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The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g., microglia), peripheral innate immune cells (e.g., blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells in n = 148 people with Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), Lewy body dementia (LBD) as compared to n = 37 healthy controls. To compare groups, we used multivariate dissimilarity analysis and principal component analysis across 19 innate immune cell types. We identified pro-inflammatory profiles that significantly differ between patients with all-cause dementia and healthy controls, with some significant differences between patient groups. Regression analysis confirmed that time to death following the blood test correlated with the individuals' immune profile weighting, positively to TREM2+ and non-classical monocytes and negatively to classical monocytes. Taken together, these results describe transdiagnostic peripheral immune profiles and highlight the link between prognosis and the monocyte cellular subdivision and function (as measured by surface protein expression). The results suggest that blood-derived innate immune profiles can inform sub-populations of cells relevant for specific neurodegenerative diseases that are significantly linked to accelerated disease progression and worse survival outcomes across diagnoses. Blood-based innate immune profiles may contribute to enhanced precision medicine approaches in dementia, helping to identify and monitor therapeutic targets and stratify patients for candidate immunotherapies., (© 2024. The Author(s).)

Background: Neuropsychiatric symptoms are common in dementia and linked to adverse outcomes. Inflammation is increasingly recognized as playing a role as a driver of early disease progression in Alzheimer's disease (AD) and related dementias. Inflammation has also been linked to primary psychiatric disorders, however its association with neuropsychiatric symptoms in neurodegenerative dementias remains uncertain., Methods: We conducted a systematic literature review investigating associations between inflammation and neuropsychiatric symptoms in neurodegenerative dementias, including AD, Lewy body, Frontotemporal, Parkinson's (PD) and Huntington's disease dementias., Results: Ninety-nine studies met our inclusion criteria, and the majority (n = 59) investigated AD and/or mild cognitive impairment (MCI). Thirty-five studies included PD, and only 6 investigated non-AD dementias. Inflammation was measured in blood, CSF, by genotype, brain tissue and PET imaging. Overall, studies exhibited considerable heterogeneity and evidence for specific inflammatory markers was inconsistent, with lack of replication and few longitudinal studies with repeat biomarkers. Depression was the most frequently investigated symptom. In AD, some studies reported increases in peripheral IL-6, TNF-a associated with depressive symptoms. Preliminary investigations using PET measures of microglial activation found an association with agitation. In PD, studies reported positive associations between TNF-a, IL-6, CRP, MCP-1, IL-10 and depression., Conclusion: Central and peripheral inflammation may play a role in neuropsychiatric symptoms in neurodegenerative dementias; however, the evidence is inconsistent. There is a need for multi-site longitudinal studies with detailed assessments of neuropsychiatric symptoms combined with replicable peripheral and central markers of inflammation., Competing Interests: John O’Brien has acted as a consultant for TauRx, Novo Nordisk, Biogen, Roche, Lilly and GE Healthcare and received grant or academic support from Avid/Lilly, Merck and Alliance Medical. The other authors report no conflicts of interest in this work., (© 2024 Swann et al.)

Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportionate to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationship with central inflammation and clinical outcome are limited. There is a pressing need for such scalable, accessible and mechanistically relevant blood markers as these will reduce the time, risk, and costs of experimental medicine trials. We therefore assessed inflammatory patterns of serum cytokines from 214 patients with clinical syndromes associated with FTLD as compared to healthy controls, including their correlation with brain regional microglial activation and disease progression. Serum assays used the MesoScale Discovery V-Plex-Human Cytokine 36 plex panel plus five additional cytokine assays. A sub-group of patients underwent 11C-PK11195 TSPO PET imaging, as an index of microglial activation. A Principal Component Analysis (PCA) was used to reduce the dimensionality of cytokine data, excluding cytokines that were undetectable in >50% of participants. Frequentist and Bayesian analyses were performed on the principal components, to compare each patient cohort to controls, and test for associations with central inflammation, neurodegeneration-related plasma markers and survival. The first component identified by the PCA (explaining 21.5% variance) was strongly loaded by pro-inflammatory cytokines, including TNF-α, TNF-R1, M-CSF, IL-17A, IL-12, IP-10 and IL-6. Individual scores of the component showed significant differences between each patient cohort and controls. The degree to which a patient expressed this peripheral inflammatory profile at baseline correlated negatively with survival (higher inflammation, shorter survival), even when correcting for baseline clinical severity. Higher pro-inflammatory profile scores were associated with higher microglial activation in frontal and brainstem regions, as quantified with 11C-PK11195 TSPO PET. A permutation-based Canonical Correlation Analysis confirmed the association between the same cytokine-derived pattern and central inflammation across brain regions in a fully data-based manner. This data-driven approach identified a pro-inflammatory profile across the FTLD clinical spectrum, which is associated with central neuroinflammation and worse clinical outcome. Blood-based markers of inflammation could increase the scalability and access to neuroinflammatory assessment of people with dementia, to facilitate clinical trials and experimental medicine studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background/objective: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to β-amyloid status., Methods: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [ 11 C]UCB-J non-displaceable binding potential (BP ND ), AD-tau pathology by [ 18 F]AV-1451 BP ND , and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had β-amyloid imaging with 11 C-labeled Pittsburgh Compound-B ([ 11 C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BP ND and gray matter volume between groups were assessed by ANOVA., Results: Compared to controls, patients with CBS had higher [ 18 F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the β-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side., Discussion: Distinct patterns of [ 11 C]UCB-J and [ 18 F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer's disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index., Competing Interests: Unrelated to this work, J.T.O.B. has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai, has acted as a consultant for Roche, and has received research support from Alliance Medical and Merck., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Balint groups use case-based discussions to explore, reflect on, and enhance the clinician-patient relationship. They facilitate the development of empathy and reflective practice and reduce burnout. This study aimed to explore how the benefits of a traditional Balint group format can be accessed and optimised for medical students during a one-year pilot programme., Methods: Eight medical student Balint groups ran for six weeks during 2022-2023, with 90 students participating. Themes were identified from student feedback using qualitative content analysis. Group leaders kept reflective session notes and used these alongside student feedback to undertake a strengths, weaknesses, opportunities, and threats analysis., Results: Strengths of the programme were emotional containment, learning to reflect, and community identity. Weaknesses were themed as strange situations, dragging along, and facilitator as an object. Opportunities were identified in expanding the scope and sharpening focus. Psychological defences and the engagement dilemma threatened the future success of the Balint group programme., Discussion: Medical student Balint groups provide a unique space to combine learning and emotional support with personal, professional and community development. However, the traditional Balint group format may need adapting to be widely accessible to undergraduate learners. Sustainably integrating Balint groups into the medical school curriculum requires ongoing engagement work at both an individual and organisational level.

Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width - RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p - [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors report no competing interests related to this study. Unrelated to this work, JTOB has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai, has acted as a consultant for Lilly and Biogen, has received honorarium for talks from GE Healthcare and research support from Alliance Medical and Merck. IK has received honoraria for talks by NovoNordisk and is a paid medical advisor for digital technology companies in the Alzheimer's disease space (Five Lives SAS, Cognetivity Ltd and Mantrah Ltd). PM has received an honorarium for a talk from GE Healthcare.

Background: Although liaison services in acute hospitals are now the norm, the reverse is not usually available for patients in mental health trusts. Following the introduction of support from geriatricians to older people's mental health inpatient wards, we wanted to see if this intervention was effective and acceptable to clinicians., Methods: We performed a retrospective cohort service evaluation on the impact of a liaison geriatrician, using routinely collected data, and assessed acceptability among medical staff by semi-structured interview., Intervention: Our service introduced regular sessions from consultant community geriatricians across older adults psychiatric wards including a mixture of video conference and face-to-face input., Results: There was no significant decrease in emergency transfers but there was a significant reduction in length of stay with an associated cost benefit for the service after the introduction of a liaison geriatrician. There was a significant increase in geriatrician consultations and a decrease in specialty consultations to other specialists. There was no change in discharge prescriptions or destination. There was a significant reduction in falls in the intervention arm but not in falls leading to emergency hospital admissions geriatricians gave confidence to psychiatrists of all grades to treat physical health care issues., Conclusions: A liaison geriatrician service may be a component in reducing length of stay (although there are many others) and improving continuity of care, although it confers no impact on emergency transfers. The intervention was highly acceptable to clinicians., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits., Objective: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression., Methods: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [ 11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [ 11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [ 11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [ 11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity., Results: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003)., Conclusions: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia. Despite considerable research progress, there remain gaps in our understanding of the pathophysiology and there is no disease-modifying treatment. Proteomics is a powerful tool to elucidate complex biological pathways across heterogenous conditions. This review summarizes the widely used proteomic methods and presents evidence for protein dysregulation in the brain and peripheral tissues in DLB. Proteomics of post-mortem brain tissue shows that DLB shares common features with other dementias, such as synaptic dysfunction, but retains a unique protein signature. Promising diagnostic biomarkers are being identified in cerebrospinal fluid (CSF), blood, and peripheral tissues, such as serum Heart-type fatty acid binding protein. Research is needed to track these changes from the prodromal stage to established dementia, with standardized workflows to ensure replicability. Identifying novel protein targets in causative biological pathways could lead to the development of new targeted therapeutics or the stratification of participants for clinical trials., Competing Interests: Competing interests Unrelated to this work, JTOB has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai, has acted as a consultant for Roche, and has received research support from Alliance Medical and Merck., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). The profile of inflammation in AD has been extensively researched in recent years, with evidence that chronic peripheral inflammation in midlife increases the risk of late-onset AD, and data supporting inflammation being associated with disease progression. In contrast, our understanding of the role of inflammation in DLB is less developed. Most research to date has examined inflammation in related disorders, such as Parkinson's disease, but there is now a growing range of literature examining inflammation in DLB itself. We present a review of the literature in this field, exploring a range of research methodologies including those quantifying markers of inflammation in cerebrospinal fluid, peripheral blood, post-mortem brain tissue, and using neuroimaging and preclinical data. Our review reveals evidence from PET imaging and peripheral blood analysis to support an increase in cerebral and peripheral inflammation in mild or prodromal DLB, that dissipates with disease progression. We present evidence from post-mortem brain tissue and pre-clinical studies that indicate α-synuclein directly promotes inflammation, but that also support the presence of AD co-pathology as an important factor in the profile of neuroinflammation in DLB. We propose that specific markers of inflammation may play a sentinel role in the mild stage of the disease, particularly when combined with AD pathology. We advocate further examination of the profile of inflammation in DLB through robust longitudinal studies, to enhance our understanding of the pathogenesis of the disease. The goal should be to utilise future results to develop a composite biomarker to aid diagnosis of DLB, and to potentially identify novel therapeutic targets., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The COVID-19 pandemic has impacted community mental health, but the effect on psychiatric admissions is unknown. We investigated factors contributing to acute psychiatric admissions, and whether this changed during the first UK lockdown., Method: A retrospective case-note review study with an exploratory mixed-methods design to examine factors for psychiatric admissions following the first UK 2020 lockdown compared to the same time periods in 2019 and 2018., Results: Themes of psychopathology, risk, social stressors, community treatment issues, and physical health concerns were generated. The mean number of codes per case was 6.19 (s . d. = 2.43), with a mean number of categories per case of 3.73, (s. d. = 0.98). Changes in routines and isolation were common factors in the study year; accommodation and substance abuse were more prominent in the control year. Relationship stressors featured strongly in both groups. There were significantly more women (χ2(1, N = 98) = 20.80, p < 0.00001) and older adults (χ2(1, N = 98) = 8.61, p = 0.0033) in the study group than the control. Single people, compared to those in a relationship (χ2(1, N = 45 ) = 4.46, p = 0.035), and people with affective disorders compared to psychotic disorders ((χ2(1, N = 28 ) = 5.19, p = 0.023), were more likely to have a COVID-19 related admission factor., Conclusions: Early stages of the COVID-19 pandemic amplified pre-existing psychosocial vulnerabilities with a disproportionate psychiatric admissions impact on the mental health of women, older adults and those with affective disorders., Competing Interests: Competing interests: None., (© 2021 Giovanni Fioriti Editore s.r.l.)

