Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

OBJECTIVE: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. METHODS: Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). RESULTS: Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. INTERPRETATION: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

Differential Synaptic Loss in ß-Amyloid Positive Versus ß-Amyloid Negative Corticobasal Syndrome.

BACKGROUND/OBJECTIVE: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to ß-amyloid status. METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had ß-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. RESULTS: Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the ß-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. DISCUSSION: Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C]UCB-J Positron Emission Tomography Study.

BACKGROUND: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. OBJECTIVE: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. METHODS: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity. RESULTS: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003). CONCLUSIONS: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Molecular pathology and synaptic loss in primary tauopathies: an 18F-AV-1451 and 11C-UCB-J PET study.

The relationship between in vivo synaptic density and molecular pathology in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology in the primary tauopathies of progressive supranuclear palsy and corticobasal degeneration as a function of disease severity. Twenty-three patients with progressive supranuclear palsy and 12 patients with corticobasal syndrome were recruited from a tertiary referral centre. Nineteen education-, sex- and gender-matched control participants were recruited from the National Institute for Health Research 'Join Dementia Research' platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands 11C-UCB-J and 18F-AV-1451, respectively. Patients with corticobasal syndrome also underwent amyloid PET imaging with 11C-PiB to exclude those with likely Alzheimer's pathology-we refer to the amyloid-negative cohort as having corticobasal degeneration, although we acknowledge other underlying pathologies exist. Disease severity was assessed with the progressive supranuclear palsy rating scale; regional non-displaceable binding potentials of 11C-UCB-J and 18F-AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for 18F-AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions and synaptic density in subcortical areas. Across brain regions, there was a positive correlation between 11C-UCB-J and 18F-AV-1451 non-displaceable binding potentials (ß = 0.4, t = 3.6, P = 0.001), independent of age or time between PET scans. However, this correlation became less positive as a function of disease severity in patients (ß = -0.02, t = -2.9, P = 0.007, R = -0.41). Between regions, cortical 18F-AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen). Brain regions with higher synaptic density are associated with a higher 18F-AV-1451 binding in progressive supranuclear palsy/corticobasal degeneration, but this association diminishes with disease severity. Moreover, higher cortical 18F-AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and molecular pathology with synapse-rich regions vulnerable to accrual of pathological aggregates, followed by a loss of synapses in response to the molecular pathology. Given the importance of synaptic function for cognition and action, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.

Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy.

OBJECTIVES: This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). METHODS: Plasma phosphorylated tau at threonine-181 (p-tau181), amyloid beta (Αß)42, Aß40, neurofilament light (NfL) and glial fibrillar acidic protein (GFAP) were measured using highly sensitive single molecule immunoassays (Simoa) in a multicentre cohort of 300 participants (controls=73, amyloid positive mild cognitive impairment (MCI+) and AD dementia=63, LBD=117, FTD=28, PSP=19). LBD participants had known positron emission tomography (PET)-Aß status. RESULTS: P-tau181 was elevated in MCI+AD compared with all other groups. Aß42/40 was lower in MCI+AD compared with controls and FTD. NfL was elevated in all dementias compared with controls while GFAP was elevated in MCI+AD and LBD. Plasma biomarkers could classify between MCI+AD and controls, FTD and PSP with high accuracy but showed limited ability in differentiating MCI+AD from LBD. No differences were detected in the levels of plasma biomarkers when comparing PET-Aß positive and negative LBD. P-tau181, NfL and GFAP were associated with baseline and longitudinal cognitive decline in a disease specific pattern. CONCLUSION: This large study shows the role of plasma biomarkers in differentiating patients with different dementias, and at monitoring longitudinal change. We confirm that p-tau181 is elevated in MCI+AD, versus controls, FTD and PSP, but is less accurate in the classification between MCI+AD and LBD or detecting amyloid brain pathology in LBD. NfL was elevated in all dementia groups, while GFAP was elevated in MCI+AD and LBD.

Sex Differences in Neuropsychological Functioning are Domain-Specific in Adolescent and Young Adult Regular Cannabis Users.

