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Neuropsychiatric symptoms (NPS) are common in Lewy body disease (LBD), but their etiology is poorly understood.In a population-based post mortem study neuropathological data was collected for Lewy body (LB) neuropathology, neurofibrillary tangles (NFT), amyloid beta burden, TDP-43, lacunar infarcts, cerebral amyloid angiopathy (CAA), and hyaline atherosclerosis. Post mortem interviews collected systematic information regarding NPS and cognitive status. A total of 1038 cases were included: no pathology (NP; n = 761), Alzheimer's disease (AD; n = 189), LBD (n = 60), and AD+LBD (n = 28).Hallucinations were associated with higher LB Braak stages, while higher NFT Braak staging was associated with depression, agitation, and greater number of symptoms in the Neuropsychiatric Inventory. Cases with dual AD+LBD pathology had the highest risk of hallucinations, agitation, apathy, and total symptoms but a multiplicative interaction between these pathologies was not significant.LB and AD pathology contribute differentially to NPS likely with an additive process contributing to the increased burden of NPS.

Background: Neuropsychiatric symptoms are common and important to people with Parkinson’s disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively, which have yet to be explored in association with the affective and psychotic symptoms in PD. Objective: To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD. Methods: We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n = 63) were assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using the Non-Motor Symptom Scale and affective symptoms were measured in the Hospital Anxiety and Depression Scale. Results: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40–47.4], p = 0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms. Conclusion: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD.

Importance Cognitive and visual impairments in Parkinson’s Disease Psychosis (PDP) raise the question of whether a specific profile of impaired cognition and visual function is linked to vulnerability to visual hallucinations (VHs). Previous studies have limited sample sizes and only included a sub-sample of tests. This is the first meta-analysis quantifying visuo-cognitive impairments in PDP patients across a spectrum of tests and taking into account potential confounding factors such as levodopa medication, illness duration and general cognitive ability. Objective Compare visual processing and cognitive performance between PD patients with and without VHs (PDVH and PDnoVH). Methods Four databases (PubMed, PsychINFO, Scopus, WebOfScience) were searched for studies on visual and/or cognitive performance of PDnoVH and PDVH published up to 02/2020. For each task, means and SDs were extracted and standardized-mean-differences (SMDs) between-groups calculated. Effect-sizes (Hedges’ g) were calculated for all comparisons and synthesized in random-effects meta-analyses with robust-variance-estimation (accounting for multiple correlated measures within each study per cognitive/visual domain). Publication bias was assessed with funnel plots and Egger intercept. Results N=99 studies including 2508 PDVH patients (mean age 68.4 years) and 5318 PDnoVH (mean age 66.4 years) were included in the seven meta-analyses. PDVH patients performed worse than PDnoVH across all measures of cognition and visual processing, with the greatest between-group effect-sizes in executive functions, attention, episodic memory and visual processing. Study characteristics were not significantly associated with between-group differences in the domains investigated. Age-differences were significantly associated with performance differences in general cognition, working memory and executive functions. Conclusion Models of PDVH need to incorporate a wider range of cognitive and processing domains than currently included. There is a need for studies disentangling the temporal relationship between cognitive/visual deficits and VHs as early identification of risk before the onset of VHs could mitigate later outcomes such as progression to dementia.

Neural underpinnings of Parkinson’s Disease psychosis (PDP) remain unclear to this day with relatively few studies and reviews available. Using a systematic review approach, here we aimed to qualitatively synthesize evidence from studies investigating PD psychosis-specific alterations in brain structure, function or chemistry using different neuroimaging modalities. PubMed, Web of Science and Embase databases were searched for fMRI, rsfMRI, DTI, PET, and SPECT studies comparing PDP patients with PD patients without psychosis (PDnP). We report findings from 18 studies (291 PDP patients, mean age ± SD = 68.65 ± 3.76 years; 48.5% males; 433 PDnP patients, mean age ± SD = 66.97 ± 3.80 years; 52% males). Qualitative synthesis revealed widespread patterns of altered brain function across task-based and resting-state fMRI studies in PDP compared to PDnP patients. Similarly, white matter abnormalities were reported in parietal, temporal, and occipital regions. Hypometabolism and reduced dopamine transporter binding were also reported whole brain and in subcortical areas. This suggests extensive alterations affecting regions involved in high order visual processing and attentional networks.

