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Background: Recent studies have demonstrated increased microglial activation using 11 C-PK11195 positron emission tomography imaging, indicating central nervous system inflammation, in cerebral small vessel disease. However, whether such areas of neuroinflammation progress to tissue damage is uncertain. We determined whether white matter destined to become white matter hyperintensities (WMH) at 1 year had evidence of altered inflammation at baseline. Methods: Forty subjects with small vessel disease (20 sporadic and 20 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and 20 controls were recruited to this case-control observational study from in- and out-patient clinics at Addenbrooke’s Hospital, Cambridge, UK and imaged at baseline with both 11 C-PK11195 positron emission tomography and magnetic resonance imaging; and magnetic resonance imaging including diffusion tensor imaging was repeated at 1 year. WMH were segmented at baseline and 1 year, and areas of new lesion identified. Baseline 11 C-PK11195 binding potential and diffusion tensor imaging parameters in these voxels, and normal appearing white matter, was measured. Results: Complete positron emission tomography-magnetic resonance imaging data was available for 17 controls, 16 sporadic small vessel disease, and 14 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy participants. 11 C-PK11195 binding in voxels destined to become new WMH was lower than in normal appearing white matter, which did not progress to WMH (−0.133[±0.081] versus −0.045 [±0.044]; P −6 versus 1045 [±149]×10 −6 mm 2 /s and 0.37±0.05 versus 0.29±0.06, both P Conclusions: White matter tissue destined to develop into new WMH over the subsequent year is associated with both lower neuroinflammation, and white matter ultrastructural damage at baseline. Our results suggest that this tissue is already damaged 1 year prior to lesion formation. This may reflect that the role of neuroinflammation in the lesion development process occurs at an early stage, although more studies over a longer period would be needed to investigate this further.

Acknowledgements: We thank Jonathan Lewis for providing us with data management assistance. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care., Funder: NIHR Cambridge Biomedical Research Unit in Dementia, Funder: Cambridgeshire and Peterborough NHS Foundation Trust, Funder: South London and Maudsley NHS Foundation Trust; funder-id: http://dx.doi.org/10.13039/100009362, Funder: King’s College London; funder-id: http://dx.doi.org/10.13039/501100000764, Funder: National Institute for Health Research Applied Research Collaboration South London; funder-id: http://dx.doi.org/10.13039/501100023232, Funder: Cambridge Centre for Parkinson’s Plus disorders, BACKGROUND: Dementia with Lewy bodies (DLBs) is a common cause of dementia but has higher mortality than Alzheimer's disease (AD). The reasons for this are unclear, but antidementia drugs (including acetylcholinesterase inhibitors [AChEIs] and memantine) symptomatically benefit people with DLB and might improve outcomes. We investigated whether AChEIs and/or memantine were associated with reduced hospital admissions and mortality. METHODS AND FINDINGS: We performed a retrospective cohort study of those diagnosed with DLB between 1 January 2005 and 31 December 2019, using data from electronic clinical records of secondary care mental health services in Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), United Kingdom (catchment area population approximately 0.86 million), as well as linked records from national Hospital Episode Statistics (HES) data. Eligible patients were those who started AChEIs or memantine within 3 months of their diagnosis (cases) and those who never used AChEIs or memantine (controls). Outcomes included admission, length of stay, and mortality. Cox proportional hazard and linear regression models were used. Of 592 patients with DLB, 219 never took AChEIs or memantine, 100 took AChEIs only, and 273 took both AChEIs and memantine. The cohorts were followed up for an average of 896 days, 981 days, and 1,004 days, respectively. There were no significant differences in the cohorts' baseline characteristics, except for socioeconomic status that was lower in patients who never took AChEIs or memantine (χ2 = 23.34, P = 0.003). After controlling for confounding by sociodemographic factors (age, sex, marital status, ethnicity, socioeconomic status), antipsychotic use, antidepressant use, cognitive status, physical comorbidity, anticholinergic burden, and global health performance, compared with patients who never took AChEIs or memantine, patients taking AChEIs only or taking both had a significantly lower risk of death (adjusted hazard ratio (HR) = 0.67, 95% CI = 0.48 to 0.93, p = 0.02; adjusted HR = 0.64, 95% CI = 0.50 to 0.83, P = 0.001, respectively). Those taking AChEIs or both AChEIs and memantine had significantly shorter periods of unplanned hospital admission for physical disorders (adjusted coefficient -13.48, 95% CI = [-26.87, -0.09], P = 0.049; adjusted coefficient -14.21, 95% CI = [-24.58, -3.85], P = 0.007, respectively), but no difference in length of stay for planned admissions for physical disorders, or for admissions for mental health disorders. No significant additional associations of memantine on admission, length of stay, and mortality were found (all P > 0.05). The main limitation was that this was a naturalistic study and possible confounds cannot be fully controlled, and there may be selection bias resulting from nonrandom prescription behaviour in clinical practice. However, we mimicked the intention-to-treat design of clinical trials, and the majority of baseline characters were balanced between cohorts. In addition, our series of sensitivity analyses confirmed the consistency of our results. CONCLUSION: In this study, we observed that use of AChEIs with or without memantine in DLB was associated with shorter duration of hospital admissions and decreased risk of mortality. Although our study was naturalistic, it supports further the use of AChEIs in DLB.

Funder: Alzheimer's Research UK; Id: http://dx.doi.org/10.13039/501100002283, Funder: GE Healthcare; Id: http://dx.doi.org/10.13039/100006775, Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100000265, Funder: National Institute for Health Research Applied Research Collaboration South West Peninsula; Id: http://dx.doi.org/10.13039/501100019219, Funder: NIHR Cambridge Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100018956, Funder: NIHR Newcastle Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012295, BACKGROUND AND PURPOSE: Mild cognitive impairment with Lewy bodies (MCI-LB) is associated with a range of cognitive, motor, neuropsychiatric, sleep, autonomic, and visual symptoms. We investigated the cumulative frequency of symptoms in a longitudinal cohort of MCI-LB compared with MCI due to Alzheimer disease (MCI-AD) and analysed the ability of a previously described 10-point symptom scale to differentiate MCI-LB and MCI-AD, in an independent cohort. METHODS: Participants with probable MCI-LB (n = 70), MCI-AD (n = 51), and controls (n = 34) had a detailed clinical assessment and annual follow-up (mean duration = 1.7 years). The presence of a range of symptoms was ascertained using a modified version of the Lewy Body Disease Association Comprehensive LBD Symptom Checklist at baseline assessment and then annually. RESULTS: MCI-LB participants experienced a greater mean number of symptoms (24.2, SD = 7.6) compared with MCI-AD (11.3, SD = 7.4) and controls (4.2, SD = 3.1; p < 0.001 for all comparisons). A range of cognitive, parkinsonian, neuropsychiatric, sleep, and autonomic symptoms were significantly more common in MCI-LB than MCI-AD, although when present, the time of onset was similar between the two groups. A previously defined 10-point symptom scale demonstrated very good discrimination between MCI-LB and MCI-AD (area under the receiver operating characteristic curve = 0.91, 95% confidence interval = 0.84-0.98), replicating our previous finding in a new cohort. CONCLUSIONS: MCI-LB is associated with the frequent presence of a particular profile of symptoms compared to MCI-AD. Clinicians should look for evidence of these symptoms in MCI and be aware of the potential for treatment. The presence of these symptoms may help to discriminate MCI-LB from MCI-AD.

