Associations Between Neuropsychiatric Symptoms and Inflammation in Neurodegenerative Dementia: A Systematic Review.

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.

Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration.

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.

Differential Synaptic Loss in ß-Amyloid Positive Versus ß-Amyloid Negative Corticobasal Syndrome.

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 ß-amyloid status. METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had ß-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]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 BPND and gray matter volume between groups were assessed by ANOVA. RESULTS: Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the ß-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. DISCUSSION: Distinct patterns of [11C]UCB-J and [18F]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.

APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure.

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.

A mixed-methods SWOT analysis of a medical student Balint group programme.

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.

'Auspicious liaisons'-evaluating the impact of a liaison geriatrician initiative on older adults psychiatric wards.

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.

Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife.

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.

Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C]UCB-J Positron Emission Tomography Study.

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.

From protein biomarkers to proteomics in dementia with Lewy Bodies.

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.

Inflammation in dementia with Lewy bodies.

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.

Factors in Psychiatric Admissions: Before and During the Covid-19 Pandemic.

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.

Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management.

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.

Unequal pupils: Understanding the eye's aperture.

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.

Management of visual hallucinations in dementia and Parkinson's disease.

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.

Improvement in Gastroesophageal Reflux Symptoms From a Food-grade Maltosyl-isomaltooligosaccharide Soluble Fiber Supplement: A Case Series.

Gastroesophageal reflux disease (GERD) is a very common medical condition. Symptom improvement from ingested prebiotic soluble fiber has not been reported previously. In fact, a related soluble fiber, fructooligosaccharides, has been shown to worsen GERD. We report on a series of 24 patients with GERD, 88% of which improved after several weeks of daily consumption of a specific maltosyl-isomaltooligosaccharide (MIMO) fermented prebiotic soluble fiber. We also report on 2 proton pump inhibitor (PPI)-dependent patients with GERD who, after beginning daily MIMO, were able to eliminate PPI therapy. The hypotheses explaining the mechanism for GERD improvement with MIMO is discussed. To the best of our knowledge, these cases are the first time any prebiotic soluble fiber has been reported to improve or eliminate symptoms of GERD and enable patients with GERD to decrease or eliminate their PPI therapy.

A Survey of Commercially Available Isomaltooligosaccharide-Based Food Ingredients.

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.