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., Competing Interests: Competing interests: Roger A Barker has acted as a consultant to UCB, Living Cell Technologies, BlueRock Therapeutics, Sana Biotechnology, FCDI, Novo Nordisk and Cellino. Clare Bradley is director and majority shareholder of Health Psychology Research Ltd, which licences her patient-reported outcome measures for others to use and manages their linguistic validation into other languages. She receives royalties when existing language versions of her questionnaires are licensed to commercial companies. Her College currently receives research grants to support her research from ViiVHealthCare and from Medtronic. She has recently received speaker fees from Astellas and routinely advises many pharmaceutical companies and contract research organisations on the use of her questionnaires in their clinical trials. Robert Dudley reports delivering training workshops and has written books about CBT, for which he has received fees, and reports delivering CBT in the National Health Service (NHS). Paul Francis has received speaking fees from Suven and Nutricia. Iracema Leroi has received speaking fees from Eisai, Boehringer Ingelheim, GE Healthcare, GlaxoSmithKline, Shire and Lundbeck. Ian McKeith has acted as a consultant for GE Healthcare, Sumitomo Dainippon Pharma, Sanofi and Eisai. John O’Brien has acted as a consultant for TauRx, Axon, GE Healthcare and Eisai. Marco Onofrj has served on the scientific advisory boards of GlaxoSmithKline, Novartis, Lundbeck, Eisai, Valeant, Medtronic and Newron; has received speaker honoraria from Zambon, the World Parkinson Congress, the Movement Disorder Society and the Atypical Dementias congress; was an invited guest and lecturer for the Mental Disorders in Parkinson Disease Congress; serves on the editorial board of Medicine (Baltimore); has been employed as a speaker for Boehringer Ingelheim, GlaxoSmithKline, UCB and Zambon and has received research support from the Italian Ministry of Health and the Italian Ministry of Education. Rimona S Weil has received speaker fees from GE Healthcare. John-Paul Taylor has received speaker fees from GE Healthcare and acted as a consultant for Heptares-Sosei. No other authors declared any conflicts., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

ABSTRACTObjectives:Visual hallucinations are a common symptom in dementia and Parkinson's disease and have been associated with greater cognitive and functional decline, but optimal management strategies are unclear. We review the frequency and pathogenesis of visual hallucinations in dementia and Parkinson's disease and examine the evidence base for their management., Design: We undertook a systematic review of the visual hallucinations in dementia, searching studies published between January 1980 and July 2017 using PubMed with the search terms visual hallucinations AND review AND (dementia OR parkinson*)., Results: We found 645 articles and screened them for relevance, finally including 89 papers (11 meta-analyses, 34 randomized controlled trials, six other trials and a number of relevant review articles). Only six of the trials reported visual hallucination outcomes separately from other neuropsychiatric symptoms., Conclusions: Atypical antipsychotics were frequently studied, but with the exception of clozapine in Parkinson's disease dementia, results were equivocal. There was some evidence that acetylcholinesterase inhibitors may help visual hallucinations. Overall, effect sizes for most treatments were small and there were few studies with long term follow up. Treatments need to be carefully weighed up with the risks and reviewed often, and many patients improved without treatment. There is a lack of data regarding visual hallucinations due to the grouping of psychotic symptoms together in commonly used rating scales. The lack of a specific rating scales, or analyzable items within other scales, for visual hallucinations, limited efficacy of current and small evidence base with short follow up are important areas for future studies to address.

