Search

Background Gait disturbance is an early, disabling feature of Parkinson's disease (PD) that is typically refractory to dopaminergic medication. The cortical cholinergic system, originating in the nucleus basalis of Meynert of the basal forebrain, has been implicated. However, it is not known if degeneration in this region relates to a worsening of disease‐specific gait impairment. Objective To evaluate associations between sub‐regional cholinergic basal forebrain volumes and longitudinal progression of gait impairment in PD. Methods 99 PD participants and 47 control participants completed gait assessments via an instrumented walkway during 2 minutes of continuous walking, at baseline and for up to 3 years, from which 16 spatiotemporal characteristics were derived. Sub‐regional cholinergic basal forebrain volumes were measured at baseline via MRI and a regional map derived from post‐mortem histology. Univariate analyses evaluated cross‐sectional associations between sub‐regional volumes and gait. Linear mixed‐effects models assessed whether volumes predicted longitudinal gait changes. Results There were no cross‐sectional, age‐independent relationships between sub‐regional volumes and gait. However, nucleus basalis of Meynert volumes predicted longitudinal gait changes unique to PD. Specifically, smaller nucleus basalis of Meynert volume predicted increasing step time variability (P = 0.019) and shortening swing time (P = 0.015); smaller posterior nucleus portions predicted shortening step length (P = 0.007) and increasing step time variability (P = 0.041). Conclusions This is the first study to demonstrate that degeneration of the cortical cholinergic system predicts longitudinal progression of gait impairments in PD. Measures of this degeneration may therefore provide a novel biomarker for identifying future mobility loss and falls. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., March Infographic: Cholinergic Basal Forebrain Volumes Predict Gait Decline in Parkinson's Disease

Cholinergic deficits are a hallmark of Alzheimer’s disease (AD) and Lewy body dementia (LBD). The nucleus basalis of Meynert (NBM) provides the major source of cortical cholinergic input; studying its functional connectivity might, therefore, provide a tool for probing the cholinergic system and its degeneration in neurodegenerative diseases. Forty-six LBD patients, 29 AD patients, and 31 healthy age-matched controls underwent resting-state functional magnetic resonance imaging (fMRI). A seed-based analysis was applied with seeds in the left and right NBM to assess functional connectivity between the NBM and the rest of the brain. We found a shift from anticorrelation in controls to positive correlations in LBD between the right/left NBM and clusters in right/left occipital cortex. Our results indicate that there is an imbalance in functional connectivity between the NBM and primary visual areas in LBD, which provides new insights into alterations within a part of the corticopetal cholinergic system that go beyond structural changes.

Dementia is the fifth leading cause of death worldwide. The most common cause of dementia is Alzheimer’s disease (AD). This fully updated and revised chapter comprehensively reviews the latest evidence on diagnosis, assessment, investigations, clinical features, management, risk factors, prognosis, and future potential treatments for AD. Importantly, the chapter explores newer evidence that has changed the way AD is viewed as regards methods of assessment using various scales to determine diagnosis, as well as current and investigative methods of treating AD. Finally, it looks at the states of disease progression, potential disease-modifying drugs for Alzheimer’s disease, and possible therapeutic approaches to treatment and management.

Parkinson's disease (PD) is associated with cholinergic dysfunction, although the role of M1 and M4 receptors remains unclear.To investigate spatial covariance patterns of cholinergic muscarinic MSome 19 PD and 24 older adult controls underwentA cholinergic MCholinergic muscarinic M

Background Acute hospitalisation and delirium have individually been shown to adversely affect trajectories of cognitive decline but have not previously been considered together. This work aimed to explore the impact on cognition of hospital admission with and without delirium, compared to a control group with no hospital admissions. Methods The Delirium and Cognitive Impact in Dementia (DECIDE) study was nested within the Cognitive Function and Ageing Study II (CFAS II)–Newcastle cohort. CFAS II participants completed two baseline interviews, including the Mini-Mental State Examination (MMSE). During 2016, surviving participants from CFAS II–Newcastle were recruited to DECIDE on admission to hospital. Participants were reviewed daily to determine delirium status. During 2017, all DECIDE participants and age, sex and years of education matched controls without hospital admissions during 2016 were invited to repeat the CFAS II interview. Delirium was excluded in the control group using the Informant Assessment of Geriatric Delirium Scale (i-AGeD). Linear mixed effects modelling determined predictors of cognitive decline. Results During 2016, 82 of 205 (40%) DECIDE participants had at least one episode of delirium. At 1 year, 135 of 205 hospitalised participants completed an interview along with 100 controls. No controls experienced delirium (i-AGeD>4). Delirium was associated with a faster rate of cognitive decline compared to those without delirium (β = −2.2, P Conclusions These results suggest that delirium during hospitalisation rather than hospitalisation per se is a risk factor for future cognitive decline, emphasising the need for dementia prevention studies that focus on delirium intervention.

Changes in sleep behavior and sleep-related cortical activity have been reported in conditions associated with abnormal alpha-synuclein (α-syn) expression, in particular Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Notably, changes can occur in patients years before the onset of cognitive decline. Sleep-related network oscillations play a key role in memory function, but how abnormal α-syn impacts the generation of such activity is currently unclear. To determine whether early changes in sleep-related network activity could also be observed, prior to any previously reported cognitive dysfunction, we used mice that over-express human mutant α-syn (A30P). Recordings in vivo were performed under urethane anesthesia in the medial prefrontal cortex (mPFC) and CA1 region of the hippocampus in young male (2.5 – 4 months old) A30P and age-matched wild type (WT) mice. We found that the slow oscillation (SO) < 1 Hz frequency was significantly faster in both the mPFC and hippocampus in A30P mice, and Up-state-associated fast oscillations at beta (20 – 30 Hz) and gamma (30 – 80 Hz) frequencies were delayed relative to the onset of the Up-state. Spindle (8 – 15 Hz) activity in the mPFC was also altered in A30P mice, as spindles were shorter in duration and had reduced density compared to WT. These changes demonstrate that dysregulation of sleep-related oscillations occurs in young A30P mice long before the onset of cognitive dysfunction. Our data suggest that, as seen in patients, changes in sleep-related oscillations are an early consequence of abnormal α-syn aggregation in A30P mice.