OBJECTIVE: Adolescence into young adulthood represents a sensitive period in which brain development significantly diverges by sex. Regular cannabis use by young people is associated with neuropsychological vulnerabilities, but the potential impact of sex on these relationships is unclear. METHOD: In a cross-sectional study, we examined sex differences in multi-domain neuropsychological functioning using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and tested whether sex moderated the relationship between cognitive performance and age of initiation, frequency of cannabis use, amount of cannabis use, and withdrawal symptoms in at least weekly adolescent and young adult cannabis users (n = 171; aged 13-25 years; 46.2% female). RESULTS: Male cannabis users had poorer visual recognition memory and female cannabis users showed worse attention and executive functions, with medium to large effect sizes. These sex effects persisted, when controlling for age, IQ, amount of alcohol and nicotine use, mood and anxiety symptoms, emotional stability and impulsive behavior. Earlier age of initiated use and more use were associated with worse attentional functions in females, but not males. More use was more strongly associated with worse episodic memory in males than in females. More use was associated with poorer learning in males only. CONCLUSIONS: Domain-specific patterns of neuropsychological performance were found by sex, such that males showed poorer visual memory and females showed worse performance on measures of attention (sustained visual, multitasking) and executive functioning (spatial planning/working memory subdomains). Larger studies including healthy controls are needed to determine if the observed sex differences are more exaggerated relative to non-users.

The revised Addenbrooke's Cognitive Examination can facilitate differentiation of dementia with Lewy bodies from Alzheimer's disease.

OBJECTIVES: Dementia with Lewy bodies (DLB) is a major cause of degenerative dementia, yet the diagnosis is often missed or mistaken for Alzheimer's disease (AD). We assessed whether the revised Addenbrooke's Cognitive Examination (ACE-R), a brief test for dementia, differentiates DLB from AD. METHODS: We first compared baseline ACE-R performance in 76 individuals with DLB, 40 individuals with AD and 66 healthy controls. We then investigated the diagnostic accuracy of a simple standardised 'memory/visuospatial' ratio calculated from the ACE-R subscores. Finally, as a comparison a logistic regression machine learning algorithm was trained to classify between DLB and AD. RESULTS: Individuals with AD had poorer memory (p = 0.001) and individuals with DLB had poorer visuospatial function (p = 0.005). Receiver operating characteristics curves confirmed that the ACE-R total score could differentiate dementia from non-dementia cases with 98% accuracy, but could not discriminate between dementia types (50%, or chance-level accuracy). However, a 'memory/visuospatial' ratio ≥1.1 differentiated DLB from AD with 82% sensitivity, 68% specificity and 77% mean accuracy. The machine learning classifier did not improve the overall diagnostic accuracy (74%) of the simple ACE-R subscores ratio. CONCLUSIONS: The ACE-R-based 'memory/visuospatial' ratio, but not total score, demonstrates good clinical utility for the differential diagnosis of DLB from AD.

In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer's disease.

INTRODUCTION: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging. METHODS: Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer's disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195. RESULTS: Global [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (ß=0.63, F(1,35)=35.24, p<0.001), deep WMH (ß=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (ß=0.66-0.76, t=3.90-5.58, FDR-corrected p (pFDR)=<0.001-0.002) and orbitofrontal cortex (ß=0.51-0.57, t=3.53-4.30, pFDR=0.001-0.004). CONCLUSION: Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.

Synaptic Loss in Primary Tauopathies Revealed by [11 C]UCB-J Positron Emission Tomography.