Background: Unequal pupils (anisocoria) may be physiological, pathological or pharmacological. Importantly, anisocoria can indicate underlying disease of the eye, orbit, brain, neck or chest. Examination of the pupils is therefore a crucial part of any eye examination., Objective: As a clinician, it is important to determine whether a patient with anisocoria can be reassured or requires referral for further investigation. This review examines the anatomy of the pupillary pathway, and provides a structured approach to examination of the pupils. The aim is to provide clinicians with confidence when encountering patients with anisocoria., Discussion: Anisocoria can imply serious underlying pathology, so accurate pupil testing and astute observation are paramount. This review discusses the differential diagnosis of a large pupil (anisocoria more obvious in the light) and a small pupil (anisocoria more obvious in the dark), and discusses the relevant afferent pupillary defect, in which there is no anisocoria but both pupils react differently depending on which eye is illuminated.

Isomaltooligosaccharides (IMOs) are included in many commercially available food products including protein/fiber bars, shakes, and other dietary supplements. Marketed as "high fiber," "prebiotic soluble fiber," and/or as a "low-calorie, low glycemic sweetener," IMO may be present in significant amounts, for example, more than 15 g/item or serving. Herein, high-pressure anion exchange chromatography with pulsed amperometric detection and high-pressure liquid chromatography with differential refractive index detection are used to compare 7 commercially available IMO-containing bulk food ingredients. The ingredients are typical of those produced either (a) via bacterial fermentation ("fermented" IMO or MIMO) of sucrose in the presence of a maltose acceptor mediated by a glucosyltransferase enzyme (dextransucrase), or (b) via transglycosylation of hydrolyzed starch with α-glucosidase ("industrial" IMO). Analysis of the results with respect to digestibility suggests that the potential glycemic impact of the ingredients and products containing "industrial" IMO may be inconsistent with the product labeling and/or certificates of analysis with respect to overall fiber content, prebiotic fiber content, and glycemic response and are thus inappropriate for diabetic patients and those on low-carbohydrate (for example, ketogenic) diets., (© 2017 Institute of Food Technologists®.)

Background: Hyperferritinemia-cataract syndrome (HCS) is a rare Mendelian condition characterized by bilateral cataract and high levels of serum ferritin in the absence of iron overload., Methods: HCS was diagnosed in three adult siblings. In two of them it was possible to assess lens changes initially in 1995 and again in 2013. Serum ferritin, iron, transferrin concentrations and transferrin saturation percentage were also measured, and the Iron Responsive Element (IRE) region of the L-ferritin gene (FTL) was studied., Results: Serum ferritin concentrations were considerably elevated while serum iron, transferrin and transferrin saturation levels were within the normal range in each sibling. Cataract changes in our patients were consistent with those previously reported in the literature. Progression of the cataract, an aspect of few studies in this syndrome, appeared to be quite limited in extent. The heterozygous +32G to T (-168G>T) substitution in the IRE of the FTL gene was detected in this family., Conclusions: Ophthalmic and biochemical studies together with genetic testing confirmed HCS in three family members. Although the disorder has been extensively described in recent years, little is known regarding cataract evolution over time. In our cases, lens evaluations encompassed many years, identified bilateral cataract of typical morphology and supported the hypothesis that this unique clinical feature of the disease tends to be slowly progressive in nature, at least in adults.

Purpose: To investigate if the accuracy of intraocular pressure (IOP) measurements using rebound tonometry over disposable hydrogel (etafilcon A) contact lenses (CL) is affected by the positive power of the CLs., Methods: The experimental group comprised 26 subjects, (8 male, 18 female). IOP measurements were undertaken on the subjects' right eyes in random order using a Rebound Tonometer (ICare). The CLs had powers of +2.00D and +6.00D. Measurements were taken over each contact lens and also before and after the CLs had been worn., Results: The IOP measure obtained with both CLs was significantly lower compared to the value without CLs (t test; p<0.001) but no significant difference was found between the two powers of CLs., Conclusions: Rebound tonometry over positive hydrogel CLs leads to a certain degree of IOP underestimation. This result did not change for the two positive lenses used in the experiment, despite their large difference in power and therefore in lens thickness. Optometrists should bear this in mind when measuring IOP with the rebound tonometer over plus power contact lenses., (Copyright © 2016 The Authors. Published by Elsevier Espana.. All rights reserved.)