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson's disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia., Cambridge NIHR Cambridge Biomedical Research Centre, NIHR Newcastle Biomedical Research Centre

The unfolded protein response has been increasingly implicated as an important pathological pathway and target for therapeutic intervention in neurodegeneration. The licensed antidepressant trazodone is one drug which has been proposed to act on this pathway and may therefore be a potential therapy. Previous examination of existing data for patients with dementia prescribed trazodone did not find a signal suggesting a disease modifying effect. Here we add to that literature by examining the electronic patient record of patients with dementia in Cambridgeshire UK. We found that trazodone is rarely prescribed and where it is used it is at a dose less than half that predicted to be disease modifying. We also found that patients prescribed trazodone had higher levels of neuropsychiatric symptoms and were relatively late in the disease course, likely beyond the optimal point for therapeutic intervention. We suggest it is therefore premature to discard potential therapies based on observational data alone, particularly when experimental medicine approaches to examine the effects of trazodone are feasible.

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods: N=42 patients with probable PSP and N=39 controls underwent 18F-flortaucipir PET. Conditional inference tree analyses on regional binding potential values identified absent/present pathology thresholds to define in vivo staging. Following the staging system for PSP pathology, the combination of absent/present values across all regions was evaluated to assign each participant to in vivo stages. Analysis of variance was applied to analyse differences among means of disease severity between stages. In vivo staging was compared with post-mortem staging in N=9 patients who also had post-mortem confirmation of the diagnosis and stage. Results: Stage assignment was estimable in 41 patients: N=10 patients were classified in stage I/II, N=26 in stage III/IV, N=5 in stage V/VI, while N=1 was not classifiable. An explorative sub-staging identified N=2 patients in stage I, N=8 in stage II, N=9 in stage III, N=17 in stage IV and N=5 in stage V. However, the nominal 18F-flortaucipir derived stage was not associated with clinical severity and was not indicative of pathology staging at post-mortem. Conclusion: 18F-flortaucipir PET in vivo does not correspond to neuropathological staging in PSP. This analytic approach, seeking to mirror in vivo the neuropathology staging with PET-to-autopsy correlational analyses might enable in vivo staging with next-generation PET tracers for tau, but further evidence and comparison with post-mortem data are needed.

How does the organisation of neural information-processing enable humans’ sophisticated cognition? Here we decompose functional interactions between brain regions into synergistic and redundant components, revealing their distinct information-processing roles. Combining functional and structural neuroimaging with meta-analytic results, we demonstrate that redundant interactions are predominantly associated with structurally-coupled, modular sensorimotor processing. Synergistic interactions instead support integrative processes and complex cognition across higher-order brain networks. The human brain leverages synergistic information to a greater extent than non-human primates, with high-synergy association cortices exhibiting the highest degree of evolutionary cortical expansion. Synaptic density mapping from Positron Emission Tomography and convergent molecular and metabolic evidence demonstrate that synergistic interactions are supported by receptor diversity and human-accelerated genes underpinning synaptic function. This information-resolved approach provides analytic tools to disentangle information integration from coupling, enabling richer, more accurate interpretations of functional connectivity, and illuminating how the human neurocognitive architecture navigates the trade-off between robustness and integration.

Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia. Despite considerable research progress, there remain gaps in our understanding of the pathophysiology and there is no disease-modifying treatment. Proteomics is a powerful tool to elucidate complex biological pathways across heterogenous conditions. This review summarizes the widely used proteomic methods and presents evidence for protein dysregulation in the brain and peripheral tissues in DLB. Proteomics of post-mortem brain tissue shows that DLB shares common features with other dementias, such as synaptic dysfunction, but retains a unique protein signature. Promising diagnostic biomarkers are being identified in cerebrospinal fluid (CSF), blood, and peripheral tissues, such as serum Heart-type fatty acid binding protein. Research is needed to track these changes from the prodromal stage to established dementia, with standardized workflows to ensure replicability. Identifying novel protein targets in causative biological pathways could lead to the development of new targeted therapeutics or the stratification of participants for clinical trials.

BACKGROUND: Persisting symptoms and increased mortality after SARS-CoV-2 infection has been described in COVID-19 survivors. OBJECTIVE: We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection. METHODS: A retrospective matched case-control study of 165 patients with dementia who survived an acute hospital admission with COVID-19 infection, and 1325 patients with dementia who survived a hospital admission but without SARS-CoV-2 infection. Potential risk factors investigated included socio-demographic factors, clinical features, and results of investigations. Data were fitted using a Cox proportional hazard model. RESULTS: Compared to patients with dementia but without SARS-CoV-2 infection, people with dementia and SARS-CoV-2 infection had a 4.4-fold risk of death (adjusted hazard ratio [aHR] = 4.44, 95% confidence interval [CI] 3.13-6.30) even beyond the acute phase of infection. This excess mortality could be seen up to 125 days after initial recovery but was not elevated beyond this time. Risk factors for COVID-19-associated mortality included prescription of antipsychotics (aHR = 3.06, 95% CI 1.40-6.69) and benzodiazepines (aHR = 3.00, 95% CI 1.28-7.03). Abnormalities on investigation associated with increased mortality included high white cell count (aHR = 1.21, 95% CI 1.04-1.39), higher absolute neutrophil count (aHR = 1.28, 95% CI 1.12-1.46), higher C-reactive protein (aHR = 1.01, 95% CI 1.00-1.02), higher serum sodium (aHR = 1.09, 95% CI 1.01-1.19), and higher ionized calcium (aHR = 1.03, 95% CI 1.00-1.06). The post-acute COVID mortality could be modeled for the first 120 days after recovery with a balanced accuracy of 87.2%. CONCLUSION: We found an increased mortality in patients with dementia beyond the acute phase of illness. We identified several investigation results associated with increased mortality, and increased mortality in patients prescribed antipsychotics or benzodiazepines.