BackgroundCognitive and executive deficits lead to worsening of quality of life and are a risk factor for developing dementia in Parkinson’s Disease (PD) patients with psychosis. However, which key cognitive domains are differentially affected in PD patients with psychosis (PDP) compared to those without (PDnP), remains unclear. Here we examined this using a Bayesian meta-analytic approach.MethodsSearches were conducted on PubMed, Web of Science, SCOPUS, Medline and PsycINFO. Hedges’ g effect-size estimates were extracted from eligible studies as a measure of standard mean differences between PDP and PDnP patients. Meta-analyses were conducted separately for each cognitive domain and sub-domain, we examined the effect of age, PD medications, PD duration and severity, depression and psychosis severity for all major domains with meta-regressions.ResultsEffect-size estimates suggest worse performance on all major domains (k=105 studies) in PDP compared to PDnP patients, with global cognition (k=103 studies,g=-0.57), processing speed (k=29 studies,g=-0.58), executive functions (k=33,g=-0.56), episodic memory (k=30 studies,g=-0.58), and perception (k=34 studies,g=-0.55) as the most likely affected domains. Age, depression, and PD duration had moderating effects on task-related performance across most of the major nine domains.ConclusionsWe report extensive deficits across nine domains as well as sub-domains in PD psychosis, with global cognition, processing speed and executive functions as the most likely impaired. Presence of depression may influence task-related performance in PDP, alongside age and PD duration, but not dose of dopamine replacement treatments.

Our recent neuroimaging study identified structural differences in cerebellar subfields linked to cortical attentional networks in patients with eye disease or Parkinson’s disease who experience visual hallucinations and a commentary on the study by Zorzi et al. provided additional evidence of functional cerebellar changes in Dementia with Lewy bodies. Here, we review evidence for cerebellar involvement in hallucinations across multiple clinical conditions and sensory modalities as well as examine its wider clinical and mechanistic implications. The combined structural and functional evidence is consistent with two models of cerebellar contribution to hallucination which differ in their implied direction of cause, effect and temporal sequence. Additionally, we contend that the relatively neuroanatomically localised nature of the cerebellum makes it particularly suited to identifying changes affecting distributed cortical networks using imaging techniques. As such, cerebellar subfield differences may offer value as candidate prognostic and predictive biomarkers as well as targets for neuromodulatory treatment across a range of clinical conditions.

BackgroundCommon neural underpinning of Parkinson’s Disease (PD) psychosis across different structural magnetic resonance imaging (MRI) studies remains unclear to this day with few studies and even fewer meta-analyses available.ObjectivesOur meta-analysis aimed to identify and summarise studies using MRI approach to identify PD psychosis-specific brain regions and examine the relation between cortical volume loss and dopaminergic and serotonergic receptor density.MethodsPubMed, Web of Science and Embase were searched for MRI studies of PD psychosis (PDP) compared to PD patients without psychosis (PDnP). Seed-baseddMapping with Permutation of Subject Images was applied in the meta-analysis where coordinates were available. Multiple linear regressions to examine the relationship between grey matter volume loss in PDP and receptor gene expression density (extracted from the Allen Human Brain Atlas) were conducted in R.ResultsWe observed lower grey matter volume in parietal-temporo-occipital regions from our meta-analysis (N studies =10, PDP n=211, PDnP, n=298). These results remained significant after adjusting for PD medications and for cognitive scores. Grey matter volume loss in PDP was associated with local expression of 5-HT1a (b=0.109,p=0.012) and 5-HT2a receptors (b=-0.106,p=0.002) also after adjusting for PD medications (5-HT1a,p= 0.005; 5-HT2a,p= 0.001).ConclusionsWidespread cortical volume loss in the parieto-temporo-occipital regions involved in information processing and integration, as well as attention, could result in PD psychosis symptoms. Neurobiological mechanisms implicating serotonergic receptors may also contribute to this condition.

ObjectivesWe aimed to investigate changes in regional cerebral blood flow (rCBF) using arterial spin labelling (ASL) in patients with visual snow syndrome (VSS), in order to understand more about the underlying neurobiology of the condition, which remains mostly unknown.MethodsWe performed an MRI study in which whole-brain maps of rCBF were obtained using pseudo-continuous ASL. Twenty-four patients with VSS and an equal number of gender and age-matched healthy volunteers took part in the study. All subjects were examined with both a visual paradigm consisting of a visual-snow like stimulus, simulating key features of the snow, and a blank screen at rest, randomly presented.ResultsPatients with VSS had higher rCBF than controls over an extensive brain network, including the bilateral cuneus, precuneus, supplementary motor cortex, premotor cortex and posterior cingulate cortex, as well as the left primary auditory cortex, fusiform gyrus and cerebellum. These areas were largely analogous comparing patients either at rest, or when looking at a ‘snow-like’ visual stimulus. This widespread, similar pattern of perfusion differences in either condition suggests a neurophysiological signature of visual snow. Furthermore, right insula rCBF was increased in VSS subjects compared with controls during visual stimulation, reflecting a greater task-related change and suggesting a difference in interoceptive processing with constant perception of altered visual input.ConclusionThe data suggest VSS patients have marked differences in brain processing of visual stimuli, validating its neurobiological basis.