The characteristics of the on- and off-responses in the human diabetic retina by a "long-duration" multifocal electroretinogram (mfERG) paradigm were investigated. Changes in the retinal antagonistic interaction were also evaluated in the early stage of diabetes mellitus (DM). Twenty type II diabetic patients with no or mild non-proliferative diabetic retinopathy (NPDR) and twenty-one age-matched healthy controls were recruited for "long-duration" mfERG measurements. A 61-hexagon mfERG stimulus was displayed under two chromatic conditions (white/black and blue/black) at matched luminance. The amplitudes and implicit times of the on-response components (N1, P1 and N2) and off-response (P2) components were analysed. The blue stimulation generally triggered greater mfERG amplitudes in P1, N2 and P2 (p<0.05) than those from white stimulation in both control and diabetic groups. The diabetic group showed significantly greater N2 amplitude than the controls under white stimulation in mid-retinal regions (Rings 2 and 4) (p<0.05). When the stimulus was changed from white to blue, the diabetic group showed a smaller percentage change in N2 amplitude than the controls in peripheral retinal region (Ring 5) (p<0.02). When a stimulus is changed from white (broad-band spectral stimulation) to blue (narrow-band spectral stimulation), a decrease in the involvement of lateral antagonism would be expected. The larger amplitude of the on-response component (N2) in the diabetic patients suggested an imbalance of lateral antagonism, and the lesser percentage change of N2 amplitude in the diabetic group may indicate an impairment of the cross-talk at the middle retinal level in early stages of DM.

The rapid advancement from single-gene testing to whole genome sequencing has significantly broadened the type and amount of information available to researchers, physicians, patients, and the public in general. Much debate has ensued about whether genomic test results should be reported to research participants, patients and consumers, and at what stage we can be sure that existing evidence justifies their use in clinical settings. Courts and judges evaluating the utility of these results will not be immune to this uncertainty. As scholars increasingly explore the duty of care standards related to reporting genomic test results, it is timely to provide a framework for understanding how uncertainty about genetic and genomic tests influences evidentiary considerations in the court room. Here, we explore the subtleties and nuances of interpreting genetic data in an environment of substantial discord related to the value that individuals should place on genetic and genomic tests. In conjunction, we discuss the roles courts should play in qualifying experts, expert testimony, and genetic and genomic tests given the intricate and complex nature of genetic and genomic information., (© 2016 American Society of Law, Medicine & Ethics.)

Structural magnetic resonance imaging (MRI) has shown great utility in diagnosing soft tissue burden in osteoarthritis (OA), though MRI measures of cartilage integrity have proven more elusive. Sodium MRI can reflect the proteoglycan content of cartilage; however, it requires specialized hardware, acquisition sequences, and long imaging times. This study was designed to assess the potential of a clinically feasible sodium MRI acquisition to detect differences in the knee cartilage of subjects with OA versus healthy controls (HC), and to determine whether longitudinal changes in sodium content are observed at 3 and 6 months. 28 subjects with primary knee OA and 19 HC subjects age and gender matched were enrolled in this ethically-approved study. At baseline, 3 and 6 months subjects underwent structural MRI and a 0.4ms echo time 3D T1-weighted sodium scan as well as the knee injury and osteoarthritis outcome score (KOOS) and knee pain by visual analogue score (VAS). A standing radiograph of the knee was taken for Kellgren-Lawrence (K-L) scoring. A blinded reader outlined the cartilage on the structural images which was used to determine median T1-weighted sodium concentrations in each region of interest on the co-registered sodium scans. VAS, K-L, and KOOS all significantly separated the OA and HC groups. OA subjects had higher T1-weighted sodium concentrations, most strongly observed in the lateral tibial, lateral femoral and medial patella ROIs. There were no significant changes in cartilage volume or sodium concentration over 6 months. This study has shown that a clinically-feasible sodium MRI at a moderate 3T field strength and imaging time with fluid attenuation by T1 weighting significantly separated HCs from OA subjects.

Purpose: To determine the prevalence of papillary changes of the upper palpebral conjunctiva and folliculosis of the lower palpebral conjunctiva in Chinese children with no history of contact lens wear., Method: Ninety-nine subjects (aged 6-15 years old) who were interested in a myopia control study were screened for papillary changes and folliculosis of the palpebral conjunctiva. Photodocumentation was performed under white and blue light (after the application of fluorescein) with a yellow filter and the photographs were graded by a group of practitioners according to a pre-set grading scale. Analysis was performed with the subjects divided into groups according to gender and age., Results: More than 48% of the subjects had clinically significant (≥Grade 3) papillary changes in the upper palpebral conjunctiva. The prevalence of significant folliculosis in the lower lid was about 33%. The prevalence of significant papillary changes and folliculosis were similar between genders. No differences were observed between younger (age≤10 years old) and older (age>10 years old) in papillary changes but younger subjects showed a higher prevalence of folliculosis., Conclusions: The prevalences of clinically significant papillary changes and folliculosis of unknown aetiology are high in Chinese children., (Copyright © 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Thymine DNA glycosylase (TDG) belongs to the superfamily of uracil DNA glycosylases (UDG) and is the first enzyme in the base-excision repair pathway (BER) that removes thymine from G:T mismatches at CpG sites. This glycosylase activity has also been found to be critical for active demethylation of genes involved in embryonic development. Here we show that wild-type p53 transcriptionally regulates TDG expression. Chromatin immunoprecipitation (ChIP) and luciferase assays indicate that wild-type p53 binds to a domain of TDG promoter containing two p53 consensus response elements (p53RE) and activates its transcription. Next, we have used a panel of cell lines with different p53 status to demonstrate that TDG mRNA and protein expression levels are induced in a p53-dependent manner under different conditions. This panel includes isogenic breast and colorectal cancer cell lines with wild-type or inactive p53, esophageal squamous cell carcinoma cell lines lacking p53 or expressing a temperature-sensitive p53 mutant and normal human bronchial epithelial cells. Induction of TDG mRNA expression is accompanied by accumulation of TDG protein in both nucleus and cytoplasm, with nuclear re-localization occurring upon DNA damage in p53-competent, but not -incompetent, cells. These observations suggest a role for p53 activity in TDG nuclear translocation. Overall, our results show that TDG expression is directly regulated by p53, suggesting that loss of p53 function may affect processes mediated by TDG, thus negatively impacting on genetic and epigenetic stability.