Background AD co-pathology is common in DLB and associated with increased decline. Plasma p-Tau181 is a blood-based biomarker which can detect AD co-pathology. Objectives We investigated whether p-Tau181 was associated with cognitive decline in MCI with Lewy bodies (MCI-LB) and MCI with AD (MCI-AD). Methods We assessed plasma p-Tau181 using a Single molecule array (Simoa) immunoassay at baseline and follow-up in a longitudinal cohort of MCI-LB, MCI-AD and controls. Results One hundred and forty-six subjects (56 probable MCI-LB, 22 possible MCI-LB, 44 MCI-AD and 24 controls) were reviewed for up to 5.7 years. Probable MCI-LB had significantly higher p-Tau-181 (22.2% mean increase) compared with controls and significantly lower (24.4% mean decrease) levels compared with MCI-AD. ROC analyses of p-Tau-181 in discriminating probable MCI-LB from controls showed AUC of 0.68 (83% specificity, 57% sensitivity); for discriminating MCI-AD from healthy controls AUC was 0.8 (83.3% specificity, 72.7% sensitivity). P-Tau-181 concentration was less useful in discriminating between probable MCI-LB and MCI-AD: AUC of 0.64 (71.4% specificity, 52.3% sensitivity). There was an association between p-Tau-181 and cognitive decline in MCI-AD but not in MCI-LB. In a subset with repeat samples there was a non-significant 3% increase per follow-up year in plasma p-Tau-181. The rate of change in p-Tau-181 was not significantly different in different diagnostic subgroups. Conclusions p-Tau-181 was not associated with an increased decline assessed using either baseline or repeat p-Tau-181. P-Tau-181 partially discriminated probable MCI-LB from controls and MCI-AD from controls but was not useful at distinguishing probable MCI-LB from MCI-AD.

Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world's population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed-particularly any that can slow down the disease's progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents-in particular the licensed antidepressant trazodone-and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia., NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) (JOB). UK Dementia Research Institute (funded by the Medical Research Council UK, Alzheimer's Research UK and the Alzheimer's Society) (G.R.M., H.S.), the Cambridge Centre for Parkinson-Plus (G.R.M. and A.B.) the European Research Council (consolidator grant UPR Neuro; no. 647479), the Joint Proramme Neurodegenerative Disease, the Centres of Excellence in Neurodegeneration and the Well come Trust Collaborative Award (G.R.M). Gnodde Goldman Sachs Translational Neuroscience (B.U &E.S)

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 behavioural 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 MRI and a neuropsychological battery, including the Addenbrooke's Cognitive Examination (ACE-R), and INECO frontal screening (IFS). General linear models compared [11 C]UCB-J binding potential maps and grey-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 voxel-wise results. INTERPRETATION: In accordance with preclinical models, and human post mortem 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. This article is protected by copyright. All rights reserved.

BACKGROUND AND OBJECTIVES: Diffusion tensor imaging (DTI) networks integrate damage from a variety of pathological processes in cerebral small vessel disease (SVD) and may be a sensitive marker to detect treatment effects. We determined whether brain network analysis could detect treatment effects in the PRESERVE trial dataset, in which intensive versus standard blood pressure (BP) lowering was compared. The primary endpoint of DTI had not shown treatment differences. METHODS: Subjects with lacunar stroke were randomised to standard (systolic 130-140 mmHg), or intensive (systolic

OBJECTIVES: Impaired olfaction may be a biomarker for early Lewy body disease, but its value in mild cognitive impairment with Lewy bodies (MCI-LB) is unknown. We compared olfaction in MCI-LB with MCI due to Alzheimer's disease (MCI-AD) and healthy older adults. We hypothesized that olfactory function would be worse in probable MCI-LB than in both MCI-AD and healthy comparison subjects (HC). DESIGN: Cross-sectional study assessing olfaction using Sniffin' Sticks 16 (SS-16) in MCI-LB, MCI-AD, and HC with longitudinal follow-up. Differences were adjusted for age, and receiver operating characteristic (ROC) curves were used for discriminating MCI-LB from MCI-AD and HC. SETTING: Participants were recruited from Memory Services in the North East of England. PARTICIPANTS: Thirty-eight probable MCI-LB, 33 MCI-AD, 19 possible MCI-LB, and 32HC. MEASUREMENTS: Olfaction was assessed using SS-16 and a questionnaire. RESULTS: Participants with probable MCI-LB had worse olfaction than both MCI-AD (age-adjusted mean difference (B) = 2.05, 95% CI: 0.62-3.49, p = 0.005) and HC (B = 3.96, 95% CI: 2.51-5.40, p < 0.001). The previously identified cutoff score for the SS-16 of ≤ 10 had 84% sensitivity for probable MCI-LB (95% CI: 69-94%), but 30% specificity versus MCI-AD. ROC analysis found a lower cutoff of ≤ 7 was better (63% sensitivity for MCI-LB, with 73% specificity vs MCI-AD and 97% vs HC). Asking about olfactory impairments was not useful in identifying them. CONCLUSIONS: MCI-LB had worse olfaction than MCI-AD and normal aging. A lower cutoff score of ≤ 7 is required when using SS-16 in such patients. Olfactory testing may have value in identifying early LB disease in memory services.

Sensitive and specific antemortem biomarkers of neurodegenerative disease and dementia are crucial to the pursuit of effective treatments, required both to reliably identify disease and to track its progression. Atrophy is the structural magnetic resonance imaging (MRI) hallmark of neurodegeneration. However in most cases it likely indicates a relatively advanced stage of disease less susceptible to treatment as some disease processes begin decades prior to clinical onset. Among emerging metrics that characterise brain shape rather than volume, fractal dimension (FD) quantifies shape complexity. FD has been applied in diverse fields of science to measure subtle changes in elaborate structures. We review its application thus far to structural MRI of the brain in neurodegenerative disease and dementia. We identified studies involving subjects who met criteria for mild cognitive impairment, Alzheimer's Disease, Vascular Dementia, Lewy Body Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease, Huntington's Disease, Multiple Systems Atrophy, Spinocerebellar Ataxia and Multiple Sclerosis. The early literature suggests that neurodegenerative disease processes are usually associated with a decline in FD of the brain. The literature includes examples of disease-related change in FD occurring independently of atrophy, which if substantiated would represent a valuable advantage over other structural imaging metrics. However, it is likely to be non-specific and to exhibit complex spatial and temporal patterns. A more harmonious methodological approach across a larger number of studies as well as careful attention to technical factors associated with image processing and FD measurement will help to better elucidate the metric's utility.

