories of memory and knowledge representation. I have further assumed that prior knowledge and expectation are a function of written and oral sources of information. Many of the early poetic and published accounts of visits were available in periodicals and it seems likely that visitor experiences were mediated by these published records. However, other sources of influence, including formal schooling and information passed orally from visitor acquaintances, estate workers and local guides, have also been considered. The structures and objects at Stourhead have been influenced and inspired by classical Roman structures, many of which were publically accessible to visitors in the 18thcentury, and especially those who embarked on Grand Tour expeditions. This source of influence and information has also therefore been considered.
In my presentation I will provide a brief description of my research into the gardens at Stourhead since October 2012, with reference to the Temple of Ceres, the Pantheon and the Temple of Apollo. My specific focus will be on the Grotto, which at Stourhead houses statues of a river god and a nymph. This structure has been interpreted by those adopting a Virgilian perspective as symbolic of Aeneas’ descent into hell. I will argue that recently discovered primary sources, including an Italian visitor account from 1787 and a 1780 poem, suggest that a more likely source of inspiration is Ovid’s tale of Daphne and Peneus from the Metamorphoses.
A series of break-out sessions will also be held, in which the latest basic or clinical research in the field of cognitive dysfunction in depression will be showcased by a member of the THINC Task Force. These will cover topics such as the neural underpinnings of cognitive dysfunction and the impact of antidepressant therapy on patient functioning, and will be followed by workshop activities. There will be the opportunity to ask questions throughout the meeting, in addition to interactive Q&A panel discussions with the presenters and members of the THINC Task Force. Attendance at this meeting is by personal invitation only.
The extant literature includes a number of visitor accounts to Stourhead though most have been relatively uninformative with respect to the content and evolution of the garden. This includes the garden buildings and their furnishings, but is particularly true of the statues that populated the various temples. A conspicuous exception to this was the record left by Horace Walpole after his visit in 1762, though his account is incomplete and contains factual errors.
In the past two years I have found several previously unconsidered accounts of the garden at Stourhead. These include the accounts of both domestic and overseas visitors, as well as several poems. Amongst the overseas visitor accounts is one by Count Carlo Gastone della Rezzonico, who visited in 1787. Gastone, a highly educated Italian visitor, offers a descriptive and critical account of Stourhead gardens from the period shortly after Henry Hoare’s death and prior to the substantial changes made by Richard Colt Hoare. In my paper I will show how Gastone, visiting the garden 45 years after Henry's return from Grand Tour, offers us an educated, native Italian interpretation of the garden features. These features were inspired by Henry Hoare’s Grand Tour. I will further show how the insight Gastone offers us illuminates our understanding of the garden element selection and their possible meaning.
• In an attempt to improve the detection of clinically meaningful cognitive decline in early Alzheimer’s disease (AD)1, we designed the Cognitive-Functional Composite (CFC).2-4
• We previously showed the CFC’s good reliability, feasibility of use and clinical relevance in mild cognitive impairment (MCI) and mild AD dementia.5,6
Aim - To investigate the CFC’s sensitivity to change over time, in comparison to traditional clinical endpoints.
Methods - We used baseline data of the Capturing Changes in Cognition (Catch-Cog) study: an international, multicenter, observational, prospective cohort-study including subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), mild dementia due to Alzheimer’s disease (AD) and Lewy Bodies dementia (DLB) (MMSE ≥ 18). The CFC comprises seven existing cognitive tests focusing on memory and executive function, and an informant-based everyday functioning measure: the Amsterdam IADL Questionnaire (A-IADL-Q). The CFC’s factor structure was investigated using a principal component analyses (PCA) of all eight subtests. We calculated a weighted cognitive composite z-score (CC z-score) for the seven cognitive subtests, as well as a CFC z-score for all eight CFC subtests. We computed Pearson’s correlation coefficients between the CFC and traditional measures, including: 1) the CC z-score, MMSE and ADAS-Cog-13; 2) the A-IADL-Q, ADCS-ADL and CDR-SB; and 3) the CFC z-score and CDR-SB. To investigate range restrictions, we compared score distributions using histograms of the CFC and the traditional tests.
Results - A total of 142 subjects completed our baseline assessment (mean age 71.7±8.4, 43% female, mean MMSE 25.3±2.9). Diagnoses included SCD (n=13), MCI (n=54), mild AD (n=60) and DLB (n=11). The PCA yielded two factors, one loading on memory tests, and one mainly on executive functioning tests and the A-IADL-Q. As expected, we found moderate-to-high correlations between the CFC and traditional measures, supporting the CFC’s concurrent and construct validity. Histograms showed expected floor and ceiling effects for the traditional measures as compared with the CFC.
Conclusions - The CFC is a measure of early dementia relevant domains of cognition and function, yielding fewer range restrictions as compared to traditional tests. It is therefore better indicated for use to adequately and meaningfully evaluate cognition and function, in line with the recent FDA recommendations. We are currently assessing the CFC longitudinally in our Catch-Cog cohort.
Methods - Multicenter, prospective, test-retest study with 2-3 weeks between assessments. We included 48 memory-clinic subjects with MCI or mild dementia due to AD (MMSE ≥ 18, age ≥ 50) and 30 healthy volunteers (age ≥ 50). All subjects underwent the cognitive tests (+/- 25 min) whilst a study partner completed the A-IADL-Q (+/- 20 min). We computed intraclass correlation coefficients (ICCs) using a two-factor random model and type absolute agreement and Cohen’s d effect sizes. Feasibility was evaluated by interviewing a subsample of patients (n=15).