BackgroundRecently published diagnostic criteria for mild cognitive impairment with Lewy bodies (MCI-LB) include five neuropsychiatric supportive features (non-visual hallucinations, systematised delusions, apathy, anxiety and depression). We have previously demonstrated that the presence of two or more of these symptoms differentiates MCI-LB from MCI due to Alzheimer's disease (MCI-AD) with a likelihood ratio >4. The aim of this study was to replicate the findings in an independent cohort.MethodsParticipants ⩾60 years old with MCI were recruited. Each participant had a detailed clinical, cognitive and imaging assessment including FP-CIT SPECT and cardiac MIBG. The presence of neuropsychiatric supportive symptoms was determined using the Neuropsychiatric Inventory (NPI). Participants were classified as MCI-AD, possible MCI-LB and probable MCI-LB based on current diagnostic criteria. Participants with possible MCI-LB were excluded from further analysis.ResultsProbable MCI-LB (n = 28) had higher NPI total and distress scores than MCI-AD (n = 30). In total, 59% of MCI-LB had two or more neuropsychiatric supportive symptoms compared with 9% of MCI-AD (likelihood ratio 6.5, p < 0.001). MCI-LB participants also had a significantly greater delayed recall and a lower Trails A:Trails B ratio than MCI-AD.ConclusionsMCI-LB is associated with significantly greater neuropsychiatric symptoms than MCI-AD. The presence of two or more neuropsychiatric supportive symptoms as defined by MCI-LB diagnostic criteria is highly specific and moderately sensitive for a diagnosis of MCI-LB. The cognitive profile of MCI-LB differs from MCI-AD, with greater executive and lesser memory impairment, but these differences are not sufficient to differentiate MCI-LB from MCI-AD.

Introduction During the current SARS-CoV-2 pandemic dementia has been identified as disproportionally common in adults aged over 65 who develop severe COVID-19.1 Observational data from the International Severe Acute Respiratory and Emerging Infections Consortium also confirms a high prevalence of dementia in older adults hospitalised with COVID-19.2 It is so far unclear whether there is any direct effect of dementia pathologies as dementia is a disease of old age, and thus likely to be associated with a variety of comorbidities, in particular, frailty, which may further exacerbate the risk of severe infection. In addition up to one third of COVID patients have demonstrated neurological sequelae3 and there may be both direct (viral infection within the brain, vascular effects) and indirect effects (e.g. host immunological response, impact of treatment) of SARS-CoV-2 on the brain.4 It is therefore possible that SARS-CoV-2 infection may accentuate any pre-existing neurodegenerative disease.

Despite improvements in diagnostic criteria for dementia with Lewy bodies (DLB), the ability to discriminate DLB from Alzheimer’s disease (AD) and other dementias remains suboptimal. Electroencephalography (EEG) is currently a supportive biomarker in the diagnosis of DLB. We performed a systematic review to better clarify the diagnostic and prognostic role of EEG in DLB and define the clinical correlates of various EEG features described in DLB. MEDLINE, EMBASE, and PsycINFO were searched using search strategies for relevant articles up to 6 August 2020. We included 43 studies comparing EEG in DLB with other diagnoses, 42 of them included a comparison of DLB with AD, 10 studies compared DLB with Parkinson’s disease dementia, and 6 studies compared DLB with other dementias. The studies were visual EEG assessment (6), quantitative EEG (35) and event-related potential studies (2). The most consistent observation was the slowing of the dominant EEG rhythm (

Neurons of the nucleus basalis of Meynert (nbM) are vulnerable to Lewy body formation and neuronal loss, which is thought to underlie cognitive dysfunction in Lewy body dementia (LBD). There is continued debate about whether Lewy bodies exert a neurodegenerative effect by affecting mitochondria, or whether they represent a protective mechanism. Therefore, the present study sought to determine whether the nbM is subject to mitochondrial dysfunctional in LBD and the association of Lewy body formation with such changes. Post-mortem nbM tissue was stained for Complex I or IV and quantitated relative to porin with immunofluorescence using confocal microscopy of individual cells from LBD (303 neurons, 8 cases), control (362 neurons, 8 cases) and asymptomatic incidental LBD (iLBD) cases (99 neurons, 2 cases). Additionally, α-synuclein, tau and amyloid-β pathology were analysed using quantitative immunohistochemistry, and respiratory chain markers were compared in cells with Lewy bodies (N = 134) and unaffected cells (N = 272). The expression of Complex I normalised to mitochondrial mass was significantly lower in LBD compared to control and iLBD cases and this was unrelated to local neuropathological burdens but trended toward a relationship with neuronal loss. Furthermore, Complex I expression was higher in cells with Lewy bodies compared to adjacent cells without α-synuclein aggregates. These findings suggest that Complex I deficits in the nbM occur in symptomatic LBD cases and may relate to neuronal loss, but that contrary to the view that Lewy body formation underlies neuronal dysfunction and damage in LBD, Lewy bodies are associated with higher Complex I expression than neurons without Lewy bodies. One could speculate that Lewy bodies may provide a mechanism to encapsulate damaged mitochondria and/or α-synuclein oligomers, thus protecting neurons from their cytotoxic effects.

Visual hallucinations (VH) are a common symptom of Parkinson’s disease with dementia (PDD), affecting up to 65% of cases. Integrative models of their etiology posit that a decline in executive control of the visuo-perceptual system is a primary mechanism of VH generation. The role of bottom-up processing in the manifestation of VH in this condition is still not clear. Here we compared amplitude and latency patterns of reversal visual evoked potentials (VEPs) in healthy controls (n=21) and PDD patients (n = 34) with a range of VH severities. PDD patients showed increased N2 latency relative to controls, but patients reporting complex VH (n=17) did not demonstrate any relationship between VEP measurements and their hallucination severity as measured on the neuropsychiatric inventory hallucinations subscale (NPIHal) score. Our VEP findings support previous reports of declining visual system physiology in PDD. However, no notable major relationships between the integrity of the visual pathway and VH were found.

Background Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series. Aims This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences. Method We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions. Results The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs. Conclusions Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.

BackgroundLewy 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.MethodsEyes-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.ResultsAlpha 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).ConclusionsWe 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.

Mild cognitive impairment (MCI) may gradually worsen to dementia, but often remains stable for extended periods of time. Little is known about the predictors of decline to help explain this variation. We aimed to explore whether this heterogeneous course of MCI may be predicted by the presence of Lewy body (LB) symptoms in a prospectively-recruited longitudinal cohort of MCI with Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD).A prospective cohort (n = 76) aged ⩾60 years underwent detailed assessment after recent MCI diagnosis, and were followed up annually with repeated neuropsychological testing and clinical review of cognitive status and LB symptoms. Latent class mixture modelling identified data-driven sub-groups with distinct trajectories of global cognitive function.Three distinct trajectories were identified in the full cohort: slow/stable progression (46%), intermediate progressive decline (41%) and a small group with a much faster decline (13%). The presence of LB symptomology, and visual hallucinations in particular, predicted decline v. a stable cognitive trajectory. With time zeroed on study end (death, dementia or withdrawal) where available (n = 39), the same subgroups were identified. Adjustment for baseline functioning obscured the presence of any latent classes, suggesting that baseline function is an important parameter in prospective decline.These results highlight some potential signals for impending decline in MCI; poorer baseline function and the presence of probable LB symptoms - particularly visual hallucinations. Identifying people with a rapid decline is important but our findings are preliminary given the modest cohort size.