BackgroundVisual hallucinations are often considered by clinicians to be suggestive of a secondary cause of psychosis, however, this association has never been assessed meta-analytically. We aimed to compare the presence of visual hallucinations in patients with psychosis due to a primary or secondary cause.MethodA meta-analysis of case-control studies directly comparing primary and secondary psychosis was conducted. PubMed, OVID, MEDLINE, Embase, PsychINFO and Global Health databases were searched without date restrictions. Two researchers performed the search independently. The inclusion criteria were studies that reported the frequency of visual hallucinations in patients with primary and secondary psychosis and were published in English. A random-effects model, following the DerSimonian and Laird method, was used to pool studies and generate overall odds ratios (OR) and 95% confidence intervals (CI).ResultsFourteen studies (904 primary and 804 secondary psychosis patients) were included. Visual hallucinations were significantly associated with secondary psychosis (OR = 3.0, 95% CI = 1.7-5.1, p2=70%). Subgroup analysis by type of secondary psychosis (organic, drug-induced, mixed) was non-significant. Analysis of the content of visual hallucinations (51 primary and 142 secondary psychosis patients) found hallucinations of inanimate objects more likely to be associated with secondary psychosis (OR = 0.1, 95% CI = 0.01-0.8, p=0.03).ConclusionsVisual hallucinations were found to be strongly associated with a secondary cause of psychosis. The presence of visual hallucinations in a patient presenting with psychosis may serve as a potential ‘red flag’ for a secondary cause and warrant further investigation.Key messagesWhat is already knownPsychotic symptoms may arise due to either an idiopathic primary (‘non-organic’) disorder or a secondary cause, such as an underlying medical (‘organic’) disorder. Whilst it is widely accepted amongst clinicians that visual hallucinations are associated with a secondary psychosis, this has never been established meta analytically.What this study addsPatients with a secondary cause of psychosis are approximately three times more likely to experience visual hallucinations than patients with a primary psychiatric disorder. The content of visual hallucinations in patients with a secondary cause also differs compared to patient with a primary cause.How this study might affect practiceFindings provide the strongest evidence to date for routinely assessing patients for the presence of visual hallucinations as part of the standard psychiatric assessment. A positive finding should be considered a ‘red flag’ for a secondary cause.

Hallucinations, percepts in the absence of external stimuli, are a shared feature of visual hallucinations caused by eye-disease (Charles Bonnet Syndrome, CBS) or Parkinson’s disease (PD) which are thought to arise through pathophysiologically distinct mechanisms: deafferentation and attentional network dysfunction respectively. Recent studies have found an association between hallucinations and structural changes in the cerebellum without obvious link to either mechanism. Here, we employed Voxel Based Morphometry (VBM), optimised for the cerebellum using the Spatially Unbiased Infratentorial Template (SUIT), to characterise similarities and differences in cerebellar structure associated with visual hallucinations in PD and CBS. Grey and white matter volume (GMV & WMV) from patients with eye-disease (n = 12 hallucinators; n = 9 non-hallucinators) and PD (n = 7 hallucinators; n = 9 non-hallucinators) was examined in a 2-way ANOVA controlling for age, sex, and intracranial volume. Comparing hallucinators to controls across both groups, lower GMV was found bilaterally within cerebellar lobule VIII extending to IX/VII. GMV reductions were also found in Crus 1, greater in PD than eye-disease. Predominantly within PD, hallucination-related lower WMV was found in the medulla. No regions of increased GMV or WMV were found. A correlation was observed between brainstem WMV and lobule VIIIb GMV suggesting a functional association. Lobule VIII comprises a functional node within the Dorsal Attention Network (DAN), linking these findings to current attentional theories of hallucination, while Crus 1 is linked to cortical visual processing. These findings provide preliminary evidence of a cerebellar contribution to hallucinations that transcends clinical conditions.

Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson’s disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson’s disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.