Funder: GE Healthcare; Id: http://dx.doi.org/10.13039/100006775, Funder: Alzheimer's Research UK; Id: http://dx.doi.org/10.13039/501100002283, Funder: NIHR Newcastle Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012295, Objectives: Autonomic symptoms are a common feature of the synucleinopathies, and may be a distinguishing feature of prodromal Lewy body disease. We aimed to assess whether the cognitive prodrome of dementia with Lewy bodies, mild cognitive impairment (MCI) with Lewy bodies (MCI‐LB), would have more severe reported autonomic symptoms than cognitively healthy older adults, with MCI due to Alzheimer's disease (MCI‐AD) also included for comparison. We also aimed to assess the utility of an autonomic symptom scale in differentiating MCI‐LB from MCI‐AD. Methods: Ninety‐three individuals with MCI and 33 healthy controls were assessed with the Composite Autonomic Symptom Score 31‐item scale (COMPASS). Mild cognitive impairment patients also underwent detailed clinical assessment and differential classification of MCI‐AD or MCI‐LB according to current consensus criteria. Differences in overall COMPASS score and individual symptom sub‐scales were assessed, controlling for age. Results: Age‐adjusted severity of overall autonomic symptomatology was greater in MCI‐LB (Ratio = 2.01, 95% CI: 1.37–2.96), with higher orthostatic intolerance and urinary symptom severity than controls, and greater risk of gastrointestinal and secretomotor symptoms. MCI‐AD did not have significantly higher autonomic symptom severity than controls overall. A cut‐off of 4/5 on the COMPASS was sensitive to MCI‐LB (92%) but not specific to this (42% specificity vs. MCI‐AD and 52% vs. healthy controls). Conclusions: Mild cognitive impairment with Lewy bodies had greater autonomic symptom severity than normal ageing and MCI‐AD, but such autonomic symptoms are not a specific finding. The COMPASS‐31 may therefore have value as a sensitive screening test for early‐stage Lewy body disease.

Funder: NIHR Newcastle Biomedical Research Centre, Funder: Alzheimer's Research UK, Funder: GE Healthcare; Id: http://dx.doi.org/10.13039/100006775, Objectives: Previous research has identified that dementia with Lewy bodies (DLB) has abnormal pareidolic responses which are associated with severity of visual hallucinations (VH), and the pareidolia test accurately classifies DLB with VH. We aimed to assess whether these findings would also be evident at the earlier stage of mild cognitive impairment (MCI) with Lewy bodies (MCI‐LB) in comparison to MCI due to AD (MCI‐AD) and cognitively healthy comparators. Methods: One‐hundred and thirty‐seven subjects were assessed prospectively in a longitudinal study with a mean follow‐up of 1.2 years (max = 3.7): 63 MCI‐LB (22% with VH) and 40 MCI‐AD according to current research diagnostic criteria, and 34 healthy comparators. The pareidolia test was administered annually as a repeated measure. Results: Probable MCI‐LB had an estimated pareidolia rate 1.2–6.7 times higher than MCI‐AD. Pareidolia rates were not associated with concurrent VH, but had a weak association with total score on the North East Visual Hallucinations Inventory. The pareidolia test was not an accurate classifier of either MCI‐LB (Area under curve (AUC) = 0.61), or VH (AUC = 0.56). There was poor sensitivity when differentiating MCI‐LB from controls (41%) or MCI‐AD (27%), though specificity was better (91% and 89%, respectively). Conclusions: Whilst pareidolic responses are specifically more frequent in MCI‐LB than MCI‐AD, sensitivity of the pareidolia test is poorer than in DLB, with fewer patients manifesting VH at the earlier MCI stage. However, the high specificity and ease of use may make it useful in specialist clinics where imaging biomarkers are not available.

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 (ROC) 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. Keywords: Addenbrooke’s Cognitive Examination-Revised, dementia with Lewy bodies, Alzheimer’s disease, neuropsychology, neurodegeneration, diagnosis

Connexin36 (Cx36) is the most abundant connexin in central nervous system neurons. It forms gap junction channels that act as electrical synapses. Similar to chemical synapses, Cx36-containing gap junctions undergo activity-dependent plasticity and complex regulation. Cx36 gap junctions represent multimolecular complexes and contain cytoskeletal, regulatory and scaffolding proteins, which regulate channel conductance, assembly and turnover. The amino acid sequence of mammalian Cx36 harbors a phosphorylation site for the Ca2+/calmodulin-dependent kinase II at serine 315. This regulatory site is homologous to the serine 298 in perch Cx35 and in close vicinity to a PDZ binding domain at the very C-terminal end of the protein. We hypothesized that this phosphorylation site may serve as a molecular switch, influencing the affinity of the PDZ binding domain for its binding partners. Protein microarray and pulldown experiments revealed that this is indeed the case: phosphorylation of serine 298 decreased the binding affinity for MUPP1, a known scaffolding partner of connexin36, and increased the binding affinity for two different 14–3–3 proteins. Although we did not find the same effect in cell culture experiments, our data suggest that phosphorylation of serine 315/298 may serve to recruit different proteins to connexin36/35-containing gap junctions in an activity-dependent manner.