Cholinergic dysfunction is central in dementia with Lewy bodies, possibly contributing to the cognitive and psychiatric phenotypes of this condition. We investigated baseline muscarinic M1/M4 receptor spatial covariance patterns in dementia with Lewy bodies and their association with changes in cognition and neuropsychiatric symptoms after 12 weeks of treatment with the cholinesterase inhibitor donepezil. Thirty-eight participants (14 cholinesterase inhibitor naive patients, 24 healthy older individuals) underwent 123I-iodo-quinuclidinyl-benzilate (M1/M4 receptor assessment) and 99mTc-exametazime (perfusion) single-photon emission computed tomography scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of inter-correlated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns associated with patients. A discreet M1/M4 pattern that distinguished patients from controls (W1,19.7 = 16.7, P = 0.001), showed relative decreased binding in right lateral temporal and insula, as well as relative preserved/increased binding in frontal, precuneus, lingual and cuneal regions, implicating nodes within attention and dorsal visual networks. We then derived from patients an M1/M4 pattern that correlated with a positive change in mini-mental state examination (r = 0.52, P = 0.05), showing relative preserved/increased uptake in prefrontal, temporal pole and anterior cingulate, elements of attention-related networks. We also generated from patients an M1/M4 pattern that correlated with a positive change in neuropsychiatric inventory score (r = 0.77, P = 0.002), revealing relative preserved/increased uptake within a bilateral temporal-precuneal-striatal system. Although in a small sample and therefore tentative, we posit that optimal response of donepezil on cognitive and neuropsychiatric signs in patients with dementia with Lewy bodies were associated with a maintenance of muscarinic M1/M4 receptor expression within attentional/executive and ventral visual network hubs, respectively., We investigated covariance patterns of muscarinic M1/M4 receptors in Lewy body dementia and their correlation with changes in cognition and neuropsychiatric signs after 12 weeks of donepezil treatment. Positive response in cognitive and neuropsychiatric symptoms could be associated with preserved/increased receptors within elements of attention/executive and ventral visual networks, respectively., Graphical Abstract

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer's disease (AD), despite a surge in recent validated evidence. This position paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity, reflecting thalamocortical and corticocortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies. (C) 2019 Elsevier Inc. All rights reserved.

Additional file 1. The Hybrid Imaging Training Needs Online Survey – description and results

Background After the success of PET/CT as a clinical diagnostic tool, the introduction of PET/MRI is a natural development aimed at further improving combined diagnostic imaging and reduced ionising radiation dose for half-body imaging. As with PET and CT, the combination of PET and MRI presents a series of issues that need to be addressed regarding workforce training and education. At present, there is a lack of agreement over the competencies, training requirements and educational pathways needed for PET/MRI operation. In the UK, following the establishment of the MR-PET imaging network, a task force was created to investigate the status of the workforce training, identify gaps and make recommendations regarding staff training. To do this, we ran a national survey on the status of the workforce training and the local practices across the UK’s seven PET/MRI sites, reviewed the literature, and convened a panel of experts, to assess all the evidence and make recommendations regarding PET/MRI competencies and training of nuclear medicine technologists and radiographers. Results There is limited literature available specifically on competencies and training for technologists and radiographers. The recommendations on the topic needed revisiting and adapting to the UK MR-PET network. The online survey confirmed the need for developing PET/MRI competencies and training pathways. Local organisational structures and practices were shared across the seven sites, based on models derived from experience outside the UK. The panel of experts agreed on the need for PET/MRI competencies and training strategies. Professional organisations started collaborative discussions with partners from both Nuclear Medicine and Radiography to set training priorities. Multidisciplinary collaboration and partnership were suggested as a key to a successful implementation of competencies and training. Conclusions The report identified the need for establishing competencies for the PET/MRI workforce, particularly for technologists and radiographers. It also helped defining these competencies as well as identifying the demand for bespoke training and the development of local and national courses to be implemented to fulfil this new training need.

Objective: Here we tested if cortical sources of resting state electroencephalographic (rsEEG) rhythms may differ in sub-groups of patients with prodromal and overt dementia with Lewy bodies (DLB) as a function of relevant clinical symptoms.Methods: We extracted clinical, demographic and rsEEG datasets in matched DLB patients (N = 60) and control Alzheimer's disease (AD, N = 60) and healthy elderly (Nold, N = 60) seniors from our international database. The eLORETA freeware was used to estimate cortical rsEEG sources.Results: As compared to the Nold group, the DLB and AD groups generally exhibited greater spatially distributed delta source activities (DLB > AD) and lower alpha source activities posteriorly (AD > DLB). As compared to the DLB ``controls", the DLB patients with (1) rapid eye movement (REM) sleep behavior disorders showed lower central alpha source activities (p < 0.005); (2) greater cognitive deficits exhibited higher parietal and central theta source activities as well as higher central, parietal, and occipital alpha source activities (p < 0.01); (3) visual hallucinations pointed to greater parietal delta source activities (p < 0.005).Conclusions: Relevant clinical features were associated with abnormalities in spatial and frequency features of rsEEG source activities in DLB patients.Significance: Those features may be used as neurophysiological surrogate endpoints of clinical symptoms in DLB patients in future cross-validation prospective studies. Ministry of Health, Italy; H2020 Marie S. Curie ITN-ETN project; H2020-TWINN-2015 project

Additional file 1: Supplementary Figure 1. ChAT expression is elevated in iLBD and porin is increased in iLBD and LBD. Supplementary Figure 2. Merged images of respiratory chain subunits demonstrate co-localisation of mitochondrial markers within ChAT-immunoreactive neurons. Supplementary Figure 3. Complex I and IV expression relative to porin in individual LBD cases are demonstrated relative to control and iLBD cases. Supplementary Figure 4. Data across individual LBD cases demonstrated highly variable patterns of deficiency across cases. Supplementary Figure 5. Scatterplot demonstrating the relationship between total number of ChAT+ neurons per case and percentage of cells with Complex I expression

