Publications by authors named "Elizabeta B Mukaetova-Ladinska"

58 Publications

Tubulin and Tubulin Posttranslational Modifications in Alzheimer's Disease and Vascular Dementia.

Front Aging Neurosci 2021 29;13:730107. Epub 2021 Oct 29.

Department of Neuroscience, Behavior and Psychology, University of Leicester, Leicester, United Kingdom.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common forms of dementia in older people. Although these two dementia types differ in their etiology, they share many pathophysiological and morphological features, including neuronal loss, which is associated with the microtubule (MT) destabilization. Stabilization of MTs is achieved in different ways: through interactions with MT binding proteins (MTBP) or by posttranslational modifications (PTMs) of tubulin. Polyglutamylation and tyrosination are two foremost PTMs that regulate the interaction between MTs and MTBPs, and play, therefore, a role in neurodegeneration. In this review, we summarize key information on tubulin PTMs in relation to AD and VaD and address the importance of studying further the tubulin code to reveal sites of potential intervention in development of novel and effective dementia therapy.
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http://dx.doi.org/10.3389/fnagi.2021.730107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586541PMC
October 2021

Acute and post-acute neurological manifestations of COVID-19: present findings, critical appraisal, and future directions.

J Neurol 2021 Oct 21. Epub 2021 Oct 21.

Department of Neurology, Centre for Global Health, Technical University of Munich, Munich, Germany.

Acute and post-acute neurological symptoms, signs and diagnoses have been documented in an increasing number of patients infected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19). In this review, we aimed to summarize the current literature addressing neurological events following SARS-CoV-2 infection, discuss limitations in the existing literature and suggest future directions that would strengthen our understanding of the neurological sequelae of COVID-19. The presence of neurological manifestations (symptoms, signs or diagnoses) both at the onset or during SARS-CoV-2 infection is associated with a more severe disease, as demonstrated by a longer hospital stay, higher in-hospital death rate or the continued presence of sequelae at discharge. Although biological mechanisms have been postulated for these findings, evidence-based data are still lacking to clearly define the incidence, range of characteristics and outcomes of these manifestations, particularly in non-hospitalized patients. In addition, data from low- and middle-income countries are scarce, leading to uncertainties in the measure of neurological findings of COVID-19, with reference to geography, ethnicity, socio-cultural settings, and health care arrangements. As a consequence, at present a specific phenotype that would specify a post-COVID (or long-COVID) neurological syndrome has not yet been identified.
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http://dx.doi.org/10.1007/s00415-021-10848-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528941PMC
October 2021

Qualitative Analysis of the Cognition and Flow (CoGFlowS) Study: An Individualized Approach to Cognitive Training for Dementia Is Needed.

J Alzheimers Dis 2021 ;83(1):209-225

Inflammatory, Injury & Recovery Science, School of Medicine, University of Nottingham, Nottingham, UK.

Background: Cognitive training (CT) may have benefits for both healthy older adults (HC) and those with early cognitive disorders [mild cognitive impairment (MCI) and dementia]. However, few studies have qualitatively evaluated home-based, computerized CT programs.

Objective: We present the qualitative arm of a feasibility randomized controlled trial evaluating a CT program for HC and people living with MCI or dementia.

Methods: Participants underwent semi-structured interviews after 12 weeks of CT. Where possible, participants were interviewed with their carers. The interview schedule and analysis were underpinned by the health belief model. Interviews were audio-recorded, transcribed, open-coded, and categorized into themes. The analytical framework was developed, and themes were condensed under five major categories: benefits, barriers, threat, self-efficacy, and cues to action.

Results: 37 participants underwent interviews. CT was feasible and acceptable to participants. Benefits included: enjoyment, improved awareness, benchmarking cognitive function, reassurance of abilities and giving back control. Barriers were more prevalent among those with dementia: problems with technology, frustration, conflict between patients and carers, apathy and lack of insight, anxiety or low mood, and lack of portability. HC and MCI perceived the severity of dementia risk as high, partially mitigated by CT. Participants living with dementia valued a more individualized approach to training, accounting for baseline characteristics.

Conclusion: CT was a feasible intervention for HC and people living with dementia and MCI. Benefits were present, but the identified barriers need to be addressed for CT to be implemented successfully.
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http://dx.doi.org/10.3233/JAD-210428DOI Listing
November 2021

Creative Art Therapy as a Non-Pharmacological Intervention for Dementia: A Systematic Review.

J Alzheimers Dis Rep 2021 May 3;5(1):353-364. Epub 2021 May 3.

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.

Background: Non-pharmacological therapies have been shown to be effective in managing challenging behavior in people with dementia. However, the efficacy of art therapy has yet to be determined.

Objective: In the present systematic review, we evaluate the efficacy of art therapy as a non-pharmacological intervention for dementia and examine whether art therapy improves wellbeing and quality of life while decreasing biological and psychological symptoms of dementia (BPSD).