BACKGROUND: Synaptic loss is a prominent and early feature of many neurodegenerative diseases. OBJECTIVES: We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson's syndrome) and amyloid-negative corticobasal syndrome (CBS). METHODS: Forty-four participants (15 CBS, 14 PSP, and 15 age-/sex-/education-matched controls) underwent PET with the radioligand [11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A, a marker of synaptic density; participants also had 3 Tesla MRI and clinical and neuropsychological assessment. RESULTS: Nine CBS patients had negative amyloid biomarkers determined by [11 C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP-Richardson's syndrome and amyloid-negative CBS were impaired in executive, memory, and visuospatial tasks. [11 C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala, and subcortical structures in both PSP and CBD patients compared to controls (P < 0.01), with median reductions up to 50%, consistent with postmortem data. Reductions of 20% to 30% were widespread even in areas of the brain with minimal atrophy. There was a negative correlation between global [11 C]UCB-J binding and the PSP and CBD rating scales (R = -0.61, P < 0.002; R = -0.72, P < 0.001, respectively) and a positive correlation with the revised Addenbrooke's Cognitive Examination (R = 0.52; P = 0.01). CONCLUSIONS: We confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [11 C]UCB-J may facilitate treatment strategies for disease-modification, synaptic maintenance, or restoration. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Are neuropsychiatric symptoms modifiable risk factors for cognitive decline in Alzheimer's disease and vascular dementia?

Alzheimer's disease and vascular dementia are associated with overlapping symptoms of anxiety and depression. More accurate discrimination between emerging neuropsychiatric and cognitive symptoms would better assist illness detection. The potential for protection against cognitive decline and dementia following early identification and intervention of neuropsychiatric symptoms warrants investigation.

Structural correlates of cognitive impairment in normal pressure hydrocephalus.

OBJECTIVES: The pathological bases for the cognitive and neuropsychiatric symptoms in normal pressure hydrocephalus (NPH) have not been elucidated. However, the symptoms may indicate dysfunction of subcortical regions. Previously, volume reductions of subcortical deep grey matter (SDGM) structures have been observed in NPH patients. The present study used automated segmentation methods to investigate whether SDGM structure volumes are associated with cognitive and neuropsychiatric measures. METHODS: Fourteen NPH patients and eight healthy controls were included in the study. Patients completed neuropsychological tests of general cognition, verbal learning and memory, verbal fluency and measures of apathy and depression pre- and postshunt surgery. Additionally, patients underwent 3 Tesla T1-weighted magnetic resonance imaging at baseline and 6 months postoperatively. Controls were scanned once. SDGM structure volumes were estimated using automated segmentation (FSL FIRST). Since displacement of the caudate nuclei occurred for some patients due to ventriculomegaly, patient caudate volumes were also estimated using manual tracing. Group differences in SDGM structure volumes were investigated, as well as associations between volumes and cognitive and neuropsychiatric measures in patients. RESULTS: Volumes of the caudate, thalamus, putamen, pallidum, hippocampus and nucleus accumbens (NAcc) were significantly reduced in the NPH patients compared to controls. In the NPH group, smaller caudate and NAcc volumes were associated with poorer performance on neuropsychological tests and increased severity of neuropsychiatric symptoms, while reduced volume of the pallidum was associated with better performance on the MMSE and reduced apathy. CONCLUSIONS: Striatal volume loss appears to be associated with cognitive and neuropsychiatric changes in NPH.

Obstetric Phenotypes in the Heterogeneity of Schizophrenia.

Schizophrenia is a complex mental disorder with genetic and environmental components. Obstetric complications (OCs) are one of the most common environmental risk factors described. However, despite being different in timing and outcome, OCs are usually described as a homogeneous entity. In the present study, we evaluate the presence of different patterns of OCs evaluated with the Lewis-Murray Scale in chronic schizophrenia patients (n = 101) and their association with a crude marker of the intrauterine environment such as weight at birth.OCs related with abnormal fetal growth (p < 0.001) and OCs during gestation (p = 0.003) were associated with lower birth weight. However, difficulties in delivery, complications in pregnancy, and OCs all together (as a set) were not associated with weight at birth.Our results infer that OCs cannot be taken as a homogeneous group. Different patterns of OCs result in different birth weights, which is associated with specific metabolic, cognitive, and brain structure outcomes.

Cognitive Training Using a Novel Memory Game on an iPad in Patients with Amnestic Mild Cognitive Impairment (aMCI).