A cerebrospinal fluid (CSF) Alzheimer’s disease (AD) profile, that is, decreased amyloid-β1-42 (Aβ42) and increased total tau protein (t-tau) and/or phosphorylated tau at threonine-181 (p-tau),1 has been identified in a substantial number of dementia with Lewy bodies (DLB) patients, and it has been related to a more rapid cognitive decline.1 We investigated the association between AD CSF biomarkers and DLB core clinical features to better understand in vivo how AD pathology influences DLB clinical presentation. We included 171 subjects with a clinical diagnosis of probable DLB2 3 from the European DLB consortium (E-DLB). The centres involved are summarised in online supplementary table 1. Clinical examination was performed as previously reported.1 Dopamine transporter (DAT) single-photon emission CT scans (123I-FP-CIT-SPECT) were performed in 80 patients.### Supplementary data [jnnp-2019-320980supp001.pdf] CSF samples were collected at each centre according to the procedures detailed in online supplementary table 1. An AD CSF profile was defined as low Aβ42 combined with high t-tau or p-tau.1 Information about pharmacological treatments of patients were not available at each centre. Statistical analyses were performed using SPSS V.24. Association between CSF biomarkers (normal or abnormal), and each core features (present or absent), were tested with χ2 test. Associations between single CSF biomarkers and groups of subjects with different core clinical features’ number (1–4) were tested with Armitage test for trend. Local ethics committees approved the study. All patients gave their written consent for the use of their …

Cholinergic dysfunction is central in dementia with Lewy bodies, possibly contributing to the cognitive and psychiatric phenotypes of this condition. We investigated baseline muscarinic M1/M4 receptor spatial covariance patterns in dementia with Lewy bodies and their association with changes in cognition and neuropsychiatric symptoms after 12 weeks of treatment with the cholinesterase inhibitor donepezil. Thirty-eight participants (14 cholinesterase inhibitor naive patients, 24 healthy older individuals) underwent 123I-iodo-quinuclidinyl-benzilate (M1/M4 receptor assessment) and 99mTc-exametazime (perfusion) single-photon emission computed tomography scanning. We implemented voxel principal components analysis, producing a series of images representing patterns of inter-correlated voxels across individuals. Linear regression analyses derived specific M1/M4 and perfusion spatial covariance patterns associated with patients. A discreet M1/M4 pattern that distinguished patients from controls (W1,19.7 = 16.7, P = 0.001), showed relative decreased binding in right lateral temporal and insula, as well as relative preserved/increased binding in frontal, precuneus, lingual and cuneal regions, implicating nodes within attention and dorsal visual networks. We then derived from patients an M1/M4 pattern that correlated with a positive change in mini-mental state examination (r = 0.52, P = 0.05), showing relative preserved/increased uptake in prefrontal, temporal pole and anterior cingulate, elements of attention-related networks. We also generated from patients an M1/M4 pattern that correlated with a positive change in neuropsychiatric inventory score (r = 0.77, P = 0.002), revealing relative preserved/increased uptake within a bilateral temporal-precuneal-striatal system. Although in a small sample and therefore tentative, we posit that optimal response of donepezil on cognitive and neuropsychiatric signs in patients with dementia with Lewy bodies were associated with a maintenance of muscarinic M1/M4 receptor expression within attentional/executive and ventral visual network hubs, respectively.

Hallucinations can occur in different sensory modalities within an individual, both simultaneously and serially in time. Historically, they have typically been studied in clinical populations as phenomena occurring in a single sensory modality. Yet, hallucinatory experiences that occur in two or more sensory systems - multimodal hallucinations (MMHs) - are more prevalent than previously thought, and may have greater adverse impact than unimodal ones, but they remain relatively under-researched. Why people experience multi- modal hallucinations, what the implications for the person are, and how this could impact how such experiences are treated when distressing remain under-studied questions. Here, we review the available literature on MMHs and discuss some key concepts in the field, namely a) the definition and categorisation of both serial and simultaneous MMHs, b) which assessment tools are available and how they can be improved, and c) the explanatory power that current hallucination theories might have for MMHs. Overall, we suggest that current models need to be updated or developed in order to account for MMHs and to inform research into the underlying processes of such hallucinatory phenomena. We make recommendations for future research and clinical practice, highlighting the potential clinical impact of MMHs, the need for better assessment tools that can reliably measure MMHs and distinguish them from other related phenomena (such as delirium), as well as the need for service-user involvement in the validation of classification systems of MMHs.

Compared with Alzheimer's disease (AD), Parkinson's disease (PD) shows peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations) that may be reflected in resting-state electroencephalographic rhythms. To test this hypothesis, clinical and resting-state electroencephalographic rhythms in age-, sex-, and education-matched PD patients (N = 136) and Alzheimer's disease patients (AD, N = 85), and healthy older participants (Nold, N = 65), were available from an international archive. Electroencephalographic sources were estimated by eLORETA software. The results are as follows: (1) compared to the Nold participants, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher posterior alpha sources activities. These results suggest that in PD patients resting in quiet wakefulness, abnormalities in cortical neural synchronization at alpha frequencies are differently related to cognitive, motor, and visual hallucinations. Interestingly, parallel PD neuropathological processes may have opposite effects on cortical neural synchronization mechanisms generating cortical alpha rhythms in quiet wakefulness. (C) 2020 Elsevier Inc. All rights reserved.

By 2050, it is estimated that 16% of people will be aged above 65 years, compared with 9% in 2019.1 Population aging is driving increased attention to the physical and mental health needs of older adults. Here, our focus is on hallucinations—given the wide range of health and aged-care service providers who encounter people with these experiences in their workplace. Hallucinations can be defined as “a perception-like experience with the clarity and impact of a true perception but without the external stimulation of the relevant sensory organ” 2 (cf. 3–5), though this belies the difficulty in discerning the boundaries between normal and abnormal perception.6 Hallucinations need to be distinguished from illusions, which are perceptual experiences in which an external stimulus is misperceived or misinterpreted.2 In practice, hallucinations vary in content (eg, perception of people, animals, or objects), character (eg, frequency, emotional valence, location), duration (from seconds to chronically present), complexity (eg, perception of simple stimuli vs organized scenes or objects), and quality (eg, perceived reality, intrusiveness) and occur in all sensory modalities. The terms used to refer to hallucinations are equally diverse publishedVersion

Additional file 1: Table S1. Group comparison of quantitative EEG characteristics, restricting the analysis to 21 electrodes from the 10-20 system. Table S2. Group comparison of quantitative EEG characteristics, splitting the set of electrodes into four macroscopic regions. Table S3. Association between Lewy body symptom severity and EEG characteristics in the MCI-LB group. Two-sample t-tests comparing EEG measures between MCI-LB patients with two symptoms/biomarkers (N=13) and MCI-LB patients with more than two symptoms/biomarkers (N=26) and Spearman’s correlations between EEG characteristics and symptom/biomarker count (ranging from 2 to 6). P-values are FDR-corrected for multiple comparisons. Table S4. Association between the severity of overall cognitive impairment (ACE-R scores) and EEG characteristics in the MCI-LB and MCI-AD groups using Spearman’s correlations. P-values are FDR-corrected for multiple comparisons.