BACKGROUND: Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear. OBJECTIVE: To investigate spatial covariance patterns of cholinergic muscarinic M1 /M4 receptors in PD and their relationship with cognition and motor symptoms. METHODS: Some 19 PD and 24 older adult controls underwent 123 I-iodo-quinuclidinyl-benzilate (QNB) (M1 /M4 receptor) and 99m Tc-exametazime (perfusion) single-photon emission computed tomography (SPECT) scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of intercorrelated voxels across individuals. Linear regression analyses derived specific M1 /M4 spatial covariance patterns associated with PD. RESULTS: A cholinergic M1 /M4 pattern that converged onto key hubs of the default, auditory-visual, salience, and sensorimotor networks fully discriminated PD patients from controls (F1,41 = 135.4, P < 0.001). In PD, we derived M1 /M4 patterns that correlated with global cognition (r = -0.62, P = 0.008) and motor severity (r = 0.53, P = 0.02). Both patterns emerged with a shared topography implicating the basal forebrain as well as visual, frontal executive, and salience circuits. Further, we found a M1 /M4 pattern that predicted global cognitive decline (r = 0.46, P = 0.04) comprising relative decreased binding within default and frontal executive networks. CONCLUSIONS: Cholinergic muscarinic M1 /M4 modulation within key brain networks were apparent in PD. Cognition and motor severity were associated with a similar topography, inferring both phenotypes possibly rely on related cholinergic mechanisms. Relative decreased M1 /M4 binding within default and frontal executive networks could be an indicator of future cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

OBJECTIVES: We conducted a prospective longitudinal study of plasma cytokines during the Mild Cognitive Impairment (MCI) stage of Lewy body disease and Alzheimer's disease, hypothesizing that cytokine levels would decrease over time and that this would be correlated with decline in cognition. METHODS: Older (≥60) people with MCI were recruited from memory services in healthcare trusts in North East England, UK. MCI was diagnosed as due to Alzheimer's disease (MCI-AD) or Lewy body disease (MCI-LB). Baseline and repeat annual clinical and cognitive assessments were undertaken and plasma samples were obtained at the same time. Cytokine assays were performed on all samples using the Meso Scale Discovery V-Plex Plus Proinflammatory Panel 1, which included IFNγ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 and TNFα. RESULTS: Fifty-six patients (21 MCI-AD, 35 MCI-LB) completed prospective evaluations and provided samples up to 3 years after baseline. Six cytokines (IFNγ, IL-1β, IL-2, IL-4, IL-6 and IL-10) showed highly significant (P < .002) decreases over time. AD and LB did not differ in rate of decrease nor were there any effects related to age or general morbidity. Decrease in five of these cytokines (IFNγ, IL-1β, IL-2, IL-4, and IL-10) was highly correlated with decrease in cognition (P < .003). CONCLUSIONS: Peripheral inflammation decreased in both disease groups during MCI suggesting this may be a therapeutic window for future anti-inflammatory agents.

BACKGROUND: Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterised by marked deficits within the cholinergic system which are more severe than in Alzheimer's disease (AD) and are mainly caused by degeneration of the nucleus basalis of Meynert (NBM) whose widespread cholinergic projections provide the main source of cortical cholinergic innervation. EEG alpha reactivity, which refers to the reduction in alpha power over occipital electrodes upon opening the eyes, has been suggested as a potential marker of cholinergic system integrity. METHODS: Eyes-open and eyes-closed resting state EEG data were recorded from 41 LBD patients (including 24 patients with DLB and 17 with PDD), 21 patients with AD, and 40 age-matched healthy controls. Alpha reactivity was calculated as the relative reduction in alpha power over occipital electrodes when opening the eyes. Structural MRI data were used to assess volumetric changes within the NBM using a probabilistic anatomical map. RESULTS: Alpha reactivity was reduced in AD and LBD patients compared to controls with a significantly greater reduction in LBD compared to AD. Reduced alpha reactivity was associated with smaller volumes of the NBM across all groups (ρ = 0.42, pFDR = 0.0001) and in the PDD group specifically (ρ = 0.66, pFDR = 0.01). CONCLUSIONS: We demonstrate that LBD patients show an impairment in alpha reactivity upon opening the eyes which distinguishes this form of dementia from AD. Furthermore, our results suggest that reduced alpha reactivity might be related to a loss of cholinergic drive from the NBM, specifically in PDD.

BACKGROUND: Alzheimer's disease (AD) begins decades before the onset of dementia. There is a need to investigate biomarkers of early AD for use in clinical trials and to facilitate early intervention. OBJECTIVE: We aimed to determine whether changes in hippocampal subfield volumes in healthy middle-aged adults were associated with risk of future dementia. METHODS: We included 150 participants from the PREVENT-Dementia cohort, which recruited subjects aged 40-59 with or without a family history of dementia (FHD; included here were 81 with FHD and 69 without). Hippocampal subfield volumes were segmented from high resolution T2-weighted 3T MRI images taken at baseline and 2-year follow-up. RESULTS: FHD and greater 20 year-risk of dementia due to cardiovascular risk factors were both associated with lower CA1 volume. FHD was also associated with a relative increase in combined CA3, CA4, and dentate gyrus volume between baseline and follow-up. CONCLUSION: CA1 atrophy may commence as early as middle-age in those with a high risk of future dementia, while increases in CA3, CA4, and dentate gyrus volume may be a response to early AD in the form of inflammation or neurogenesis.

INTRODUCTION: Planar 123I-MIBG (meta-iodobenzylguanidine) cardiac imaging is listed as an indicative biomarker in the 2017 international consensus criteria for the diagnosis of dementia with Lewy bodies. There has been very little research into the relationship between apparent cardiac uptake and patient size, or in the possible advantage of attenuation and scatter corrected SPECT-CT compared to planar imaging. We aimed to evaluate this in both a chest phantom and in older adults with normal cognition. MATERIALS AND METHODS: An anthropomorphic chest phantom was filled with 123I solution using activities typical of healthy subjects. The phantom was scanned on a Siemens Intevo gamma camera with MELP collimators using both planar and SPECT-CT techniques. Further scans were acquired with a PMMA chest plate added, then water filled plastic breasts. The SPECT-CT images were reconstructed using a resolution recovery OSEM method with and without attenuation and scatter correction (ACSC) applied. Twenty-nine adults over 60 years of age (mean 75.2 ± 8.3 years) underwent planar cardiac MIBG imaging, followed by SPECT-CT. SPECT images were reconstructed as above. Heart-to-mediastinum ratios (HMRs) were calculated for planar and SPECT images. RESULTS: Phantom planar HMR decreased by 20% with the PMMA chest plate added; 39% with plate and breasts. ACSC SPECT cardiac counts showed less dependence on phantom size than SPECT without ACSC (3% versus 37%). The body mass indices (BMI) of the older adults ranged from 22 to 38. There was a significant linear relationship between planar HMR and BMI (R2 = 0.44, p

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 [11 C]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. [11 C]UCB-J PET may facilitate early, pre-symptomatic assessment, monitoring of disease progression and evaluation of new preventive treatment strategies for frontotemporal dementia.

Cerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying pathogenesis is poorly understood, but both neuroinflammation and increased blood-brain barrier permeability have been hypothesized to play a role, and preclinical studies suggest the two processes may be linked. We used PET magnetic resonance to simultaneously measure microglial activation using the translocator protein radioligand 11C-PK11195, and blood-brain barrier permeability using dynamic contrast enhanced MRI. A case control design was used with two disease groups with sporadic SVD (n = 20), monogenic SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL), and normal controls (n = 20) were studied. Hotspots of increased glial activation and blood-brain barrier permeability were identified as values greater than the 95th percentile of the distribution in controls. In sporadic SVD there was an increase in the volume of hotspots of both 11C-PK11195 binding (P = 0.003) and blood-brain barrier permeability (P = 0.007) in the normal appearing white matter, in addition to increased mean blood-brain barrier permeability (P

Vascular dementia is one of the most common causes of dementia after Alzheimer's disease, causing around 15% of cases. However, unlike Alzheimer's disease, there are no licensed treatments for vascular dementia. Progress in the specialty has been difficult because of uncertainties over disease classification and diagnostic criteria, controversy over the exact nature of the relation between cerebrovascular pathology and cognitive impairment, and the paucity of identifiable tractable treatment targets. Although there is an established relation between vascular and degenerative Alzheimer's pathology, the mechanistic link between the two has not yet been identified. This Series paper critiques some of the key areas and controversies, summarises treatment trials so far, and makes suggestions for what progress is needed to advance our understanding of pathogenesis and thus maximise opportunities for the search for new and effective management approaches.

Attention and executive dysfunction are features of Lewy body dementia (LBD) but their neuroanatomical basis is poorly understood. To investigate underlying dysfunctional attention-executive network (EXEC) interactions, we examined functional connectivity (FC) in 30 patients with LBD, 20 patients with Alzheimer's disease (AD), and 21 healthy controls during an event-related functional magnetic resonance imaging (fMRI) experiment. Participants performed a modified Attention Network Test (ANT), where they were instructed to press a button in response to the majority direction of arrows, which were either all pointing in the same direction or with one pointing in the opposite direction. Network activations during both target conditions and a baseline condition (no target) were derived by (ICA) Independent Component Analysis, and interactions between these networks were examined using the beta series correlations approach. Our study revealed that FC of ventral and dorsal attention networks DAN was reduced in LBD during all conditions, although most prominently during incongruent trials. These alterations in connectivity might be driven by a failure of engagement of ventral attention networks, and consequent over-reliance on the DAN. In contrast, when comparing AD patients with the other groups, we found hyperconnectivity between the posterior part of the default mode network (DMN) and the DAN in all conditions, particularly during incongruent trials. This might be attributable to either a compensatory effect to overcome DMN dysfunction, or be arising as a result of a disturbed transition of the DMN from rest to task. Our results demonstrate that dementia syndromes can be characterized both by hyper- and hypoconnectivity of distinct brain networks, depending on the interplay between task demand and available cognitive resources. However these are dependent upon the underlying pathology, which needs to be taken into account when developing specific cognitive therapies for LBD as compared to Alzheimer's.

Late-life depression (LLD) has been associated with both generalized and focal neuroanatomical changes including gray matter atrophy and white matter abnormalities. However, previous literature has not been consistent and, in particular, its impact on the topology organization of brain networks remains to be established. In this multimodal study, we first examined cortical thickness, and applied graph theory to investigate structural covariance networks in LLD. Thirty-three subjects with LLD and 25 controls underwent T1-weighted, fluid-attenuated inversion recovery and clinical assessments. Freesurfer was used to perform vertex-wise comparisons of cortical thickness, whereas the Graph Analysis Toolbox (GAT) was implemented to construct and analyze the structural covariance networks. LLD showed a trend of lower thickness in the left insular region (p < 0.001 uncorrected). In addition, the structural network of LLD was characterized by greater segregation, particularly showing higher transitivity (i.e., measure of clustering) and modularity (i.e., tendency for a network to be organized into subnetworks). It was also less robust against random failure and targeted attacks. Despite relative cortical preservation, the topology of the LLD network showed significant changes particularly in segregation. These findings demonstrate the potential for graph theoretical approaches to complement conventional structural imaging analyses and provide novel insights into the heterogeneous etiology and pathogenesis of LLD.

Inflammation is increasingly implicated as a risk factor for dementia, stroke, and small vessel disease (SVD). However, the underlying mechanisms and causative pathways remain unclear. We systematically reviewed the existing literature on the associations between markers of inflammation and SVD (i.e., white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB)) in cohorts of older people with good health, cerebrovascular disease, or cognitive impairment. Based on distinctions made in the literature, markers of inflammation were classified as systemic inflammation (e.g. C-reactive protein, interleukin-6, fibrinogen) or vascular inflammation/endothelial dysfunction (e.g. homocysteine, von Willebrand factor, Lp-PLA2). Evidence from 82 articles revealed relatively robust associations between SVD and markers of vascular inflammation, especially amongst stroke patients, suggesting that alterations to the endothelium and blood-brain barrier may be a driving force behind SVD. Conversely, cross-sectional findings on systemic inflammation were mixed, although longitudinal investigations demonstrated that elevated levels of systemic inflammatory markers at baseline predicted subsequent SVD severity and progression. Importantly, regional analysis revealed that systemic and vascular inflammation were differentially related to two distinct forms of SVD. Specifically, markers of vascular inflammation tended to be associated with SVD in areas typical of hypertensive arteriopathy (e.g., basal ganglia), while systemic inflammation appeared to be involved in CAA-related vascular damage (e.g., centrum semiovale). Nonetheless, there is insufficient data to establish whether inflammation is causal of, or secondary to, SVD. Findings have important implications on interventions, suggesting the potential utility of treatments targeting the brain endothelium and blood brain barrier to combat SVD and associated neurodegenerative diseases. Keywords: small vessel disease; inflammation; stroke; endothelial dysfunction; white matter hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds

Neuroinflammation occurs in frontotemporal dementia, however its timing relative to protein aggregation and neuronal loss is unknown. Using positron emission tomography and magnetic resonance imaging to quantify these processes in a pre-symptomatic carrier of the 10 + 16 MAPT mutation, we show microglial activation in frontotemporal regions, despite a lack of protein aggregation or atrophy in these areas. The distribution of microglial activation better discriminated the carrier from controls than did protein aggregation at this pre-symptomatic disease stage. Our findings suggest an early role for microglial activation in frontotemporal dementia. Longitudinal studies are needed to explore the causality of this pathophysiological association.

