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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 β‐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 β‐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 β‐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. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence for early and extensive synaptic loss in frontotemporal lobar degeneration syndromes from in vivo and post‐mortem studies. We proposed that synaptic loss would affect behaviour, in relation to changes in functional connectivity. Method: We recruited 29 participants with progressive supranuclear palsy, 16 participants with amyloid‐negative corticobasal syndrome, 8 participants with behavioural variant frontotemporal dementia and 24 similarly‐aged healthy volunteers. All participants underwent resting‐state functional 3T MRI and positron emission tomography with [11C]UCB‐J, that binds synaptic vesicle 2A. We compared the connectivity metrics of nodal weighted degree and voxelwise regional homogeneity with [11C]UCB‐J non‐displaceable binding potential (BPND), in associative and commonality analyses. We then used independent component analysis to extract [11C]UCB‐J BPND signal variance across participants, followed by derivation of participant‐specific scores of functional spatial covariance with the [11C]UCB‐J components. We applied model selection to assess whether connectivity scores would improve prediction of and moderate the effect of synaptic loss on clinical severity. Result: Reduced [11C]UCB‐J BPND was associated with reduced connectivity, with synaptic density predicting both measures of connectivity over and above grey matter volume (Figure 1). The anatomical distribution of synaptic loss partially overlapped in PSP, bvFTD and CBS, but there were also disease‐specific effects (Figure 2). The effect of synaptic loss on functional connectivity was expressed local to the regions of severe synaptic loss, and in remote regions. Moreover, functional connectivity explained additional variance and moderated the relationship between synaptic density and clinical severity (Figure 3). Conclusion: In vivo synaptic loss is associated with reduced connectivity, and changes in behaviour, with implications for modelling disease pathogenesis and translational studies. [ABSTRACT FROM AUTHOR]

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 [11C]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 [11C]UCB‐J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty‐two participants with PSP/CBD had a follow‐up [11C]UCB‐J positron emission tomography scan after 1 year. We calculated the annualized change in [11C]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. [ABSTRACT FROM AUTHOR]

Background: Brain inflammation is an important pathogenic mechanism in many dementias, occurring early in the disease and being predictive of clinical decline. However, data on blood markers of inflammation across different dementia subtypes are limited. Here we assess inflammatory patterns of serum cytokines from patients with Alzheimer's disease (AD), Lewy‐body dementia (DLB), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and motor neurone disease (MND). Method: Blood samples were obtained from 422 participants (29 controls, 46 patients with AD, 35 with mild cognitive impairment (MCI), 38 with DLB, 52 with behavioural variant FTD, 51 with primary progressive aphasia, 58 with PSP, 53 with CBS, 60 with MND. Serum assays for 41 inflammatory markers used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to identify leading multivariate components, or profiles, of inflammation. Analysis of variance and Bayesian pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls. Result: Fifteen cytokines were undetectable in the majority (>50%) of participants and were thus excluded. The PCA of remaining 26 cytokines identified 3 components (explaining 18.3%, 8.5% and 6.4% variance, respectively). Component 1 was strongly represented by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on the first component detected significant differences across the groups (χ2(8) = 24.3, p = 0.0021), and the Bayesian pairwise t‐tests identified significant differences between each patient cohort and controls, except for people with MCI (Figure 1, right). Component 2 did not differ between patients and controls. Component 3 split the cytokines into two subgroups, and was mainly loaded by patients with MCI, AD and MND (χ2(8) = 64.6, p<0.0001). Conclusion: This data‐driven approach identified similar profiles of pro‐inflammatory responses across multiple neurodegenerative dementia types. Further analyses will clarify differences between diagnoses, relationships of the pro‐inflammatory patterns with clinical severity and brain changes captured by neuroimaging (PET and MRI). [ABSTRACT FROM AUTHOR]

