Wrist-worn actigraphy in agitated late-stage dementia patients: A feasibility study on digital inclusion.

BACKGROUND: Wrist-worn actigraphy can be an objective tool to assess sleep and other behavioral and psychological symptoms in dementia (BPSD). We investigated the feasibility of using wearable actigraphy in agitated late-stage dementia patients. METHODS: Agitated, late-stage Alzheimer's dementia care home residents in Greater London area (n = 29; 14 females, mean age ± SD: 80.8 ± 8.2; 93.1% White) were recruited to wear an actigraphy watch for 4 weeks. Wearing time was extracted to evaluate compliance, and factors influencing compliance were explored. RESULTS: A high watch-acceptance (96.6%) and compliance rate (88.0%) was noted. Non-compliance was not associated with age or BPSD symptomatology. However, participants with "better" cognitive function (R = 0.42, p = 0.022) and during nightshift (F1.240, 33.475  = 8.075, p = 0.005) were less compliant. Female participants were also marginally less compliant (F1, 26  = 3.790, p = 0.062). DISCUSSIONS: Wrist-worn actigraphy appears acceptable and feasible in late-stage agitated dementia patients. Accommodating the needs of both the patients and their carers may further improve compliance.

A clinico-anatomical dissection of the magnocellular and parvocellular pathways in a patient with the Riddoch syndrome.

KEY MESSAGE: The Riddoch syndrome is thought to be caused by damage to the primary visual cortex (V1), usually following a vascular event. This study shows that damage to the anatomical input to V1, i.e., the optic radiations, can result in selective visual deficits that mimic the Riddoch syndrome. The results also highlight the differential susceptibility of the magnocellular and parvocellular visual systems to injury. Overall, this study offers new insights that will improve our understanding of the impact of brain injury and neurosurgery on the visual pathways. The Riddoch syndrome, characterised by the ability to perceive, consciously, moving visual stimuli but not static ones, has been associated with lesions of primary visual cortex (V1). We present here the case of patient YL who, after a tumour resection surgery that spared his V1, nevertheless showed symptoms of the Riddoch syndrome. Based on our testing, we postulated that the magnocellular (M) and parvocellular (P) inputs to his V1 may be differentially affected. In a first experiment, YL was presented with static and moving checkerboards in his blind field while undergoing multimodal magnetic resonance imaging (MRI), including structural, functional, and diffusion, acquired at 3 T. In a second experiment, we assessed YL's neural responses to M and P visual stimuli using psychophysics and high-resolution fMRI acquired at 7 T. YL's optic radiations were partially damaged but not severed. We found extensive activity in his visual cortex for moving, but not static, visual stimuli, while our psychophysical tests revealed that only low-spatial frequency moving checkerboards were perceived. High-resolution fMRI revealed strong responses in YL's V1 to M stimuli and very weak ones to P stimuli, indicating a functional P lesion affecting V1. In addition, YL frequently reported seeing moving stimuli and discriminating their direction of motion in the absence of visual stimulation, suggesting that he was experiencing visual hallucinations. Overall, this study highlights the possibility of a selective loss of P inputs to V1 resulting in the Riddoch syndrome and in hallucinations of visual motion.

Cognitive and executive impairments in Parkinson's disease psychosis: a Bayesian meta-analysis.

BACKGROUND: Cognitive and executive deficits lead to worsening of quality of life and are a risk factor for developing dementia in people with Parkinson's disease (PD) with psychosis (PDP). However, which key cognitive domains are differentially affected in PDP compared with those without (PDnP), remains unclear. Here, we examined this using a Bayesian meta-analytical approach. METHODS: Searches 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 participants. Meta-analyses were conducted separately for each cognitive domain and subdomain, we examined the effect of age, PD medications, PD duration and severity, depression and psychosis severity for all major domains with meta-regressions. RESULTS: Effect-size estimates suggest worse performance on all major domains (k=105 studies) in PDP compared with PDnP participants, 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. CONCLUSIONS: We report extensive deficits across nine domains as well as subdomains in PD psychosis, with global cognition, processing speed and executive functions as the most likely impaired. The presence of depression may influence task-related performance in PDP, alongside age and PD duration, but not dose of dopamine replacement treatments.