Inflammation is increasingly recognized as part of the pathology of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, but its role in dementia with Lewy bodies remains unclear. Using multimodal imaging and peripheral cytokine analysis, we therefore investigated central and peripheral inflammation in this common form of dementia. Nineteen participants with probable dementia with Lewy bodies and 16 similarly aged controls underwent 3 T MRI and PET imaging with 11C-PK11195, a marker of microglial activation in vivo. Peripheral blood inflammatory cytokines were also measured in all subjects, as well as in an additional 10 controls, using the Mesoscale Human Cytokine 36 plex panel and additional assays for high sensitivity c-reactive protein, tumour necrosis factor receptor 1, IL-34, YKL-40 (chitinase-3-like protein 1) and colony stimulating factor 1. To test for the presence of in vivo amyloid, 11C-Pittsburgh compound B PET imaging was also performed in 16 of the dementia with Lewy body participants. Microglial activation was elevated in dementia with Lewy bodies subjects with mild disease when compared to those with moderate/severe impairment, where disease severity was indexed by cognitive performance on the revised Addenbrooke's Cognitive Examination. In patients, strong correlations were found between cognitive performance and 11C-PK11195 non-displaceable binding potential in several regions including the caudate nucleus (R = 0.83, P = 0.00008) and cuneus (R = 0.77, P = 0.0005). Several inflammatory cytokines were altered in the patients compared to controls, with elevated macrophage inflammatory protein-3 (P = 0.001), IL-17A (P = 0.008) and IL-2 (P = 0.046) and reduced IL-8 (P = 0.024). There was no correlation between cortical 11C-Pittsburgh compound B standardized uptake value ratio and clinical features, regional 11C-PK11195 binding or peripheral cytokine levels. Nor was there any regional correlation between 11C-PK11195 non-displaceable binding potentials and 11C-Pittsburgh compound B standardized uptake value ratios. Our findings provide evidence for both central and peripheral inflammatory changes in dementia with Lewy bodies, with microglial activation occurring early in the disease in key regions known to be associated with pathology, before declining as cognition declines. Raised peripheral cytokines associated with T cell function further suggest a role for the adaptive immune system in the pathogenesis of the disease.

OBJECTIVE: To provide guidance to researchers, funders, regulators and study delivery teams to ensure that research on COVID-19 is inclusive, particularly of groups disproportionately affected by COVID-19 and who may have been historically under-served by research. SUMMARY OF KEY POINTS: Groups who are disproportionately affected by COVID-19 include (but are not limited to) older people, people with multiple long-term conditions, people with disabilities, people from Black, Asian and Ethnic minority groups, people living with obesity, people who are socioeconomically deprived and people living in care homes. All these groups are under-served by clinical research, and there is an urgent need to rectify this if COVID-19 research is to deliver relevant evidence for these groups who are most in need. We provide a framework and checklists for addressing key issues when designing and delivering inclusive COVID-19 research, based on the National Institute for Health Research INnovations in CLinical trial design and delivery for the UnDEr-served project roadmap. Strong community engagement, codevelopment and prioritisation of research questions and interventions are essential. Under-served groups should be represented on funding panels and ethics committees, who should insist on the removal of barriers to participation. Exclusion criteria should be kept to a minimum; intervention delivery and outcome measurement should be simple, flexible and tailored to the needs of different groups, and local advice on the best way to reach and engage with under-served communities should be taken by study delivery teams. Data on characteristics that allow identification of under-served groups must be collected, analyses should include these data to enable subgroup comparisons and results should be shared with under-served groups at an early stage. CONCLUSION: Inclusive COVID-19 research is a necessity, not a luxury, if research is to benefit all the communities it seeks to serve. It requires close engagement with under-served groups and attention to aspects of study topic, design, delivery, analysis and dissemination across the research life cycle.

Funder: GE Healthcare; doi: http://dx.doi.org/10.13039/100006775, Funder: NIHR Newcastle Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100012295, Funder: Newcastle University, Objective: To use arterial spin labelling to investigate differences in perfusion in mild cognitive impairment with Lewy bodies (MCI-LB) compared to Alzheimer type MCI (MCI-AD) and healthy controls. Methods: We obtained perfusion images on 32 MCI-LB, 30 MCI-AD and 28 healthy subjects of similar age. Perfusion relative to cerebellum was calculated, and we aimed to examine differences in relative perfusion between MCI-LB and the other groups. This included whole brain voxelwise comparisons, as well as using predefined region-of-interest ratios of medial occipital to medial temporal, and posterior cingulate to precuneus. Differences in occipital perfusion in eyes open vs eyes closed conditions were also examined. Results: Compared to controls, the MCI-LB showed reduced perfusion in the precuneus, parietal, occipital and fusiform gyrus regions. In our predefined regions, the ratio of perfusion in occipital/medial temporal was significantly lower, and the posterior cingulate/precuneus ratio was significantly higher in MCI-LB compared to controls. Overall, the occipital perfusion was greater in the eyes open vs closed condition, but this did not differ between groups. Conclusion: We found patterns of altered perfusion in MCI-LB which are similar to those seen in dementia with Lewy bodies, with reduction in posterior parietal and occipital regions, but relatively preserved posterior cingulate.

Hanna Jokinen tutkimusryhmän jäsenenä (VICCCS Grp) Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2. Methods: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. Results: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. Discussion: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration. (C) 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients.METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine.RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone.CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