It is believed that inadequate environmental light, especially in facilities such as care homes, contribute to the diurnal changes of behavioural and psychological symptoms of dementia (BPSD) historically referred to as "sundowning syndrome". Conceptual models of sundowning phenomena have shifted emphasis from the role of light in vision (image forming) to its role in circadian rhythm modulation. However, the grounds for this change are unclear and the evidence on which it is based has not been examined comprehensively.We have searched literature on sundowning syndrome and its association with light and studies evaluating BPSD, behavioural rhythm and environmental light in care homes in four databases (PubMed, Web of Science, Embase and Cochrane Library) from inception to 31 January 2021.Of the nine studies investigating light, behavioural rhythm and BPSD in care homes identified, we found evidence that insufficient natural light exposure was associated with worsening of BPSD and disrupted activity rhythm but it was not clear whether this related to image forming or disrupted circadian rhythm. There was a paucity of evidence in relation to the role of low levels of light for image forming in the context of a specific BPSD symptom: visual hallucinations. We also found literature on the possible role of light outside the visible spectrum influencing cognition. Based on the evidence, we proposed a new model integrating different components of light in BPSD and sundowning syndrome that combines its image forming and circadian roles.Inadequate light may be a risk factor for BPSD and sundowning syndrome for dementia patients through a range of different mechanisms. It is recommended that multiple neuro-endocrinological and socio-environmental factors relevant to light such as adjusting the environmental setting, increasing light exposure, and scheduling activities should be considered when treating dementia patients with BPSD.

Visuospatial learning depends on the parahippocampal place area (PPA), a functionally heterogenous area which current visuospatial processing models place downstream from parietal cortex and only from area V4 of early visual cortex (EVC). However, evidence for anatomical connections between the PPA and other EVC areas is inconsistent, and these connections are not discussed in current models. Through a data-driven analysis based on diffusion MRI tractography, we present evidence that the PPA sits at the confluence of two white matter systems. The first conveys information from the retrosplenial complex to the anterior PPA and runs within the cingulum bundle. The second system connects all peripheral EVC areas to the posterior PPA and corresponds to the medial occipital longitudinal tract (MOLT), a white matter pathway that is distinct from the cingulum and that we describe here in detail. Based on further functional connectivity analysis and meta-analytic data, we propose that the MOLT supports early stage encoding of visuospatial information by allowing direct reciprocal exchange between the PPA and EVC. Our findings may improve symptom interpretation in stroke and tumour patients with damage to the medial occipito-temporal region and call for revisiting current visuospatial processing models.

Establishing preclinical models of Alzheimer’s disease that predict clinical outcomes remains a critically important, yet to date not fully realised, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer’s disease where we sought a match between individual disease characteristics in cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-β burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-β in vitro as measured by synapse loss and function. Our findings indicate that patient induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer’s disease pathology, but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual’s in-life clinical vulnerability thus represent a tractable method of Alzheimer’s disease modelling using clinical data in combination with cellular phenotypes.

Visual hallucinations (VH) in Lewy body disease (LBD) have a heterogenous phenomenology classified into minor phenomena (MVH) and complex hallucinations (CVH). Mechanisms underpinning VH and their temporal aspects are largely unknown. According to the hodotopic model, we investigated whether changes in distinct cognitive domains and neural networks in the hallucination trait underpin temporal aspects of MVH and CVH in the hallucination state. 35 LBD patients with VH underwent a complete neuropsychological evaluation and resting-state fMRI. North-East-Visual-Hallucinations-Interview was used to assess their typical VH content, duration, and frequency. We found that MVH was not associated with cognitive impairment, while CVH was associated with impairments in visuoperceptual processes, attention and visual abstract reasoning. In seed-to-seed functional connectivity (FC) analysis we identified functional couplings associated with MVH and CVH temporal severity (duration x frequency), duration and frequency. MVH severity was negatively associated with FC between early visual areas (EVA) and ventral-visual-stream regions, and negatively associated with FC between brainstem and EVA, which may be linked to LBD brainstem neuropathology. CVH duration was positively associated with FC between ventral-visual stream and salience network (SN). CVH frequency was negatively associated with FC between DMN and SN. Functional alterations in distinct visual and attentional networks and their dynamic interaction in trait LBD hallucinators are linked to both the phenomenology of state content and its temporal characteristics. Within a network, VH frequency and duration may be linked to different types of functional alterations: increased connectivity leading to sustained activity prolonging VH (duration) and decreased connectivity increasing dysregulated, spontaneous activity (frequency). These findings support the hodotopic hypothesis of VH and may reflect a link between VH phenomenology, LBD neuropathological progression and the involvement of specific neurotransmitter systems.