The association between visual hallucinations and secondary psychosis: a systematic review and meta-analysis.

INTRODUCTION: Visual hallucinations are often considered 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. METHOD: We conducted a meta-analysis of case-control studies directly comparing primary and secondary psychosis. A random-effects model, following the DerSimonian and Laird method, was used to pool studies and generate overall odds ratios (OR), 95% confidence intervals (CI) and prediction intervals (PI). RESULTS: Fourteen 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, p < 0.001) with moderate between-study heterogeneity (I2 = 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 were significantly more likely to be associated with secondary psychosis (OR = 0.1, 95% CI = 0.01-0.8, p = 0.03). CONCLUSIONS: Visual hallucinations were 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.

Neural patterns of conscious visual awareness in the Riddoch syndrome.

The Riddoch syndrome is one in which patients blinded by lesions to their primary visual cortex can consciously perceive visual motion in their blind field, an ability that correlates with activity in motion area V5. Our assessment of the characteristics of this syndrome in patient ST, using multimodal MRI, showed that: 1. ST's V5 is intact, receives direct subcortical input, and decodable neural patterns emerge in it only during the conscious perception of visual motion; 2. moving stimuli activate medial visual areas but, unless associated with decodable V5 activity, they remain unperceived; 3. ST's high confidence ratings when discriminating motion at chance levels, is associated with inferior frontal gyrus activity. Finally, we report that ST's Riddoch Syndrome results in hallucinatory motion with hippocampal activity as a correlate. Our results shed new light on perceptual experiences associated with this syndrome and on the neural determinants of conscious visual experience.

Understanding visual hallucinations: A new synthesis.

Despite decades of research, we do not definitively know how people sometimes see things that are not there. Eight models of complex visual hallucinations have been published since 2000, including Deafferentation, Reality Monitoring, Perception and Attention Deficit, Activation, Input, and Modulation, Hodological, Attentional Networks, Active Inference, and Thalamocortical Dysrhythmia Default Mode Network Decoupling. Each was derived from different understandings of brain organisation. To reduce this variability, representatives from each research group agreed an integrated Visual Hallucination Framework that is consistent with current theories of veridical and hallucinatory vision. The Framework delineates cognitive systems relevant to hallucinations. It allows a systematic, consistent, investigation of relationships between the phenomenology of visual hallucinations and changes in underpinning cognitive structures. The episodic nature of hallucinations highlights separate factors associated with the onset, persistence, and end of specific hallucinations suggesting a complex relationship between state and trait markers of hallucination risk. In addition to a harmonised interpretation of existing evidence, the Framework highlights new avenues of research, and potentially, new approaches to treating distressing hallucinations.

Grey matter volume loss in Parkinson's disease psychosis and its relationship with serotonergic gene expression: A meta-analysis.

BACKGROUND: Neuroanatomical alterations underlying psychosis in Parkinson's Disease (PDP) remain unclear. We carried out a meta-analysis of MRI studies investigating the neural correlates of PDP and examined its relation with dopaminergic and serotonergic receptor gene expression. METHODS: PubMed, Web of Science and Embase were searched for MRI studies (k studies = 10) of PDP compared to PD patients without psychosis (PDnP). Seed-based d Mapping with Permutation of Subject Images and multiple linear regression analyses was used to examine the relationship between pooled estimates of grey matter volume (GMV) loss in PDP and D1/D2 and 5-HT1a/5-HT2a receptor gene expression estimates from Allen Human Brain Atlas. RESULTS: We observed lower grey matter volume in parietal-temporo-occipital regions (PDP n = 211, PDnP, n = 298). GMV 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) but not dopaminergic receptors. CONCLUSION: Widespread GMV loss in the parieto-temporo-occipital regions may underlie PDP. Association between grey matter volume and local expression of serotonergic receptor genes may suggest a role for serotonergic receptors in PDP.

Neuropathological correlates of neuropsychiatric symptoms in dementia.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are common in Lewy body disease (LBD), but their etiology is poorly understood. METHODS: 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). RESULTS: 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. DISCUSSION: LB and AD pathology contribute differentially to NPS likely with an additive process contributing to the increased burden of NPS.