See Jeganathan and Breakspear (doi:10.1093/brain/awz132) for a scientific commentary on this article. Schumacher et al. report a marked and generalised slowing of whole-brain EEG dynamics in Lewy body dementia that distinguishes it from Alzheimer’s disease and healthy ageing. The slowing is related to a loss of dynamic interaction between basal ganglia-thalamic networks and large-scale cortical networks, and may contribute to fluctuating cognition., Lewy body dementia includes dementia with Lewy bodies and Parkinson’s disease dementia and is characterized by transient clinical symptoms such as fluctuating cognition, which might be driven by dysfunction of the intrinsic dynamic properties of the brain. In this context we investigated whole-brain dynamics on a subsecond timescale in 42 Lewy body dementia compared to 27 Alzheimer’s disease patients and 18 healthy controls using an EEG microstate analysis in a cross-sectional design. Microstates are transiently stable brain topographies whose temporal characteristics provide insight into the brain’s dynamic repertoire. Our additional aim was to explore what processes in the brain drive microstate dynamics. We therefore studied associations between microstate dynamics and temporal aspects of large-scale cortical-basal ganglia-thalamic interactions using dynamic functional MRI measures given the putative role of these subcortical areas in modulating widespread cortical function and their known vulnerability to Lewy body pathology. Microstate duration was increased in Lewy body dementia for all microstate classes compared to Alzheimer’s disease (P < 0.001) and healthy controls (P < 0.001), while microstate dynamics in Alzheimer’s disease were largely comparable to healthy control levels, albeit with altered microstate topographies. Correspondingly, the number of distinct microstates per second was reduced in Lewy body dementia compared to healthy controls (P < 0.001) and Alzheimer’s disease (P < 0.001). In the dementia with Lewy bodies group, mean microstate duration was related to the severity of cognitive fluctuations (ρ = 0.56, PFDR = 0.038). Additionally, mean microstate duration was negatively correlated with dynamic functional connectivity between the basal ganglia (r = − 0.53, P = 0.003) and thalamic networks (r = − 0.38, P = 0.04) and large-scale cortical networks such as visual and motor networks in Lewy body dementia. The results indicate a slowing of microstate dynamics and disturbances to the precise timing of microstate sequences in Lewy body dementia, which might lead to a breakdown of the intricate dynamic properties of the brain, thereby causing loss of flexibility and adaptability that is crucial for healthy brain functioning. When contrasted with the largely intact microstate dynamics in Alzheimer’s disease, the alterations in dynamic properties in Lewy body dementia indicate a brain state that is less responsive to environmental demands and might give rise to the apparent slowing in thinking and intermittent confusion which typify Lewy body dementia. By using Lewy body dementia as a probe pathology we demonstrate a potential link between dynamic functional MRI fluctuations and microstate dynamics, suggesting that dynamic interactions within the cortical-basal ganglia-thalamic loop might play a role in the modulation of EEG dynamics.

Importance: Blood pressure lowering is considered neuroprotective in patients with cerebral small vessel disease, however more “intensive” regimens may increase cerebral hypoperfusion. We examined the effect of intensive vs. standard blood pressure treatment on cerebral perfusion in severe small vessel disease patients. Objective: To determine whether intensive vs. standard blood pressure lowering over 3 months causes decreased cerebral perfusion. Design, Setting and Participants: This randomised, parallel, controlled, blinded-outcomes clinical trial took place in 2 English university medical centres. A central, online randomisation system (1:1 ratio) allocated grouping. 70 hypertensive patients with MRI confirmed symptomatic lacunar infarct and confluent white matter hyperintensities were recruited between 2012 and 2015, and randomised (36/34 in standard/intensive arms). Analysable data were available in 62 patients, 33/29 in the standard/intensive groups respectively, for intention to treat analysis. This experiment examines the 3 month follow-up period. Intervention: Patients were randomised to “standard” (systolic=130-140mmHg) or “intensive” (systolic=

OBJECTIVE: We tested whether in vivo neuroinflammation relates to the distinctive distributions of pathology in Alzheimer disease (AD) and progressive supranuclear palsy (PSP). METHODS: Sixteen patients with symptomatic AD (including amnestic mild cognitive impairment with amyloid-positive PET scan), 16 patients with PSP-Richardson syndrome, and 13 age-, sex-, and education-matched healthy controls were included in this case-control study. Participants underwent [11C]PK11195 PET scanning, which was used as an in vivo index of neuroinflammation. RESULTS: [11C]PK11195 binding in the medial temporal lobe and occipital, temporal, and parietal cortices was increased in patients with AD, relative both to patients with PSP and to controls. Compared to controls, patients with PSP showed elevated [11C]PK11195 binding in the thalamus, putamen, and pallidum. [11C]PK11195 binding in the cuneus/precuneus correlated with episodic memory impairment in AD, while [11C]PK11195 binding in the pallidum, midbrain, and pons correlated with disease severity in PSP. CONCLUSIONS: Together, our results suggest that neuroinflammation has an important pathogenic role in the 2 very different human neurodegenerative disorders of AD and PSP. The increase and distribution of microglial activation suggest that immunotherapeutic strategies may be useful in slowing the progression of both diseases.

OBJECTIVES: There is growing evidence for the role of systemic inflammation in Alzheimer's disease (AD) and other neurodegenerative diseases; however the systemic inflammatory profile in dementia with Lewy bodies (DLB) has never before been investigated. This study aimed to characterise systemic inflammatory mediators in established DLB and AD, as well as in their prodromal, mild cognitive impairment (MCI) phases. METHODS: We obtained plasma samples from patients with DLB (n=37), AD (n=20), MCI with DLB profile (n=38), MCI with AD profile (n=20) and healthy control subjects (n=20). The following inflammatory biomarkers were measured using Roche cobas c702 and Meso Scale Discovery V-Plex Plus: high-sensitivity C-reactive protein, interferon-gamma, interleukin (IL)-10, IL-12p70, IL-13, IL-1beta, IL-2, IL-4, IL-6, IL-8 and tumour necrosis factor-alpha. RESULTS: We found significantly higher levels of IL-10, IL-1beta, IL-4 and IL-2 in both MCI groups (P

Dementia with Lewy bodies (DLB) is a common form of dementia and is characterized by cognitive fluctuations, visual hallucinations, and Parkinsonism. The phenotypic expression of the disease may, in part, relate to alterations in functional connectivity within and between brain networks. This resting‐state study sought to clarify this in DLB, how networks differed from Alzheimer's disease (AD), and whether they were related to clinical symptoms in DLB. Resting‐state networks were estimated using independent component analysis. We investigated functional connectivity changes in 31 DLB patients compared to 31 healthy controls and a disease comparator group of 29 AD patients using dual regression and FSLNets. Within‐network connectivity was generally decreased in DLB compared to controls, mainly in motor, temporal, and frontal networks. Between‐network connectivity was mainly intact; only the connection between a frontal and a temporal network showed increased connectivity in DLB. Differences between AD and DLB were subtle and we did not find any significant correlations with the severity of clinical symptoms in DLB. This study emphasizes the importance of reduced connectivity within motor, frontal, and temporal networks in DLB with relative sparing of the default mode network. The lack of significant correlations between connectivity measures and clinical scores indicates that the observed reduced connectivity within these networks might be related to the presence, but not to the severity of motor and cognitive impairment in DLB patients. Furthermore, our results suggest that AD and DLB may show more similarities than differences in patients with mild disease.