Background: Novel, validated imaging biomarkers for assessing disease severity and progression in dementia with Lewy Bodies (DLB) are needed as standard neuroimaging changes such as atrophy are not pronounced. Both multi‐modal MR and PET offer opportunities, for example cortical microstructure and dendritic imaging can be assessed using advanced MR diffusion weighted imaging (DWI) methods such as neurite orientation dispersion and density imaging (NODDI) and PET with UCB‐J can assess synaptic density. We applied these and other markers to people with DLB and controls. Method: In linked studies, people with probable DLB and similarly aged controls (n = 10‐30 per group depending on study) underwent multimodal 3T‐MRI (including structural, multi‐shell DWI and arterial spin labelling imaging) and PET imaging with AV1451 (for assessment of tau), PiB (for amyloid status) and [11C]UCB‐J PET/MR. For MR, T1‐MRI and DWI datasets were processed using FreeSurfer 7.2 and FSL 6.0.4 respectively with whole‐brain ODI derived from the Microstructure Diffusion Toolbox. The [11C]UCB‐J and [18F]AV1451 binding potentials (BPND) were assessed using a simplified reference tissue model (reference centrum semiovale for UCBJ and cerebellum for AV1451). Group differences in ODI, UCB‐J and AV1451 BPND were examined and correlated with structural changes and clinical and cognitive variables (ACE‐R score). Result: Compared to controls, people with DLB showed significantly thinner neocortex (T = ‐2.8, p = 0.01) in temporo‐parietal regions but more widespread reductions in cortical microstructure (ODI, T = ‐3.9, p < 0.001)(Figure 1). Within the DLB group, hippocampal ODI was positively correlated with cognitive performance (robust linear regression: p < 0.001)(Figure 2). Reduced synaptic density (UCB‐J BPND) was found for the DLB group in posterior regions (p<0.05, FWE corrected)(Figure 3), with a trend for greater reductions in those who were amyloid positive. ACE‐R scores significantly correlated with synaptic density (p<0.05, FWE corrected). There were no significant differences in AV1451 binding between DLB and controls. Conclusion: Extensive reductions in ODI and reduced synaptic density, both associated with cognitive impairment and occurring in regions without significant atrophy or tau deposition, suggests that NODDI and synaptic PET imaging are promising biomarkers for DLB which merit further investigation, including in longitudinal studies. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is an important pathogenic mechanism in frontotemporal dementia (FTD) and related disorders. Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, and as proportionate to symptom severity and rate of progression. However, data on inflammation blood markers of inflammation and their relationship with central inflammation are limited. Here we assess inflammatory patterns of 41 serum cytokines from patients with FTD and related conditions, and their association with regional microglial activation (TSPO PET). Method: Blood samples were obtained from 29 healthy controls, and 214 patients with a clinical diagnosis of behavioural variant FTD (bvFTD = 52), primary progressive aphasia (PPA = 51), progressive supranuclear palsy (PSP = 58) and corticobasal syndrome (CBS = 53). Serum assays used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to reduce dimensionality of cytokine data. A sub‐group of patients (bvFTD = 10, PPA = 17, PSP = 17) underwent PET imaging with [11C]PK11195 PET, as index of microglial activation. Kruskal‐Wallis and pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls. [11C]PK11195 non‐displaceable binding potential (BPND) was calculated in 83 regions of interest (ROIs) across the whole brain. Spearman correlations tested associations between cytokine components and regional [11C]PK11195 BPND. Result: Sixteen cytokines were undetectable in >50% of participants and thus excluded. The first component identified by the PCA on the remaining 25 cytokines (explaining 19.7%) was strongly loaded by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on detected significant differences across the groups (χ2(4) = 11.0, p = 0.027), and the pairwise t‐tests identified significant differences between each patient cohort and controls (Figure 1, right). Spearman correlations identified regional positive associations between individual cytokine‐component scores and microglial activation in frontal and brainstem regions across the whole group (R≥0.25), and syndrome‐specific regional patterns (Figure 2). Conclusion: This data‐driven approach identified a pro‐inflammatory profile across FTD and related conditions, which is positively associated with higher levels of microglial activation in syndrome‐related key brain regions. Blood‐based tests could greatly increase the scalability and access to neuroinflammatory assessment in dementia and experimental medicine studies. [ABSTRACT FROM AUTHOR]

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 [11C]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 [11C]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 [11C]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 [11C]UCB‐J binding potential from regions of interest (ROIs). Results: Patients with bvFTD showed severe synaptic loss compared to controls. [11C]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. [11C]UCB‐J PET could support translational studies and experimental medicine strategies for new disease‐modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142–154 [ABSTRACT FROM AUTHOR]

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 (β = 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 (β = -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. [ABSTRACT FROM AUTHOR]