Neurons derived from individual early Alzheimer's disease patients reflect their clinical vulnerability.

Establishing preclinical models of Alzheimer's disease that predict clinical outcomes remains a critically important, yet to date not fully realized, 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 the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-ß 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-ß 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.

Transcranial Direct Current Stimulation in the Treatment of Visual Hallucinations in Charles Bonnet Syndrome: A Randomized Placebo-Controlled Crossover Trial.

OBJECTIVE: To investigate the potential therapeutic benefits and tolerability of inhibitory transcranial direct current stimulation (tDCS) on the remediation of visual hallucinations in Charles Bonnet syndrome (CBS). DESIGN: Randomized, double-masked, placebo-controlled crossover trial. PARTICIPANTS: Sixteen individuals diagnosed with CBS secondary to visual impairment caused by eye disease experiencing recurrent visual hallucinations. INTERVENTION: All participants received 4 consecutive days of active and placebo cathodal stimulation (current density: 0.29 mA/cm2) to the visual cortex (Oz) over 2 defined treatment weeks, separated by a 4-week washout period. MAIN OUTCOME MEASURES: Ratings of visual hallucination frequency and duration following active and placebo stimulation, accounting for treatment order, using a 2 × 2 repeated-measures model. Secondary outcomes included impact ratings of visual hallucinations and electrophysiological measures. RESULTS: When compared with placebo treatment, active inhibitory stimulation of visual cortex resulted in a significant reduction in the frequency of visual hallucinations measured by the North East Visual Hallucinations Interview, with a moderate-to-large effect size. Impact measures of visual hallucinations improved in both placebo and active conditions, suggesting support and education for CBS may have therapeutic benefits. Participants who demonstrated greater occipital excitability on electroencephalography assessment at the start of treatment were more likely to report a positive treatment response. Stimulation was found to be tolerable in all participants, with no significant adverse effects reported, including no deterioration in preexisting visual impairment. CONCLUSIONS: Findings indicate that inhibitory tDCS of visual cortex may reduce the frequency of visual hallucinations in people with CBS, particularly individuals who demonstrate greater occipital excitability prior to stimulation. tDCS may offer a feasible intervention option for CBS with no significant side effects, warranting larger-scale clinical trials to further characterize its efficacy.

Investigation of structural brain changes in Charles Bonnet Syndrome.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Plasma Neurofilament Light and p-tau181 and Risk of Psychosis in Parkinson's Disease.

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.

Light, sleep-wake rhythm, and behavioural and psychological symptoms of dementia in care home patients: Revisiting the sundowning syndrome.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The medial occipital longitudinal tract supports early stage encoding of visuospatial information.

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.

Visual hallucinations in Lewy body disease: pathophysiological insights from phenomenology.

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.

Mapping brain structural differences and neuroreceptor correlates in Parkinson's disease visual hallucinations.

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 identify cortical regions and networks involved in VH and their relation to receptor binding. Differences of morphometrics analysed show a wider cortical involvement underlying VH than previously recognised, including primary visual cortex and surrounding regions, and the hippocampus, independent of its role in cognitive decline. Structural covariance analyses point to the involvement of the attentional control networks in PD-VH, while associations with receptor density maps suggest neurotransmitter loss may be linked to the cortical changes.

Cognition, hallucination severity and hallucination-specific insight in neurodegenerative disorders and eye disease.

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 < 0.001) and less severe hallucinations (rs = -0.28, p < .01). Linear mixed-models controlling for diagnostic group showed that insight was related to higher MMSE (p < .001), to hallucination severity (p = 0.003), and to VH duration (p = 0.04). Interestingly, insight was linked to the distress component but not the frequency component of severity. No significant relationship was found between MMSE and hallucination severity in these analyses.Conclusion: Our findings highlight the importance of hallucination-specific insight, distress and duration across groups. A better understanding of the role these factors play in VH may help with the development of future therapeutic interventions trans-diagnostically.

Cognitive and visual processing performance in Parkinson's disease patients with vs without visual hallucinations: A meta-analysis.

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.