Intracellular accumulation of alpha-synuclein (α-syn) is a key pathological process evident in Lewy body dementias (LBDs), including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD results in marked cognitive impairments and changes in cortical networks. To assess the impact of abnormal α-syn expression on cortical network oscillations relevant to cognitive function, we studied changes in fast beta/gamma network oscillations in the hippocampus in a mouse line that over-expresses human mutant α-syn (A30P). We found an age-dependent reduction in the power of the gamma (20–80 Hz) frequency oscillations in slices taken from mice aged 9–16 months (9+A30P), that was not present in either young 2–6 months old (2+A30P) mice, or in control mice at either age. The mitochondrial blockers potassium cyanide and rotenone both reduced network oscillations in a concentration-dependent manner in aged A30P mice and aged control mice but slices from A30P mice showed a greater reduction in the oscillations. Histochemical analysis showed an age-dependent reduction in cytochrome c oxidase (COX) activity, suggesting a mitochondrial dysfunction in the 9+A30P group. A deficit in COX IV expression was confirmed by immunohistochemistry. Overall, our data demonstrate an age-dependent impairment in mitochondrial function and gamma frequency activity associated with the abnormal expression of α-syn. These findings provide mechanistic insights into the consequences of over-expression of α-syn which might contribute to cognitive decline.

Background Dementia with Lewy bodies is characterized by transient clinical features, including fluctuating cognition and visual hallucinations, implicating dysfunction of cerebral hub regions, such as the pulvinar nuclei of the thalamus. However, the pulvinar is typically only mildly affected by Lewy body pathology in dementia with Lewy bodies, suggesting additional factors may account for its proposed dysfunction. Methods We conducted a comprehensive analysis of postmortem pulvinar tissue using whole-transcriptome RNA sequencing, protein expression analysis, and histological evaluation. Results We identified 321 transcripts as significantly different between dementia with Lewy bodies cases and neurologically normal controls, with gene ontology pathway analysis suggesting the enrichment of transcripts related to synapses and positive regulation of immune functioning. At the protein level, proteins related to synaptic efficiency were decreased, and general synaptic markers remained intact. Analysis of glial subpopulations revealed astrogliosis without activated microglia, which was associated with synaptic changes but not neurodegenerative pathology. Discussion These results indicate that the pulvinar, a region with relatively low Lewy body pathological burden, manifests changes at the molecular level that differ from previous reports in a more severely affected region. We speculate that these alterations result from neurodegenerative changes in regions connected to the pulvinar and likely contribute to a variety of cognitive changes resulting from decreased cortical synchrony in dementia with Lewy bodies. © 2018 International Parkinson and Movement Disorder Society.

Mild cognitive impairment has gained recognition as a construct and a potential prodromal stage to dementia in both Alzheimer's disease and Parkinson's disease (PD). Although mild cognitive impairment has been recognized in the Alzheimer's disease field, it is a relatively more recent topic of interest in PD. Recent advances include the development of diagnostic criteria for PD mild cognitive impairment to provide more uniform definitions for clinical and research use. Studies reveal that mild cognitive impairment in PD is frequent, but also heterogeneous, with variable clinical presentations, differences in its progression to dementia, and likely differences in underlying pathophysiology. Application of the International Parkinson and Movement Disorder Society PD Mild Cognitive Impairment Task Force diagnostic criteria has provided insights regarding cognitive measures, functional assessments, and other key topics that may require additional refinement. Furthermore, it is important to consider definitions of PD mild cognitive impairment in the landscape of other related Lewy body disorders, such as dementia with Lewy bodies, and in the context of prodromal and early-stage PD. This article examines the evolution of mild cognitive impairment in concept and definition, particularly in PD, but also in related disorders such as Alzheimer's disease and dementia with Lewy bodies; the development and application of International Parkinson and Movement Disorder Society PD Mild Cognitive Impairment diagnostic criteria; and insights and future directions for the field of PD mild cognitive impairment. © 2018 International Parkinson and Movement Disorder Society.

BACKGROUND: The prevalence of dementia with Lewy bodies (DLB) and dementia in Parkinson's disease (PDD) in routine clinical practice is unclear. Prevalence rates observed in clinical and population-based cohorts and neuropathological studies vary greatly. Small sample sizes and methodological factors in these studies limit generalisability to clinical practice.METHODS: We investigated prevalence in a case series across nine secondary care services over an 18-month period, to determine how commonly DLB and PDD cases are diagnosed and reviewed within two regions of the UK.RESULTS: Patients with DLB comprised 4.6% (95% CI 4.0-5.2%) of all dementia cases. DLB was represented in a significantly higher proportion of dementia cases in services in the North East (5.6%) than those in East Anglia (3.3%; χ2 = 13.6, p < 0.01). DLB prevalence in individual services ranged from 2.4 to 5.9%. PDD comprised 9.7% (95% CI 8.3-11.1%) of Parkinson's disease cases. No significant variation in PDD prevalence was observed between regions or between services.CONCLUSIONS: We found that the frequency of clinical diagnosis of DLB varied between geographical regions in the UK, and that the prevalence of both DLB and PDD was much lower than would be expected in this case series, suggesting considerable under-diagnosis of both disorders. The significant variation in DLB diagnostic rates between these two regions may reflect true differences in disease prevalence, but more likely differences in diagnostic practice. The systematic introduction of more standardised diagnostic practice could improve the rates of diagnosis of both conditions.