Background and Aims: Cannabis is a commonly used recreational drug in young adults. The worldwide prevalence in 18- to 25-year-olds is approximately 35%. Significant differences in cognitive performance have been reported previously for groups of cannabis users. However, the groups are often heterogeneous in terms of cannabis use. Here, we study daily cannabis users with a confirmed diagnosis of cannabis use disorder (CUD) to examine cognitive performance on measures of memory, executive function and risky decision-making. Methods: Forty young adult daily cannabis users with diagnosed CUD and 20 healthy controls matched for sex and premorbid intelligence quotient (IQ) were included. The neuropsychological battery implemented was designed to measure multiple modes of memory (visual, episodic and working memory), risky decision-making and other domains of executive function using subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Results: Our results showed that young adult daily cannabis users with CUD perform significantly poorer on tasks of visual and episodic memory compared with healthy controls. In addition, executive functioning was associated with the age of onset. Conclusions: Further research is required to determine whether worse performance in cognition results in cannabis use or is a consequence of cannabis use. Chronic heavy cannabis use during a critical period of brain development may have a particularly negative impact on cognition. Research into the persistence of cognitive differences and how they relate to functional outcomes such as academic/career performance is required. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Synaptic loss is an early and clinically relevant feature of many neurodegenerative diseases. Here we assess three adults at risk of frontotemporal dementia from C9orf72 mutation, using [11C]UCB‐J PET to quantify synaptic density in comparison with 19 healthy controls and one symptomatic patient with behavioural variant frontotemporal dementia. The three pre‐symptomatic C9orf72 carriers showed reduced synaptic density in the thalamus compared to controls, and there was an additional extensive synaptic loss in frontotemporal regions of the symptomatic patient. [11C]UCB‐J PET may facilitate early, pre‐symptomatic assessment, monitoring of disease progression and evaluation of new preventive treatment strategies for frontotemporal dementia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Novel psychoactive substances (NPS) are popular "club/party" drugs that first attracted attention in the UK in 2009 and remained legal until the 2016 Psychoactive Substances Act criminalized their distribution. Unlike "traditional" illicit drugs, very little is known about the influence of their analogs on neuropsychological functioning. We characterized the cognitive and emotional profile of NPS/polydrug users using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and EMOTICOM test battery in adult male (aged 20–49 years) recreational users without psychiatric comorbidities (n = 27; "psychonauts"), service users attending a UK specialist "Club Drug" Clinic for problematic use (n = 20) and healthy control volunteers without significant drug-taking histories (n = 35). Tasks were selected to distinguish "hot" cognitive processes that are highly influenced by emotion from "cold" cognitive processes that are largely independent of emotional influence. Both user groups reported significantly higher sensation-seeking traits compared with non-users. Recreational NPS users demonstrated more risk-taking behavior compared with controls and treatment-seeking NPS users showed poorer learning, episodic memory and response inhibition compared with the other two groups. These effects persisted, when controlling for age, intelligence, alcohol and cannabis use severity, nicotine dependence, trait anxiety, depression, childhood adversity, impulsivity, and sensation seeking. Overall, recreational NPS users showed elevated "hot" (emotion-laden) cognition in the absence of "cold" (non-emotional) cognitive deficits, whereas "cold" cognitive dysfunction was pronounced in individuals seeking treatment for problematic NPS use. High trait impulsivity and poor self-control may confer additional risk to NPS/polydrug use severity and separate those seeking treatment from those using NPS recreationally. [ABSTRACT FROM AUTHOR]

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 (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=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 (β=0.66-0.76, t=3.90-5.58, FDR-corrected p (pFDR)=<0.001-0.002) and orbitofrontal cortex (β=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. [ABSTRACT FROM AUTHOR]

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 [11C]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 [11C]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. [11C]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 [11C]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. [11C]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. [ABSTRACT FROM AUTHOR]