Background Levodopa and dopamine agonists (dopamine replacement therapy [DRT]) are implicated in Parkinson's disease psychosis (PDP), but the relationship between DRT and neurotransmitter dysfunction inherent to PD remains unclear. Objectives To examine the relationship between baseline striatal dopamine transporter (DAT) binding in drug‐naïve idiopathic PD, introduction of DRT, or dose change and incident early‐onset PDP. Methods Baseline DAT binding was compared between patients with and without incident psychosis (defined here as hallucinations or delusions), controlling for age, sex, baseline cognition, and prospective DRT in the Parkinson's Progression Markers Initiative cohort. Incident illusions were not considered psychosis symptoms. Results Of 386 patients, 30 (8%) developed PDP (predominantly hallucinations, mean onset 42 months) and 355 (92%) had either no PDP symptoms (mean follow‐up 64 months) or reported illusions only (111/355, 31%). Incident PDP was associated with reduced baseline striatal DAT binding, controlling for confounders (F 1,377 = 10.9; P = 0.001), but not with a specific DRT regime. A total of 6 patients developed PDP when DRT free. There was no suggestion that PDP onset was coincident with starting levodopa or levodopa dose increase. Incident illusions were not associated with reduced DAT binding. Conclusion The findings highlight the role of disease‐related dopamine mechanisms in the pathophysiology of hallucinations in Parkinson's disease alongside medication. It remains to be determined how dopamine mechanisms, medication, and other neurotransmitter systems implicated in PDP interact.

SummaryVisuospatial learning depends on the parahippocampal place area (PPA), a functionally heterogenous area which current visuospatial processing models place downstream from parietal cortex and only from area V4 of early visual cortex (EVC). However, evidence for anatomical connections between the PPA and other EVC areas is inconsistent, and these connections are not discussed in current models. Through a data-driven analysis based on diffusion MRI tractography, we present evidence that the PPA sits at the confluence of two white matter systems. The first conveys information from the retrosplenial complex to the anterior PPA and runs within the cingulum bundle. The second system connects all peripheral EVC areas to the posterior PPA and corresponds to the medial occipital longitudinal tract (MOLT), a novel white matter pathway distinct from the cingulum. Based on further functional connectivity analysis and meta-analytic data, we propose that the MOLT supports early stage encoding of visuospatial information by allowing direct reciprocal exchange between the PPA and EVC.

Parkinson’s psychosis (PDP) describes a spectrum of symptoms that may arise in Parkinson’s disease (PD) including visual hallucinations (VH). Imaging studies investigating the neural correlates of PDP have been inconsistent in their findings, due to differences in study design and limitations of scale. Here we use empirical Bayes harmonisation to pool together structural imaging data from multiple research groups into a large-scale mega-analysis, allowing us to apply new methodological approaches to identify cortical regions and networks involved in VH and their relation to receptor binding. Differences of cortical thickness and surface area show a wider cortical involvement underlying VH than previously recognised, including primary visual cortex and its surrounds, and the hippocampus, independent of its role in cognitive decline. Structural covariance analyses point to a strong involvement of the attentional control networks in PD-VH, while associations with receptor density maps suggest neurotransmitter loss may drive the cortical changes.

Background and objectives\ud In Charles Bonnet Syndrome (CBS), visual hallucinations (VH) are experienced by people with sight loss due to eye disease or lesional damage to early visual pathways. The aim of this cross-sectional study was to investigate structural brain changes using magnetic resonance imaging (MRI) in CBS.\ud \ud Methods\ud Sixteen CBS patients, 17 with eye disease but no VH, and 19 normally sighted people took part. Participants were imaged on a 3T scanner, with 1 mm resolution T1 weighted structural imaging, and diffusion tensor imaging with 64 diffusion directions.\ud \ud Results\ud The three groups were well matched for age, sex and cognitive scores (MMSE). The two eye disease groups were matched on visual acuity. Compared to the sighted controls, we found reduced grey matter in the occipital cortex in both eye disease groups. We also found reductions of fractional anisotropy and increased diffusivity in widespread areas, including occipital tracts, the corpus callosum, and the anterior thalamic radiation. We did not find any significant differences between the eye disease participants with VH versus without VH, but did observe a negative association between hippocampal volume and VH severity in the CBS group.\ud \ud Discussion\ud Our findings suggest that although there are cortical and subcortical effects associated with sight loss, structural changes do not explain the occurrence of VHs. CBS may relate instead to connectivity or excitability changes in brain networks linked to vision.