BackgroundThe accurate clinical characterisation of mild cognitive impairment (MCI) is becoming increasingly important. The aim of this study was to compare the neuropsychiatric symptoms and cognitive profile of MCI with Lewy bodies (MCI-LB) with Alzheimer's disease MCI (MCI-AD).MethodsParticipants were ⩾60 years old with MCI. Each had a thorough clinical and neuropsychological assessment and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single photon emission computed tomography FP-CIT SPECT). MCI-LB was diagnosed if two or more diagnostic features of dementia with Lewy bodies were present (visual hallucinations, cognitive fluctuations, motor parkinsonism, rapid eye movement sleep behaviour disorder or positive FP-CIT SPECT). A Lewy body Neuropsychiatric Supportive Symptom Count (LBNSSC) was calculated based on the presence or absence of the supportive neuropsychiatric symptoms defined by the 2017 DLB diagnostic criteria: non-visual hallucinations, delusions, anxiety, depression and apathy.ResultsMCI-LB (n = 41) had a higher LBNSSC than MCI-AD (n = 24; 1.8 ± 1.1 v. 0.7 ± 0.9, p = 0.001). 67% of MCI-LB had two or more of those symptoms, compared with 16% of MCI-AD (Likelihood ratio = 4.2, p < 0.001). MCI-LB subjects scored lower on tests of attention, visuospatial function and verbal fluency. However, cognitive test scores alone did not accurately differentiate MCI-LB from MCI-AD.ConclusionsMCI-LB is associated with neuropsychiatric symptoms and a cognitive profile similar to established DLB. This supports the concept of identifying MCI-LB based on the presence of core diagnostic features of DLB and abnormal FP-CIT SPECT imaging. The presence of supportive neuropsychiatric clinical features identified in the 2017 DLB diagnostic criteria was helpful in differentiating between MCI-LB and MCI-AD.

We present evidence that Willy Loman, the protagonist of Arthur Miller's play "Death of a Salesman", meets current diagnostic criteria for probable dementia with Lewy bodies. In particular, he presents with attentional deficits and executive dysfunction (with additional subtle visuoperceptual deficits) in addition to dramatic fluctuations in attention and vivid visual hallucinations. Dementia with Lewy bodies is the second most common neurodegenerative dementia. However, it is frequently misdiagnosed or underdiagnosed, even-we contest-in one of the most well-known characters in modern literature.

Aims and methodThis work builds on a survey first done in 1999 to understand how old age psychiatry teaching is embedded in undergraduate medical schools in the UK and Ireland and the influence of academic old age psychiatrists on teaching processes. We invited deans of 31 medical schools in the UK and Ireland in 2015 to complete an online survey to reassess the situation 16 years later.ResultsResponse rate was 74%. As found in the original survey, there was variation across medical schools in how old age psychiatry is taught. Half of schools stated there was not enough space in the curriculum dedicated to old age psychiatry, and not all medical school curricula offered a clinical attachment. Medical schools that involved academic old age psychiatrists in teaching (59%) showed a greater diversity of teaching methods.Clinical implicationsThere is a need to recognise the importance of old age psychiatry teaching, with the consensus of opinion continuing to be that more curriculum space needs to be given to old age psychiatry. To achieve this we advocate increasing the number of old age psychiatrists with teaching roles, as relying on academics to teach and lead on curriculum development is challenging given their greater research pressures.

The research was supported by the Alzheimer’s Society (Grant Number: AS-PG-2013-011). Tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074) and by Brains for Dementia research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. Cerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer’s disease (AD) pathology, i.e. hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) deposition. WML seen in AD have a posterior predominance compared to non-demented individuals but it is unclear whether the pathological and molecular signatures of WML differ between these two groups. We investigated differences in the composition and aetiology of parietal WML from AD and non-demented controls. Parietal WML tissue from 55 human post-mortem brains (AD, n = 27; non-demented controls, n = 28) were quantitatively assessed for axonal loss and demyelination, as well as for cortical HPτ and Aβ burden and SVD. Biochemical assessment included Wallerian degeneration protease calpain and the myelin-associated glycoprotein (MAG) to proteolipid protein (PLP) ratio (MAG:PLP) as a measure of hypoperfusion. WML severity was associated with both axonal loss and demyelination in AD, but only with demyelination in controls. Calpain was significantly increased in WML tissue in AD, whereas MAG:PLP was significantly reduced in controls. Calpain levels were associated with increasing amounts of cortical AD-pathology but not SVD. We conclude that parietal WML seen in AD differ in their pathological composition and aetiology compared to WML seen in aged controls: WML seen in AD may be associated with Wallerian degeneration that is triggered by cortical AD-pathology, whereas WML in aged controls are due to ischaemia. Hence, parietal WML as seen on MRI should not invariably be interpreted as a surrogate biomarker for SVD as they may be indicative of cortical AD-pathology, and therefore, AD should also be considered as the main underlying cause for cognitive impairment in cases with parietal WML. Publisher PDF

Marco Onofrj,1,2 Danilo Carrozzino,3,4 Aurelio D’Amico,1,2 Roberta Di Giacomo,1,2 Stefano Delli Pizzi,1 Astrid Thomas,1,2 Valeria Onofrj,5 John-Paul Taylor,6 Laura Bonanni1,2 1Department of Neuroscience Imaging and Clinical Sciences, University “G. d’Annunzio” of Chieti-Pescara, 2CE.S.I. University Foundation, 3Department of Psychological, Health, and Territorial Sciences, University “G.d’Annunzio” of Chieti-Pescara, Chieti, Italy; 4Psychiatric Research Unit, Psychiatric Centre North Zealand, Copenhagen University Hospital, Hillerød, Denmark; 5Department of Bioimaging, University Cattolica del Sacro Cuore, Rome, Italy; 6Institute of Neuroscience, Campus for Ageing and Vitality Newcastle University Newcastle upon Tyne, Newcastle upon Tyne, UK Abstract: Psychosis in Parkinson’s disease (PD) is currently considered as the occurrence of hallucinations and delusions. The historical meaning of the term psychosis was, however, broader, encompassing a disorganization of both consciousness and personality, including behavior abnormalities, such as impulsive overactivity and catatonia, in complete definitionsby the International Classification of Diseases-10 (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Our review is aimed at reminding that complex psychotic symptoms, including impulsive overactivity and somatoform disorders (thelast being a recent controversial entity in PD), were carefully described in postencephalitic parkinsonism (PEP), many decades before dopaminergic treatment era, and are now described in other parkinsonisms than PD. Eminent neuropsychiatrists of the past century speculated that studying psychosis in PEP might highlight its mechanisms in other conditions. Yet, functional assessments were unavailable at the time. Therefore, the second part of our article reviews the studies of neural correlates of psychosis in parkinsonisms, by taking into account both theories on the narrative functions of the default mode network (DMN) and hypotheses on DMN modulation. Keywords: postencephalitic parkinsonism, Parkinson’s disease, psychosis, default mode network, atypical parkinsonism