Background: The peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). We assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition. Methods: 145 participants underwent 3T brain MRI and cognitive assessment. 112 were patients with mild cognitive impairment, Alzheimer's disease, progressive supranuclear palsy, dementia with Lewy bodies, or frontotemporal dementia. PSMD, SVD burden [white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds, lacunes], average mean diffusivity (MD), gray matter (GM), white matter (WM), and total intracranial volume were quantified. Robust linear regression was conducted to examine associations between variables. Dominance analysis assessed the relative importance of markers in predicting various outcomes. Regional analyses examined spatial overlap between PSMD and WMH. Results: PSMD was associated with global and regional SVD measures, especially WMH and microbleeds. Dominance analysis demonstrated that among SVD markers, WMH was the strongest predictor of PSMD. Furthermore, PSMD was more closely associated to WMH than with GM and WM volumes. PSMD was associated with WMH across all regions, and correlations were not significantly stronger in corresponding regions (e.g., frontal PSMD and frontal WMH) compared to non-corresponding regions. PSMD outperformed all four conventional SVD markers and MD in predicting cognition, but was comparable to GM and WM volumes. Discussion: PSMD was robustly associated with established SVD markers. This new measure appears to be a marker of diffuse brain injury, largely due to vascular pathology, and may be a useful and convenient metric of overall cerebrovascular burden. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The epigenetic mechanism of DNA methylation has been implicated in the pathophysiology of neurodegenerative disorders such as Lewy body dementia (LBD). DNA methylation profiling may help to identify novel treatment targets and early disease markers. We hypothesized that DNA methylation alterations are detectable in blood due the influence of genetic and environmental factors as well as immune system changes associated with LBD. Method: Genome‐wide DNA methylation profiling was carried out using reduced representation bisulfite sequencing in blood samples from 89 LBD patients and 67 controls. Fifty five LBD patients had amyloid PET imaging. Data processing was performed using FastQC, TrimGalore, Bismark and MethylKit. DNA methylation alterations at specific CpG sites as well as at promoter, CpG island and CpG shore regions were compared between LBD cases and controls. A log odds logistic regression was used to identify differential DNA methylation after adjusting for age, sex and smoking status. The false discovery rate (FDR) was used for correction for multiple testing. We also tested the diagnostic classification performance of the differentially methylated regions using receiver operating characteristic (ROC) curve analysis and examined the potential of DNA methylation as a predictor of amyloid PET positivity in LBD. Result: Two single CpG sites at TNFRSF1B and EMC6 and three CpG shore regions at ABCG5, ETAA1 and TENM4 reached genome‐wide significance in the differential DNA methylation analysis comparing LBD cases and controls. The combined panel of the top three differentially methylated CpG shores reached an area under the curve (AUC) of 0.91 for the diagnosis of LBD compared to controls (sensitivity 0.89, specificity 0.85). DNA methylation at TENM4 was associated with amyloid PET positivity in LBD with an AUC of 0.84 (sensitivity 0.99, specificity 0.55). Conclusion: Our data suggest that DNA methylation alterations in blood are observed in a cohort of LBD patients compared to controls. Our findings need to be replicated in larger cohorts and tested for specificity in LBD in order to explore their future potential as diagnostic markers and/or targets for novel therapeutics. [ABSTRACT FROM AUTHOR]

Work and study increasingly rely on the use of technologies requiring individuals to switch attention rapidly between emails, texts and tasks. This has led to healthy people having problems of attention and concentration and difficulties getting into the "flow," which impedes goal attainment and task completion. Possibly related to this, there is an increasing diagnosis of attention deficit hyperactivity disorder (ADHD) and prescriptions of drugs such as methylphenidate. In addition to ADHD, attention is impaired in other neuropsychiatric disorders, such as schizophrenia and in traumatic brain injury (TBI). Based on neuropsychological and neuroimaging evidence, we developed "Decoder," a novel game for targeted cognitive training of visual sustained attention on an iPad. We aimed to investigate the effects of cognitive training in 75 healthy young adults randomly assigned to a Cognitive Training (8 h of playing Decoder over 4 weeks; n = 25), Active Control (8 h of playing Bingo over 4 weeks; n = 25) or Passive Control (continuation of activities of daily living; n = 25) group. Results indicated that cognitive training with Decoder was superior to both control groups in terms of increased target sensitivity (A') on the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information processing (CANTAB RVP) test, indicating significantly improved sustained visual attention. Individuals playing Decoder also showed significantly better performance on the Trail Making Test (TMT) compared with those playing Bingo. Significant differences in visual analogue scales were also found between the two gaming groups, such that Decoder received higher ratings of enjoyment, task-related motivation and alertness across all hours of game play. These data suggest that cognitive training with Decoder is an effective non-pharmacological method for enhancing attention in healthy young adults, which could be extended to clinical populations in which attentional problems persist. [ABSTRACT FROM AUTHOR]