Introduction Hallucinations occur across neurodegenerative disorders, with increasing severity, poorer cognition and impaired hallucination-specific insight associated with worse outcomes and faster disease progression. It remains unclear how changes in cognition, temporal aspects of hallucinations, hallucination-specific insight and distress relate to each other. Methods Extant samples of patients experiencing visual hallucinations were included in the analyses: Parkinson’s Disease (n = 103), Parkinson’s Disease Dementia (n = 41), Dementia with Lewy Bodies (n = 27) and Eye Disease (n = 113). We explored the relationship between factors of interest with Spearman’s correlations and random-effect linear models. Results Spearman’s correlation analyses at the whole-group level showed that higher hallucination-specific insight was related to higher MMSE score (rs = 0.39, p

Background: The coronavirus pandemic is having a profound impact on non-COVID-19 related research, including the delivery of clinical trials for patients with Parkinson's disease.Objectives: A preliminary investigation to explore the views of Parkinson's disease (PD) patients, with and without experience of psychosis symptoms, and carers on the resumption of clinical research and adaptations to trials in light of COVID-19.Methods: An anonymous self-administered online survey was completed by 30 PD patients and six family members/carers via the Parkinson's UK Research Support Network to explore current perceptions on taking part in PD research and how a planned clinical trial for psychosis in PD may be adapted so participants feel safe.Results: Ninety-one percent of respondents were enthusiastic about the continuation of non-COVID-19 related research as long as certain safety measures were in place. Ninety-four percent stated that they would be happy to complete assessments virtually. However, they noted that care should be taken to ensure that this does not exclude participants, particularly those with more advanced PD who may require assistance using portable electronic devices. Regular and supportive communication from the research team was also seen as important for maintaining the psychological well-being of participants while taking part in the trial.Conclusions: In the era of COVID-19 pandemic, standard approaches will have to be modified and rapid adoption of virtual assessments will be critical for the continuation of clinical research. It is important that alongside the traditional methods, new tools are developed, and older ones validated for virtual assessments, to allow safe and comprehensive assessments vital for ongoing research in people with Parkinson's.

Background: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. Aims: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. Methods: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. Results: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity ( p=0.04) and working memory-related theta oscillations ( p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. Conclusions: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine.

Objective To determine possible associations of hemispheric-regional alpha/theta ratio (α/θ) with neuropsychological test performance in Parkinson’s Disease (PD) non-demented patients. Methods 36 PD were matched to 36 Healthy Controls (HC). The α/θ in eight hemispheric regions was computed from the relative power spectral density of the resting-state quantitative electroencephalogram (qEEG). Correlations between α/θ and performance in several neuropsychological tests were conducted, significant findings were included in a moderation analysis. Results The α/θ in all regions was lower in PD than in HC, with larger effect sizes in the posterior regions. Right parietal, and right and left occipital α/θ had significant positive correlations with performance in Judgement of Line Orientation Test (JLOT) in PD. Adjusted moderation analysis indicated that right, but not left, occipital α/θ influenced the JLOT performance related to PD. Conclusions Reduction of the occipital α/θ, in particular on the right side, was associated with visuospatial performance impairment in PD. Significance Visuospatial impairment in PD, which is highly correlated with the subsequent development of dementia, is reflected in α/θ in the right posterior regions. The right occipital α/θ may represent a useful qEEG marker for evaluating the presence of early signs of cognitive decline in PD and the subsequent risk of dementia.

Parkinson's disease (PD) is the second commonest neurodegenerative disorder in the world with a rising prevalence. The pathophysiology is multifactorial but aggregation of misfolded α-synuclein is considered to be a key underpinning mechanism. Amyloid-β (Aβ) and tau deposition are also comorbid associations and especially Aβ deposition is associated with cognitive decline in PD. Some existing evidence suggests that low cerebrospinal fluid (CSF) Aβ42 is predictive of future cognitive impairment in PD. Recent studies also show that CSF Aβ is associated with the postural instability and gait difficulties (PIGD) or the newly proposed cholinergic subtype of PD, a possible risk factor for cognitive decline in PD. The glial-lymphatic system, responsible for convective solute clearance driven by active fluid transport through aquaporin-4 water channels, may be implicated in brain amyloid deposition. A better understanding of the role of this system and more specifically the role of Aβ in PD symptomatology, could introduce new treatment and repurposing drug-based strategies. For instance, apomorphine infusion has been shown to promote the degradation of Aβ in rodent models. This is further supported in a post-mortem study in PD patients although clinical implications are unclear. In this review, we address the clinical implication of cerebral Aβ deposition in PD and elaborate on its metabolism, its role in cognition and motor function/gait, and finally assess the potential effect of apomorphine on Aβ deposition in PD.