Purpose: To investigate early functional changes of local retinal defects in type II diabetic patients using the global flash multifocal electroretinogram (MOFO mfERG)., Methods: Thirty-eight diabetic patients and 14 age-matched controls were recruited. Nine of the diabetics were free from diabetic retinopathy (DR), while the remainder had mild to moderate non-proliferative diabetic retinopathy. The MOFO mfERG was performed at high (98 %) and low (46 %) contrast levels. MfERG responses were grouped into 35 regions for comparison with DR classification at those locations. Z-scores of the regional mfERG responses were compared across different types of DR defects., Results: The mfERG waveform consisted of the direct component (DC) and the induced component (IC). Local reduction in DC and IC amplitudes were found in diabetic patients with and without DR. With increasing severity of retinopathy, there was a further deterioration in amplitude of both components. Under MOFO mfERG paradigm, amplitude was a useful screening parameter., Conclusion: The MOFO mfERG can help in detecting early functional anomalies before the appearance of visible signs, and may assist in monitoring further functional deterioration in diabetic patients.

Purpose: To measure reproducibility, longitudinal and cross-sectional differences in T2* maps at 3 Tesla (T) in the articular cartilage of the knee in subjects with osteoarthritis (OA) and healthy matched controls., Materials and Methods: MRI data and standing radiographs were acquired from 33 subjects with OA and 21 healthy controls matched for age and gender. Reproducibility was determined by two sessions in the same day, while longitudinal and cross-sectional group differences used visits at baseline, 3 and 6 months. Each visit contained symptomological assessments and an MRI session consisting of high resolution three-dimensional double-echo-steady-state (DESS) and co-registered T2* maps of the most diseased knee. A blinded reader delineated the articular cartilage on the DESS images and median T2* values were reported., Results: T2* values showed an intra-visit reproducibility of 2.0% over the whole cartilage. No longitudinal effects were measured in either group over 6 months. T2* maps revealed a 5.8% longer T2* in the medial tibial cartilage and 7.6% and 6.5% shorter T2* in the patellar and lateral tibial cartilage, respectively, in OA subjects versus controls (P < 0.02)., Conclusion: T2* mapping is a repeatable process that showed differences between the OA subject and control groups., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: To assess the accuracy of intraocular pressure (IOP) measurements using rebound tonometry over disposable hydrogel (etafilcon A) and silicone hydrogel (senofilcon A) contact lenses (CLs) of different powers., Methods: The experimental group comprised 36 subjects (19 male, 17 female). IOP measurements were undertaken on the subject's right eyes in random order using a rebound tonometer (ICare). The CLs had powers of +2.00D, -2.00D and -6.00D. Six measurements were taken over each contact lens and also before and after the CLs had been worn., Results: A good correlation was found between IOP measurements with and without CLs (all r≥0.80; p<0.05). Bland Altman plots did not show any significant trend in the difference in IOP readings with and without CLs as a function of IOP value. A two-way ANOVA revealed a significant effect of material and power (p<0.01) but no interaction. All the comparisons between the measurements without CLs and with hydrogel CLs were significant (p<0.01). The comparisons with silicone hydrogel CLs were not significant., Conclusions: Rebound tonometry can be reliably performed over silicone hydrogel CLs. With hydrogel CLs, the measurements were lower than those without CLs. However, despite the fact that these differences were statistically significant, their clinical significance was minimal., (2011 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

Background: Optomap uses the ultra-wide field scanning laser ophthalmoscopy to provide retinal examination. It permits fundus examination without the use of a mydriatic, which is more comfortable for the patients. This paper determines the sensitivity and specificity of the Optomap for detecting retinal signs under non-mydriatic conditions., Methods: Fifty-four eyes identified with retinal/choroidal signs and eight normal eyes were recruited from 31 Hong Kong Chinese subjects. Photo-documentation of fundal changes was obtained with the Optomap under non-mydriatic conditions before a dilated fundus examination by a clinician using standard procedures. The eyelid was retracted using a cotton bud when necessary. Dilated fundus examinations were performed by another clinician using binocular indirect ophthalmoscopy and slitlamp biomicroscopy with a fundus lens. The Optomap images were evaluated by four other investigators under masked condition. The International Classification of Disease, Ninth Revision (ICD-9-CM) was adopted for recording retinal features. Screening results were compared with those obtained using the dilated fundus examination as the gold standard., Results: The cotton bud method for eyelid retraction showed an improvement in the area of retina that could be visualised. The sensitivity and specificity of the Optomap averaged 76.4 and 71.9 per cent, respectively. Some fundal signs were missed by all observers in the Optomap but not with the biomicroscope. These included white-without-pressure, lattice degeneration, paramacular drusen and pigmentary changes at central fundus., Conclusion: Optomap serves as a reliable screening tool for fundus examination especially because it covers a much wider area of the peripheral retina than other digital instruments for fundus photography.