Impaired social cognitive processes are putative psychological mechanisms implicated in the formation and maintenance of paranoid beliefs. Paranoia denotes unfounded fears about the hostile intentions of others and is prevalent in a significant proportion of the general population. We investigated social cognition in healthy participants selectively recruited to have a broad occurrence of paranoid thinking (n = 89). Participants completed a novel computerized task of moral emotions and two social economic exchange games (Prisoner's Dilemma, Ultimatum Game) from the EMOTICOM neuropsychological test battery. Regression analyses revealed that delusional ideation predicted shameful feelings when the victim of deliberate harm by another person. Cooperative behavior on the Prisoner's Dilemma was greatest when the participant and opponent contributed equally to joint earnings. Participants demonstrated significantly more punishment behavior when contributions were unequal and stole more from the opponent using a suspicious strategy of gameplay. In addition, paranoid thinking was positively associated with more stealing from the cooperative opponent. On the Ultimatum Game, participants accepted significantly more unequal offers when the opponent contributed more and sensitivity to fairness was greatest when the participant contributed more. These data demonstrate that delusional ideation predicts a maladaptive emotional response to interpersonal harm and that paranoid thinking may lead to reduced cooperation toward mutual reward. The effects of paranoia on moral emotions and pro-social behavior at more severe levels of persecutory thinking warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: Post‐mortem clinical studies and animal models described severe synaptic loss as an early feature of neurodegenerative disease, including frontotemporal dementia. Recently, PET radiotracers that bind to synaptic vesicle glycoprotein 2A have been developed and proven to enable in vivo quantification of synaptic loss in people with neurodegenerative diseases. This study used [11C]UCB‐J PET to quantify synaptic loss in people with behavioural variant frontotemporal dementia (bvFTD). Method: We recruited 10 people with a clinical diagnosis of bvFTD and 24 age‐ and sex‐matched healthy controls. Participants underwent dynamic [11C]UCB‐J PET‐MR, and a neuropsychological assessment, including the Addenbrooke's cognitive examination (ACE‐R) as a global measure of cognitive performance, and the INECO frontal screening. Synaptic density was estimated using [11C]UCB‐J non‐displaceable binding potential (BPND) at voxel level and in whole‐brain regions of interest. General linear models were used to compare [11C]UCB‐J binding voxel‐wise between groups, and correlate synaptic density with cognitive performance in bvFTD cohort. These analyses were also performed using regional [11C]UCB‐J binding potentials, with and without partial‐volume correction. Regional correlations were performed with both frequentist and Bayesian approaches. Result: People with bvFTD showed severe synaptic loss compared to controls at individual level and as a group. [11C]UCB‐J binding was significantly reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insula cortex and medial temporal lobe (5.1 ≤ t ≤ 9.3, p < 0.05 FWE at voxel level, Figure 1A). Results from ROI‐based analyses mirrored the voxel‐wise results, with and without partial‐volume correction. Synaptic loss in the left frontal and cingulate regions significantly correlated with cognitive impairments as assessed with ACE‐R and INECO (r > 0.8, p<0.001 at voxel level, p<0.05 FWE at cluster level, Figure 1B). Correlations were confirmed by regional‐based analyses, with both frequentist and Bayesian approaches (Figure 1C). Conclusion: Different analytic approaches converged showing a significant and widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to disease severity. [11C]UCB‐J PET could therefore be a useful supporting tool for translational studies and experimental medicines strategies for new disease‐modifying treatments in this condition. [ABSTRACT FROM AUTHOR]

Today, there is continued, and in some cases growing, availability of not only psychoactive substances, including treatments for mental health disorders such as cognitive enhancers, which can enhance or restore brain function, but also 'recreational' drugs such as novel psychoactive substances (NPS). The use of psychoactive drugs has both benefits and risks: whilst new drugs to treat cognitive symptoms in neuropsychiatric or neurodegenerative disorders could have great benefits for many patient groups, the increasing ease of accessibility to recreational NPS and the increasing lifestyle use of cognitive enhancers by healthy people means that the effective management of psychoactive substances will be an issue of increasing importance. Clearly, the potential benefits of cognitive enhancers are large and increasingly relevant, particularly as the population ages, and for this reason, we should continue to devote resources to the development of cognitive enhancers as treatments for neurodegenerative diseases and psychiatric disorders, including Alzheimer's disease, attention deficit hyperactivity disorder and schizophrenia. However, the increasing use of cognitive enhancers by healthy individuals raises safety, ethical and regulatory concerns, which should not be ignored. Similarly, understanding the short- and long-term consequences of the use of NPS, as well as better understanding the motivations and profiles of users could promote more effective prevention and harm reduction measures. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc. [ABSTRACT FROM AUTHOR]