Mild cognitive impairment (MCI) is prevalent in 15%–40% of Parkinson's disease (PD) patients at diagnosis. In this investigation, we study brain intra- and inter-network alterations in resting state functional magnetic resonance imaging (rs-fMRI) in recently diagnosed PD patients and characterise them as either cognitive normal (PD-NC) or with MCI (PD-MCI). Patients were divided into two groups, PD-NC (N = 62) and PD-MCI (N = 37) and for comparison, healthy controls (HC, N = 30) were also included. Intra- and inter-network connectivity were investigated from participants’ rs-fMRIs in 26 resting state networks (RSNs). Intra-network differences were found between both patient groups and HCs for networks associated with motor control (motor cortex), spatial attention and visual perception. When comparing both PD-NC and PD-MCI, intra-network alterations were found in RSNs related to attention, executive function and motor control (cerebellum). The inter-network analysis revealed a hyper-synchronisation between the basal ganglia network and the motor cortex in PD-NC compared with HCs. When both patient groups were compared, intra-network alterations in RSNs related to attention, motor control, visual perception and executive function were found. We also detected disease-driven negative synchronisations and synchronisation shifts from positive to negative and vice versa in both patient groups compared with HCs. The hyper-synchronisation between basal ganglia and motor cortical RSNs in PD and its synchronisation shift from negative to positive compared with HCs, suggest a compensatory response to basal dysfunction and altered basal-cortical motor control in the resting state brain of PD patients. Hum Brain Mapp 38:1702–1715, 2017. © 2016 Wiley Periodicals, Inc.

Objective The Lewy body dementias (LBD, dementia with Lewy bodies and Parkinson's disease dementia) are the second most common cause of neurodegenerative dementia but remain under-recognised, with long delays from initial assessment to diagnosis. Whilst validated instruments have been developed for key symptoms, there is no brief instrument for overall diagnostic assessment suitable for routine practice. We here report the development of such assessment toolkits. Methods We developed the LBD assessment toolkits in three stages. First, we conducted a systematic search for brief validated assessments for key symptoms and combined these into draft instruments. Second, we obtained feedback on acceptability and feasibility through two rounds of interviews with our patient and public involvement group. This led to modification of the toolkits. Finally, we piloted the toolkits in a feasibility study in routine dementia and Parkinson's disease services to produce final instruments suitable for routine clinical practice. Results Eleven clinicians, working in both dementia/memory assessment and Parkinson's disease/movement disorder services, consented to pilot the assessment toolkits and provide feedback on their feasibility. Clinicians worked in routine health service (not academic) settings and piloted the draft toolkits by integrating them into their regular clinical assessments. Feedback obtained informally, by written comments and through qualitative interviews led to modifications and production of final acceptable versions. Conclusions We were able to address an important need, the under-diagnosis of LBD, by developing toolkits for improving the recognition and diagnosis of the LBD, which were acceptable to clinicians working in routine dementia and Parkinson's disease services. Copyright © 2016 John Wiley & Sons, Ltd.

Background Dementia with Lewy bodies (DLB) is the second most common form of dementia. Current symptomatic treatment with medications remains inadequate. Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a potential new treatment option in dementias. Objective To assess the safety and tolerability of low frequency (20 Hz) NBM DBS in DLB patients and explore its potential effects on both clinical symptoms and functional connectivity in underlying cognitive networks. Methods We conducted an exploratory randomised, double-blind, crossover trial of NBM DBS in six DLB patients recruited from two UK neuroscience centres. Patients were aged between 50 and 80 years, had mild-moderate dementia symptoms and were living with a carer-informant. Patients underwent image guided stereotactic implantation of bilateral DBS electrodes with the deepest contacts positioned in the Ch4i subsector of NBM. Patients were subsequently assigned to receive either active or sham stimulation for six weeks, followed by a two week washout period, then the opposite condition for six weeks. Safety and tolerability of both the surgery and stimulation were systematically evaluated throughout. Exploratory outcomes included the difference in scores on standardised measurements of cognitive, psychiatric and motor symptoms between the active and sham stimulation conditions, as well as differences in functional connectivity in discrete cognitive networks on resting state fMRI. Results Surgery and stimulation were well tolerated by all six patients (five male, mean age 71.33 years). One serious adverse event occurred: one patient developed antibiotic-associated colitis, prolonging his hospital stay by two weeks. No consistent improvements were observed in exploratory clinical outcome measures, but the severity of neuropsychiatric symptoms reduced with NBM DBS in 3/5 patients. Active stimulation was associated with functional connectivity changes in both the default mode network and the frontoparietal network. Conclusion Low frequency NBM DBS can be safely conducted in DLB patients. This should encourage further exploration of the possible effects of stimulation on neuropsychiatric symptoms and corresponding changes in functional connectivity in cognitive networks. Trial registration number NCT02263937.

Electroencephalography (EEG) slowing with prealpha dominant frequency (DF) in posterior derivations is a biomarker for dementia with Lewy bodies (DLB) diagnosis, in contrast with Alzheimer's disease (AD). However, an intrasubject re-evaluation of the original data, which contributed to the identification of EEG DLB biomarker, showed that DF was slower in anterior than posterior derivations. We suppose this anterior-posterior gradient of DF slowing could arise in DLB from a thalamocortical dysrhythmia, differently involving the anterior and posterior cortical areas, and correlating with cognitive impairment (Mini-Mental State Examination). EEG was recorded in 144 DLB, 116 AD, and 65 controls from 7 Centers of the European DLB Consortium. Spectra were divided into delta, theta, prealpha, alpha frequency bands. In DLB, mean DF was prealpha both anteriorly and posteriorly, but lower anteriorly (p < 0.001). In 14% of DLB, DF was prealpha anteriorly, whereas alpha posteriorly. In AD and controls, DF was constantly alpha. EEG slowing in DLB correlated with cognitive impairment. Thalamocortical dysrhythmia gives rise to prealpha rhythm with an anterior-posterior gradient and correlates with impaired cognition.