Results A total of 43 patients (40% female, aged 69.9 (SD=7.4), MMSE 25.2 (SD=3.2), years of education 14.3 (SD=5.1)) and 30 controls (50% female, age 65 (SD=7.1), years of education 16.9 (SD=4.0)) completed both study visits. Overall, patients were older (p=.006) and received less education (p=. 022) than controls. Cognitive subtest ICCs were all >0.70, indicating high test-retest reliability (Table 1). We found very high test-retest reliability for the A-IADL-Q (ICC = .96). For the cognitive subtests, we found a statistical significant change on the DSST in patients and controls, and on the COWAT in controls (Figure 1). However, effect sizes for change scores indicated limited practice effects, especially in patients (Table 1). Feasibility interviews indicated that the patients’ general impression of the CFC was mainly positive. In general, its total duration (20-25 minutes) was experienced as acceptable. Test materials were described as clear and very readable.
Conclusions -Our results demonstrate that the CFC meets important quality metrics for clinically meaningful outcome measures. The next step in our validation plan is to determine its sensitivity to change over time.
facilitate the definitive evaluation of the cognitive effects of novel compounds in drug development. Since then this system (the Cognitive Drug Research computersied assessment system) has been used in hundreds of clinical trials worldwide and data from the system has been widely disseminated including over 150 peered reviewed papers and chapters. A huge normative database has been established over the age range 20 to 90 years. The system has also been used widely in different types of dementia as well as in trials of AAMI, ARCD and MCI. The tests have also been extensively validated and correlated widely with functional everyday scales. This presentation will critically review the information which can be gained from screening with this instrument, and describe the extent to which such data can be used to support the identification and diagnoses of various cognitive disorders associated with aging.
Methods - Data were included from 14 trials (four Phase 2 and 10 Phase 3). Double- blind treatment periods were 8–12 weeks for Phase 2 and 24–104 weeks for Phase 3. In most studies, patients with hypercholesterolemia received maximally tolerated statin; other LLTs were also permitted in the majority of studies. Alirocumab was administered at a dose of 75 or 150 mg every 2 weeks (Q2W). All Phase 2 and five Phase 3 studies compared alirocumab with placebo; five Phase 3 studies compared alirocumab with ezetimibe. Neurocognitive TEAEs were self-reported by patients. In the current analysis, they were defined using a broad company custom Medical Dictionary of Regulatory Activities (MedDRA) query proposed by the sponsor. An analysis was performed to examine the rate of neurocognitive TEAEs in different age groups (<65 years, 65–74 years, and ≥75 years).
Results - Data were available for 5234 patients (n=3340 alirocumab, n=1276 placebo, n=618 ezetimibe). Exposure to alirocumab was 4029 patient-years. The mean age across all treatment groups was 58.5–62.1 years. In the placebo-controlled pool, 22 patients (0.9%) receiving alirocumab and nine patients (0.7%) receiving placebo had a neurocognitive TEAE (HR 1.24; 95% CI 0.57–2.68); corresponding values in the ezetimibe-controlled pool were 10 (1.2%) and eight (1.3%) for alirocumab and ezetimibe, respectively (HR 0.81; 95% CI 0.32–2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with two consecutive values of LDL-C <25 mg/dL (n=5/839; 0.6%;0.5/100 patient-years) versus patients receiving alirocumab with levels≥25 mg/dL (n=26/2501; 1.0%; 0.8/100 patient-years) and patients in control groups (n=17/1894; 0.9%; 0.7/100 patient-years) (Figure 2). No patients in the control groups achieved LDL-C <25 mg/dL. One (0.1%) patient receiving alirocumab, two (0.2%) receiving placebo,and three (0.4%) receiving ezetimibe had neurocognitive TEAEs leading to treatment discontinuation. Most neurocognitive TEAEs were mild or moderate. One patient receiving placebo had a severe neurocognitive TEAE, compared with none receiving alirocumab or ezetimibe. Across groups, neurocognitive TEAE rates were highest in patients aged ≥75 years (3.9–6.9%) and lowest for patients aged <65 years (0.3–0.8%), with no significant difference between treatment groups in any age bracket.
Conclusions - In four Phase 2 and 10 Phase 3 trials involving 5200 patients for up to 104 weeks, there was no apparent increase in neurocognitive TEAEs with alirocumab treatment overall or in different age groups. Based on the analyzed Phase 2 and 3 trials, LDL-C levels <25 mg/dL were not associated with a higher frequency of neurocognitive TEAEs. Further evaluation in longer-term studies is planned, with more detailed neurocognitive assessment and evaluation of potential contributing factors such as age, comorbidities and concomitant medication. A study on the neurocognitive effects of longer-term alirocumab treatment has begun (NCT XXX), using formal neurocognitive testing.
• The influence of classical Roman literature on the eighteenth-century English country garden
• Greek influences in eighteenth-century English country gardens
• The influence of the Grand Tour on eighteenth-century English country gardens
• Visitor accounts of Stourhead and other eighteenth-century English country gardens
• Eighteenth-century English country garden designers
• The picturesque and the design and reception of the eighteenth-century English country garden
• Depiction of the eighteenth-century English country garden in the fine arts
• The country garden and publishing: newspapers, periodicals, guidebooks and journals
• Topographical poetry
• Theories of meaning in the eighteenth-century English country garden
• Relationships between houses, gardens and wider estates
• Lord Burlington and his circle