We measured optical and biometric parameters of emmetropic eyes as a function of age. There were approximately 20 subjects each in age groups 18-29, 30-39, 40-49, 50-59, and 60-69 years with similar male and female numbers. One eye was tested for each subject, having spherical equivalent in the range -0.88 D to +0.75 D and

The presence of interface debris is commonly reported in patients having undergone LASIK refractive surgery. The patient described here had numerous large particles believed to be plastic and metal artefacts from the surgery at the level of the stroma/flap interface, along with a corneal scar consistent with a foreign body injury. The aetiology and possible sequelae of the particles and scar are discussed.

Purpose: To measure function with the rod-mediated multifocal electroretinogram (mfERG) in younger and older subjects with normal vision and with early age-related maculopathy (ARM)., Methods: Thirty subjects were studied: 10 healthy subjects with a mean age of 31 years (young group), 10 healthy subjects with a mean age of 71 years (old group), and 10 early ARM subjects with a mean age of 71 years (early ARM group). The influence of cataract was approximated by retesting five subjects of the young group through an 0.3 neutral density filter (ND filter group). We analyzed first-order N1P1-amplitude and P1-implicit time (P1-IT) mfERG responses and correlated them with funduscopic changes as defined by the Age-Related Eye Disease Study (AREDS) group., Results: Averaged concentric ring P1-ITs were significantly delayed in the old (p = 0.02) and early ARM (p < 0.001) compared with the young group and in the early ARM group compared with the old and ND group (p < or = 0.01). There were no significant differences in N1P1-amplitudes between groups, but there was a significant location effect for all groups with highest mean amplitudes for the most peripheral ring of hexagons (p < 0.01). Significantly delayed overall P1-ITs (p < 0.05) were correlated with progressive funduscopic changes., Conclusions: Aging and early ARM affects the rod-mediated mfERG, and there is good correlation with funduscopic changes. Although a lens effect cannot be excluded, a neuronal transmission alteration at the postreceptoral level is suggested.

Purpose: To investigate the global-flash multifocal electroretinogram (mfERG) in early age-related maculopathy (ARM)., Methods: Thirty-two eyes from 20 healthy control subjects and 12 age-matched subjects with early ARM were investigated with the conventional and the global-flash mfERG. Early ARM subjects were graded according to an international grading system. The conventional mfERG consisted of 103 hexagons flickering according to a pseudorandom m-sequence. The global-flash mfERG paradigm used four frames starting with the conventional m-sequence stimulation, followed by a dark frame, a global flash, and another dark frame. The responses include a direct response (DR) and a later induced component (IC). The first-order kernel peak-to-trough response densities of the conventional mfERG (N1P1), the global-flash DR and IC, and the implicit times of the conventional P1, global-flash DR, and IC peak were analyzed after averaging the results into five groups according to five field locations: a central area and four quadrants., Results: There was a significant reduction of the global-flash mfERG DR response density (P < or = 0.05) in the early ARM group compared with the control group. Neither the IC response density nor DR and IC implicit times were significantly impaired. However, the superior retina showed longer implicit times than did the inferior retina for the DR in the early ARM group. There was no significant correlation between funduscopic features and the central averaged responses of the global-flash mfERG (for the DR response density: r = -0.19, P = 0.3, or for the DR implicit time: r = -0.18, P = 0.3). None of the conventional mfERG parameters was significantly different between the two groups., Conclusions: The global-flash mfERG detects deficits in early ARM before the conventional mfERG. Retinal ischemia may play a role in producing function impairment in ARM.

Blepharitis is a ubiquitous disease and arguably, among the most common conditions that eye care practitioners encounter. Usually, its diagnosis is straight forward. However, any deviation from its predicted clinical appearance should cause the practitioner to consider other possibilities. The patient described in this report was diagnosed with blepharitis and treated as such. However, the true cause of her difficulties was basal cell carcinoma. This condition is briefly reviewed.

Purpose: To investigate the multifocal electroretinogram (mfERG) and subjective function in early age-related maculopathy (ARM)., Methods: Seventeen subjects with early ARM with visual acuity (VA) of 6/12 or better and 20 age-matched control subjects were examined. We assessed mfERGs, high and low contrast distance VA, near VA, low luminance VA, contrast sensitivity, saturated and desaturated Panel D-15 and visual fields (mean sensitivity). The mfERG responses were analysed by comparing central-overall (method 1) and superior-inferior (method 2) ratios., Results: The mfERG did not discriminate between the groups whereas colour vision (tritan deficiency), contrast sensitivity, and high contrast and low contrast VA showed significantly reduced responses for the early ARM group compared with the control group (p < or = 0.01). The mfERG first-order kernel responses correlated significantly with the desaturated D-15 in both methods (r = -0.5, p < or = 0.05). Fundus grading was not correlated with the mfERG measures., Conclusions: Although the mfERG correlated significantly with the desaturated D-15 in early ARM, suggesting it operates at a sensitive level, it failed to discriminate between the control and ARM groups. In our sample, the subjective function measures were more sensitive than the mfERG measures.