Introduction Lewy body disease is postulated, by the Braak model, to originate in the enteric nervous system, before spreading to the central nervous system. Therefore, a high prevalence of gastroparesis symptoms would be expected in prodromal dementia with Lewy bodies (DLB) and be highest in those with a dopaminergic deficit on imaging. The aim of this study was to explore whether gastroparesis symptoms are an early diagnostic marker of prodromal DLB and explore the relationship between symptoms and dopaminergic imaging findings on FP-CIT SPECT. Methods We recruited 75 patients over 60 with mild cognitive impairment (MCI), 48 with MCI with suspected Lewy body disease (MCI-LB) and 27 with MCI with suspected Alzheimer's disease (MCI-AD). All patients completed the Gastroparesis Cardinal Symptom Index (GSCI) questionnaire and also underwent FP-CIT [123 I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)] dopaminergic imaging. Results At least one symptom suggestive of gastroparesis was reported in 48% (n = 23) MCI-LB vs 37% MCI-AD (n = 10) (P = 0.36). Rates of definite symptoms of gastroparesis, as defined by a GCSI total score ≥ 1.90, were rare and rates in MCI-LB were not different from MCI-AD (6% vs 0%, p = 0.55). After adjusting for gender differences between groups, no difference in gastroparesis symptom prevalence (2.27 vs 0.81 P = 0.05) or severity score (0.62 vs 0.28, p = 0.28) was noted between normally and abnormally visually rated FP-CIT SPECT scans. Conclusion The GCSI is not a useful tool for differentiating MCI-LB from MCI-AD. A low rate of definite gastroparesis was detected in prodromal DLB. No association was found between gastroparesis symptoms and FP-CIT SPECT findings.

Cholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic therapies. However, such drugs have focused on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests that targeted cholinergic therapeutics to the muscarinic receptor subtypes will be vital in treating several disorders associated with cognitive dysfunction and behavioural and psychological symptoms.

Background: Primary Sjogren’s syndrome (pSS) sufferers have rated physical and mental fatigue (’brain fog’) as the most important symptoms needing improvement. Previous data from our group suggest that stimulation of the vagus nerve can invoke immunological responses and concurrently an improvement of patient reported symptoms of fatigue1. Objectives: This follow up study uses the gammaCore device (electroCore) and a sham device to assess the effects of non-invasive vagus nerve stimulation (nVNS) on patient reported symptoms of fatigue in pSS. In addition, neurocognitive tests were used to assess the effect of nVNS on short term memory, executive function and attention. Methods: 40 pSS participants were assigned to use active (n = 20) or sham (n = 20) nVNS devices. Participants and research staff were blinded to the active/sham device assignment. The participants were instructed to use the device twice daily for a study period of 56 days. The following patient reported measures of fatigue and neuropsychological tests were collected at baseline and day 56; Profile of Fatigue (PRO-F, Physical and Mental), visual analogue scale (VAS) of abnormal fatigue, trail making, Digit Symbol Substitution Test (DSST), Stroop test and digit span. 7 subjects were excluded from the analysis due to withdrawal from the study. Changes in fatigue and test scores from baseline to day 56 were compared between devices using t-tests. Results: Physical fatigue was significantly reduced between baseline and day 56 in the active group but not the placebo group (p = 0.047) The mean reduction in physical fatigue was 30% and 6% for the active and sham arms respectively (Figure 1). In both the active and sham subject groups there were no significant changes in the patient reported mental fatigue or neuropsychological test scores. Conclusion: This sham controlled scientific study of vagus nerve stimulation in pSS suggests nVNS may improve patient reported symptoms of physical fatigue, which is consistent with our published data. There were no improvements in the neurosychological test scores which is consistent with no improvements in patient reported mental fatigue. nVNS has been shown to activate the anti-inflammatory reflex, therefore assessment of peripheral inflammatory markers may help our understanding of nVNS, inflammation and fatigue. Reference [1] Tarn, J., Legg, S., Mitchell, S., Simon, B. & Ng, W.-F. The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue and Immune Responses in Patients With Primary Sjogren’s Syndrome. Neuromodulation49, 844 (2018). Disclosure of Interests: Jessica Tarn: None declared, Victoria Macrae: None declared, Sheryl Mitchell: None declared, Bruce Simon Shareholder of: Bruce Simon is an employee and shareholder of electroCore., Peter Gallagher: None declared, John-Paul Taylor: None declared, Stuart Watson: None declared, Mark Baker: None declared, Stephen Rushton: None declared, Andrew Blamire: None declared, Julia Newton: None declared, Wan Fai Ng: None declared

The diagnosis of dementia with Lewy bodies (DLB) versus Alzheimer's disease (AD) can be difficult especially early in the disease process. However, one inexpensive and non‐invasive biomarker which could help is electroencephalography (EEG). Previous studies have shown that the brain network architecture assessed by EEG is altered in AD patients compared with age‐matched healthy control people (HC). However, similar studies in Lewy body diseases, that is, DLB and Parkinson's disease dementia (PDD) are still lacking. In this work, we (a) compared brain network connectivity patterns across conditions, AD, DLB and PDD, in order to infer EEG network biomarkers that differentiate between these conditions, and (b) tested whether opting for weighted matrices led to more reliable results by better preserving the topology of the network. Our results indicate that dementia groups present with reduced connectivity in the EEG α band, whereas DLB shows weaker posterior–anterior patterns within the β‐band and greater network segregation within the θ‐band compared with AD. Weighted network measures were more consistent across global thresholding levels, and the network properties reflected reduction in connectivity strength in the dementia groups. In conclusion, β‐ and θ‐band network measures may be suitable as biomarkers for discriminating DLB from AD, whereas the α‐band network is similarly affected in DLB and PDD compared with HC. These variations may reflect the impairment of attentional networks in Parkinsonian diseases such as DLB and PDD.

We studied the dynamic functional connectivity profile of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) compared to controls, how it differs between the two dementia subtypes, and a possible relation between dynamic connectivity alterations and temporally transient clinical symptoms in DLB.Resting state fMRI data from 31 DLB, 29 AD, and 31 healthy control participants were analyzed using dual regression to determine between-network functional connectivity. Subsequently, we used a sliding window approach followed by k-means clustering and dynamic network analyses to study dynamic functional connectivity. Dynamic connectivity measures that showed significant group differences were tested for correlations with clinical symptom severity.Our results show that AD and DLB patients spent more time than controls in sparse connectivity configurations with absence of strong positive and negative connections and a relative isolation of motor networks from other networks. Additionally, DLB patients spent less time in a more strongly connected state and the variability of global brain network efficiency was reduced in DLB compared to controls. There were no significant correlations between dynamic connectivity measures and clinical symptom severity.An inability to switch out of states of low inter-network connectivity into more highly and specifically connected network configurations might be related to the presence of dementia in general as it was observed in both AD and DLB. In contrast, the loss of global efficiency variability in DLB might indicate the presence of an abnormally rigid brain network and the lack of economical dynamics, factors which could contribute to cognitive slowing and an inability to respond appropriately to situational demands. Keywords: Resting state fMRI, Dual regression, Sliding window, Dynamic network analysis, Neurodegeneration, Cognitive fluctuations