Background: Cognitive training is effective in patients with mild cognitive impairment but does not typically address the motivational deficits associated with older populations with memory difficulties. Methods: We conducted a randomized controlled trial of cognitive training using a novel memory game on an iPad in 42 patients with a diagnosis of amnestic mild cognitive impairment assigned to either the cognitive training (n=21; 8 hours of gameplay over 4 weeks) or control (n=21; clinic visits as usual) groups. Results: Significant time-by-pattern-by-group interactions were found for cognitive performance in terms of the number of errors made and trials needed on the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning task (P=.044; P=.027). Significant time-by-group interactions were also found for the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning first trial memory score (P=.002), Mini-Mental State Examination (P=.036), the Brief Visuospatial Memory Test (P=.032), and the Apathy Evaluation Scale (P=.026). Within-group comparisons revealed highly specific effects of cognitive training on episodic memory. The cognitive training group maintained high levels of enjoyment and motivation to continue after each hour of gameplay, with self-confidence and self-rated memory ability improving over time. Conclusions: Episodic memory robustly improved in the cognitive training group. "Gamified" cognitive training may also enhance visuospatial abilities in patients with amnestic mild cognitive impairment. Gamification maximizes engagement with cognitive training by increasing motivation and could complement pharmacological treatments for amnestic mild cognitive impairment and mild Alzheimer's disease. Larger, more controlled trials are needed to replicate and extend these findings.

Apathy, ventriculomegaly and neurocognitive improvement following shunt surgery in normal pressure hydrocephalus.

INTRODUCTION: Apathy - impaired motivation and goal-directed behaviour - is a common yet often overlooked symptom in normal pressure hydrocephalus (NPH). Caudate atrophy often yields apathetic symptoms; however, this structural and functional relationship has not yet been explored in NPH. Additionally, little is known about the relationship between apathy and post-shunt cognitive recovery. METHODS: This audit investigated whether apathetic symptoms improve following shunt surgery in NPH, and whether this relates to cognitive response. In addition, we assessed the relationship between ventriculomegaly and apathy using the bicaudate ratio. Twenty-two patients with NPH completed the Mini-Mental State Examination (MMSE), the Apathy Evaluation Scale (AES) and the Geriatric Depression Scale (GDS) before and 3-9 months after shunt surgery. Pre-operative ventriculomegaly was correlated with pre-operative AES and GDS scores. Difference scores (post-shunt minus baseline values) for AES and GDS were correlated with cognitive outcome. RESULTS: Greater pre-operative ventriculomegaly was associated with increased level of apathy and depression. A reduction in apathetic symptoms following shunt surgery was associated with improved performance on the MMSE. CONCLUSIONS: Apathy may be indicative of a greater degree of subcortical atrophy in NPH and may relate to functional outcome.

Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans.

BACKGROUND: Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood. METHODS: We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results. RESULTS: Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control. CONCLUSIONS: The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding.

Role of adenosine A2A receptors in hot and cold cognition: Effects of single-dose istradefylline in healthy volunteers.

The role of the adenosine neurochemical system in human cognition is under-studied, despite such receptors being distributed throughout the brain. The aim of this study was to shed light on the role of the adenosine A2A receptors in human cognition using single-dose istradefylline. Twenty healthy male participants, aged 19-49, received 20 mg istradefylline and placebo, in a randomized, double-blind, placebo-controlled cross-over design. Cognition was assessed using computerized cognitive tests, covering both cold (non-emotional) and hot (emotion-laden) domains. Cardiovascular data were recorded serially. Cognitive effects of istradefylline were explored using repeated measures analysis of variance and paired t-tests as appropriate. On the EMOTICOM battery, there was a significant effect of istradefylline versus placebo on the Social Information Preference task (t = 2.50, p = 0.02, d=-0.59), indicating that subjects on istradefylline interpreted social situations more positively. No other significant effects were observed on other cognitive tasks, nor in terms of cardiovascular measures (pulse and blood pressure). De-briefing indicated that blinding was successful, both for participants and the research team. Further exploration of the role of adenosine A2A receptors in emotional processing may be valuable, given that abnormalities in related cognitive functions are implicated in neuropsychiatric disorders. The role of adenosine systems in human cognition requires further clarification, including with different doses of istradefylline and over different schedules of administration.

Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study.

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of 'cold' cognition (including inhibition, cognitive flexibility, memory) and 'hot cognition' including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on 'cold' or 'hot' cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the 'blunting' effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339 .