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

Objective To investigate the pathophysiology of visual snow (VS), through a combined functional neuroimaging and magnetic resonance spectroscopy (1H‐MRS) approach. Methods We applied a functional MRI block‐design protocol studying the responses to a visual stimulation mimicking VS, in combination with 1H‐MRS over the right lingual gyrus, in 24 patients with VS compared to an equal number of age‐ and gender‐matched healthy controls. Results We found reduced BOLD responses to the visual stimulus with respect to baseline in VS patients compared to controls, in the left (k = 291; P = 0.025; peak MNI coordinate [‐34 12 ‐6]) and right (k = 100; P = 0.003; peak MNI coordinate [44 14 ‐2]) anterior insula. Our spectroscopy analysis revealed a significant increase in lactate concentrations in patients with respect to controls (0.66 ± 0.9 mmol/L vs. 0.07 ± 0.2 mmol/L; P

Objectives The idea that delirium is a risk factor for dementia, broadly defined, is derived from heterogeneous patient samples. We reviewed available evidence as to whether stroke survivors who developed delirium during the acute phase of treatment are at a higher prospective risk of incident post-stroke cognitive impairment or dementia. Design We searched 8721 records in the Cochrane database for reviews or protocols dealing with the study objective, Medline, EMBASE, PsycInfo and CINAHL for observational studies in the general adult population and PubMed for in-process articles. Additional searches of the reference lists of retrieved articles were also undertaken. Qualitative syntheses and meta-analysis were conducted according to conventional guidelines. Results Twelve relevant articles were fully appraised. Four out of these studies, comprising 743 stroke survivors, including 199 with delirium, met criteria for qualitative syntheses. Overall, the studies presented low to moderate level evidence suggesting an association between post-stroke delirium and dementia. Conclusions There is a need for further studies to investigate the association of post-stroke delirium and dementia using well-defined cohorts of patients and controlling for factors such as pre-stroke cognition, stroke severity and location and the presence of persistent delirium. Such studies will help understand the place of delirium identification and prevention in reducing the risk of dementia after stroke. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd

Dr Ffytche is Reader in Visual Psychiatry at King’s College London, Institute of Psychiatry, Psychology and Neuroscience and Consultant Old Age Psychiatrist at the Maudsley Hospital where he runs a national specialist clinic for visual hallucinations and related symptoms. He has published extensively on clinical and neuroscientific aspects of visual hallucinations and is an international expert on Charles Bonnet Syndrome.Hallucinations - particularly those in the visual modality - are emerging as important symptoms in degenerative brain and eye disease because of their prevalence, clinical impact and implications for future cognitive trajectory. Yet hallucinations are only one of several visual perceptual pathologies that occur in these conditions and the question arises whether experiences traditionally considered distinct from hallucinations - illusions, misperceptions, pareidolias and metamorphopsias, for example - share the pathophysiological mechanism and prognostic implications of hallucinations. Using evidence from Parkinson’s disease, Charles Bonnet Syndrome and different dementias, I will argue that perceptual experiences at the margins of hallucination reflect a range of pathological mechanisms, some shared with hallucinations others not. The findings suggest that closer clinical attention to the phenomenological detail of visual perceptual pathology is required to better predict future outcome and inform treatment decisions.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia associated with poor prognosis and high carers' burden. Neuropsychiatric symptoms worsen this prognosis and are a high source of distress for service users and their carers. However, there is currently insufficient evidence to support the pharmacological and non-pharmacological management of these symptoms. Acetylcholinesterase inhibitors are the first-line pharmacological option, but challenging risky behaviours may persist despite their use. Antipsychotic medications are indicated in such clinical scenarios, but there is very limited evidence to support the efficacy and safety of these medications for managing neuropsychiatric symptoms in DLB. Hence, we report an individual with DLB with severe distressing persistent visual hallucinations and agitation. After multiple treatment options had failed, clozapine was successfully initiated with substantial improvement in both clinical and functional outcomes. Further studies are warranted for evaluating the efficacy of clozapine in managing neuropsychiatric symptoms in DLB.

Background Establishing the cognitive phenotype of psychotic symptoms in Alzheimer's disease (AD) could localise discrete pathology and target symptomatic treatment. This study aimed to establish whether psychotic symptoms would be associated with poorer performance on neuropsychological tests known to correlate with striatal dopaminergic function and to investigate whether these differences would be attributed to the paranoid (persecutory delusions) or misidentification (misidentification phenomena +/− hallucinations) subtype. Methods Seventy patients with probable AD (34 psychotic and 36 nonpsychotic) were recruited to the study. Analysis of covariance was used to compare motor speed and the rapid visual processing test of sustained visual attention, after adjusting for potential confounding factors. Multivariate analyses were used to compare performance across other cognitive domains. Significant findings were explored by separating patients on the basis of subtype. Results Rapid visual processing performance accuracy was reduced in patients with psychotic symptoms (F1,58 = 5.94, p = 0.02) and differed significantly across subtypes (F2,51 = 3.94, p = 0.03), largely because of poorer performance in the misidentification compared with nonpsychotic group. Multivariate analyses (corrected for multiple comparisons) showed poorer performance on the incomplete letters task in psychotic patients (F1,63 = 8.77, p = 0.004) and across subtypes (F2,55 = 10.90, p