An unusual case of bilateral oculodermal melanocytosis or the naevus of Ota is reviewed. In this condition, there is hyperpigmentation of ocular structures and the skin of the face. In this case, a pigmentary mottling of the fundus was observed using long wavelength light.

Background: Diabetes mellitus is a systemic disease affecting approximately 750,000 Australians of whom more than 70,000 are Queenslanders. It can have serious ocular consequences and patients with diabetes require regular eye examinations to determine the degree of ocular involvement and the stage of retinopathy, if present. It is important that optometrists detect diabetic retinal changes and refer appropriately. We sought to determine the proficiency of optometrists at detecting retinal changes caused by diabetes., Methods: The study comprised four parts: 1. Nineteen randomly recruited Australian optometrists practising in Queensland completed a questionnaire on their experiences seeing patients with diabetes. 2. They examined the ocular fundi of 10 patients. 3. They viewed retinal slides of 12 additional cases. 4. They attended a follow-up seminar on diabetes and the cases. They were informed that the patients did not necessarily have diabetes and instructed not to discuss the condition with the patient or their colleagues. The optometrists were allowed seven minutes per station to examine the patient or the slides and write down their responses before moving to the next station., Results: When the slides and patients were considered together, cases where diabetic retinopathy was present were correctly identified by 94.0 per cent of the optometrists and cases where retinopathy was not present were correctly identified by 93.6 per cent of the optometrists. When all assessments were considered together, the correct detection/differential diagnosis rate was 88.3 per cent. Sub-classification of diabetic retinopathy severity agreed with that of the reference examiners in 58.3 per cent of assessments and there was agreement on management in 79.4 per cent of cases. Of the 22 assessments undertaken by each optometrist, there were, on average, 2.5 errors., Conclusion: Randomly selected Australian optometrists are able to detect and grade diabetic retinal changes solely by retinal examination and refer the patients requiring specialist care.

A case of giant papillary conjunctivitis associated with the wearing of an ocular prosthesis is described. Potential causes and treatment regimens are briefly reviewed.

Hyperpigmentation of the ocular tissues and of the skin around the eye is uncommon. In ocular melanosis, the episclera, uveal tract and the angle of the anterior chamber may be involved. Heterochromia iridis may be present, if the iris is affected. In oculodermal melanocytosis or the naevus of Ota, hyperpigmentation of the skin follows the distribution of the first and second divisions of the fifth cranial nerve. This report documents a patient with episcleral pigment, heterochromia iridis and numerous tiny pigmented nodules on the iris (mammillations). The possible significance of these findings is discussed.

We describe a family that shows autosomal dominant pattern dystrophy of the retinal pigment epithelium. There were 10 affected family members encompassing three generations. The various manifestations of these dystrophies, their inheritance characteristics, affects on vision function and their pathogenesis are discussed.

Static automated visual field testing is now an integral part of the detection and monitoring of primary open angle glaucoma. However, although many aspects of testing are automated, interpretation of the large amounts of data produced by these instruments is not. Two major challenges facing the practitioner are differentiating between the visual fields of a patient with early glaucoma and those of a normal patient, and identifying whether small reductions in sensitivity are due to a true defect or a product of other factors. This paper presents a clinical overview of how to systematically review visual field plots and how to recognise defects arising from patient factors, as well as some of the alternative testing techniques available for the assessment of the glaucoma patient.

BACKGROUND: In all Australian states optometrists are permitted to use diagnostic topical ocular drugs in the practice of their profession. In addition, legislation has just been passed in Victoria allowing optometrists to prescribe topical S4 medications for ocular conditions. Changing optometric legislation to incorporate S4 ophthalmic agents is a topical issue within optometry. METHODS: By postal survey, we asked Queensland optometrists to gauge their level of education, current mode of practice and whether they were in favour of gaining access to prescription-only therapeutic medications. Their opinions on the education requirements, perceived potential public benefits and the possible barriers to optometrists gaining prescribing rights to therapeutic agents were also investigated. RESULTS: A 45 per cent response rate to the survey (231 responses out of 517) was obtained. The majority of respondents (88 per cent) wanted to be able to prescribe therapeutic agents. Over 50 per cent considered themselves competent and believed they were capable of treating dry eye, blepharitis, allergic conjunctivitis, corneal abrasions and contact lens induced papillary conjunctivitis. Over 90 per cent would be confident recommending topical lubricants and antihistamines, while 65 per cent felt they were adequately prepared to prescribe topical antibiotics. Education level, in particular the completion of a therapeutic drugs course, was the main factor that determined whether the respondents practised or were willing to practise at a higher level. CONCLUSION: The majority of Queensland optometrists are well aware of the issues surrounding the use of pharmaceutical agents. Many optometrists feel they are well prepared for prescribing ocular therapeutic agents.