Men with antisocial personality disorder show lifelong abnormalities in adaptive decision making guided by the weighing up of reward and punishment information. Among men with antisocial personality disorder, modification of the behaviour of those with additional diagnoses of psychopathy seems particularly resistant to punishment.We did a case-control functional MRI (fMRI) study in 50 men, of whom 12 were violent offenders with antisocial personality disorder and psychopathy, 20 were violent offenders with antisocial personality disorder but not psychopathy, and 18 were healthy non-offenders. We used fMRI to measure brain activation associated with the representation of punishment or reward information during an event-related probabilistic response-reversal task, assessed with standard general linear-model-based analysis.Offenders with antisocial personality disorder and psychopathy displayed discrete regions of increased activation in the posterior cingulate cortex and anterior insula in response to punished errors during the task reversal phase, and decreased activation to all correct rewarded responses in the superior temporal cortex. This finding was in contrast to results for offenders without psychopathy and healthy non-offenders.Punishment prediction error signalling in offenders with antisocial personality disorder and psychopathy was highly atypical. This finding challenges the widely held view that such men are simply characterised by diminished neural sensitivity to punishment. Instead, this finding indicates altered organisation of the information-processing system responsible for reinforcement learning and appropriate decision making. This difference between violent offenders with antisocial personality disorder with and without psychopathy has implications for the causes of these disorders and for treatment approaches.National Forensic Mental Health Research and Development Programme, UK Ministry of Justice, Psychiatry Research Trust, NIHR Biomedical Research Centre.

This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson’s disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson’s disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.

BACKGROUND The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally. OBJECTIVE To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD). METHODS From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB. RESULTS 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%. CONCLUSION Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy.

In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors - for example, autonomic dysfunction - that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis.

Although illusions, hallucinations and delusions did not play a prominent role in James Parkinson's original clinical descriptions, the longitudinal view of disease progression he advocated has important lessons for the study of such symptoms today. A focus on longitudinal progression rather than individual symptoms led to the concept of PD psychosis-a spectrum of positive symptoms in Parkinson's disease. The publication of criteria for PD psychosis in 2007 helped unify the disparate set of symptoms, raising their profile and resulting in a rapid expansion of literature focussing on clinical aspects, mechanisms, and treatment. Here we review this literature and the evolving view of PD psychosis. Adding to previous evidence of a prospective risk for dementia and the move to supervised care, key recent developments include: recognition of prevalence increase with disease duration; a broadening of symptoms included in PD psychosis; better characterization of higher visual and cognitive dysfunction risk factors; structural, functional, and neurotransmitter imaging biomarker evidence; and approval of pimavanserin in the United States for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research that promise a better understanding of the clinical management of PD psychosis and its role as a biomarker for PD stage and progression.

A substantial body of work has demonstrated that persons with schizophrenia have a deficit in the perception of emotional stimuli. More recently this deficit has been linked to poor functional outcomes (FO) in this group. The current research investigated the perception of emotional stimuli in a group of 64 schizophrenia patients and 65 matched healthy controls. In the patient group, across two different emotion perception tasks and a social perception task, small deficits were found in the perception of negative, positive and neutrally valenced stimuli. Only the ability to perceive negative and neutrally valenced stimuli significantly correlated with a set of FO measures in the patients, with one task indicating these associations were strongest for the perception of fear. Subsequent regression modelling, controlling for the effects of symptomatology, demonstrated that for each of the three tasks, the measure of negative valence perception accounted for a similar but small amount (4%) of the variance seen in the functional status of the patients.

Neural oscillations in the gamma band are of increasing interest, but separating them from myogenic electrical activity has proved difficult. A novel algorithm has been developed to reduce the effect of tonic scalp and neck muscle activity on the gamma band of the EEG. This uses mathematical modelling to fit individual muscle spikes and then subtracts them from the data. The method was applied to the detection of motor associated gamma in two separate groups of eight subjects using different sampling rates. A reproducible increase in high gamma (65–85 Hz) magnitude occurred immediately after the motor action in the left central area (p = 0.02 and p = 0.0002 for the two cohorts with individually optimized algorithm parameters, compared to p = 0.03 and p = 0.16 before correction). Whilst the magnitude of this event-related gamma synchronisation was not reduced by the application of the EMG reduction algorithm, the baseline left central gamma magnitude was significantly reduced by an average of 23 % with a faster sampling rate (p