Methods: Research undertaken between 2015 and 2020 was examined and a total of seventeen studies met the specified search criteria, with 853 participants (657 people with dementia, 180 formal and informal carers, and 16 volunteers) involved.

Results: We identified four outcome domains: wellbeing, quality of life, BPSD, and cognitive function. One or more significant outcomes as having an impact on the efficacy of the intervention were reported in 88% (15/17) of the studies, whereas 17% (3/17) demonstrated significant outcomes across quality of life, wellbeing, and BPSD.

Conclusion: People with dementia benefit from art therapy. These interventions when incorporating elements of being 'in the moment' increase opportunities for communication between people with dementia and their caregiver(s) and facilitate person-centered therapeutic activities.
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http://dx.doi.org/10.3233/ADR-201002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203286PMC
May 2021

Hepcidin Increases Cytokines in Alzheimer's Disease and Down's Syndrome Dementia: Implication of Impaired Iron Homeostasis in Neuroinflammation.

Front Aging Neurosci 2021 30;13:653591. Epub 2021 Apr 30.

John van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom.

The liver-derived hormone hepcidin, a member of the defensin family of antimicrobial peptides, plays an important role in host defense and innate immunity due to its broad antibacterial and antiviral properties. Ferritin, an iron storage protein is often associated with iron deficiency, hypoferritinemia, hypoxia, and immune complications, which are all significant concerns for systemic infection in Alzheimer's disease (AD) and Down's syndrome (DS) dementia. Serum and post-mortem brain samples were collected from AD, DS and age-matched control subjects. Serum samples were analyzed with ELISA for ferritin, hepcidin and IL-6. Additionally, post-mortem brain sections were assessed by immunohistochemistry for iron-related and inflammatory proteins. A significant increase in serum hepcidin levels was found in DS, compared to controls and AD subjects ( < 0.0001). Hepcidin protein was visible in the epithelial cells of choroid plexus, meningeal macrophages and in the astrocytes close to the endothelium of blood vessels. Hepcidin co-localized with IL-6, indicating its anti-inflammatory properties. We found significant correlation between hypoferritinemia and elevated levels of serum hepcidin in AD and DS. Hepcidin can be transported macrophages and the majority of the vesicular hepcidin enters the brain a compromised blood brain barrier (BBB). Our findings provide further insight into the molecular implications of the altered iron metabolism in acute inflammation, and can aid towards the development of preventive strategies and novel treatments in the fight against neuroinflammation.
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http://dx.doi.org/10.3389/fnagi.2021.653591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120149PMC
April 2021

Prevalence and 1-year incidence of HIV-associated neurocognitive disorder (HAND) in adults aged ≥50 years attending standard HIV clinical care in Kilimanjaro, Tanzania.

Int Psychogeriatr 2021 Mar 24:1-12. Epub 2021 Mar 24.

Newcastle University, Newcastle upon Tyne, UK.

Objectives: HIV-associated neurocognitive disorders (HANDs) are prevalent in older people living with HIV (PLWH) worldwide. HAND prevalence and incidence studies of the newly emergent population of combination antiretroviral therapy (cART)-treated older PLWH in sub-Saharan Africa are currently lacking. We aimed to estimate HAND prevalence and incidence using robust measures in stable, cART-treated older adults under long-term follow-up in Tanzania and report cognitive comorbidities.

Design: Longitudinal study.

Participants: A systematic sample of consenting HIV-positive adults aged ≥50 years attending routine clinical care at an HIV Care and Treatment Centre during March-May 2016 and followed up March-May 2017.

Measurements: HAND by consensus panel Frascati criteria based on detailed locally normed low-literacy neuropsychological battery, structured neuropsychiatric clinical assessment, and collateral history. Demographic and etiological factors by self-report and clinical records.

Results: In this cohort (n = 253, 72.3% female, median age 57), HAND prevalence was 47.0% (95% CI 40.9-53.2, n = 119) despite well-managed HIV disease (Mn CD4 516 (98-1719), 95.5% on cART). Of these, 64 (25.3%) were asymptomatic neurocognitive impairment, 46 (18.2%) mild neurocognitive disorder, and 9 (3.6%) HIV-associated dementia. One-year incidence was high (37.2%, 95% CI 25.9 to 51.8), but some reversibility (17.6%, 95% CI 10.0-28.6 n = 16) was observed.

Conclusions: HAND appear highly prevalent in older PLWH in this setting, where demographic profile differs markedly to high-income cohorts, and comorbidities are frequent. Incidence and reversibility also appear high. Future studies should focus on etiologies and potentially reversible factors in this setting.
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http://dx.doi.org/10.1017/S1041610221000156DOI Listing
March 2021

COVID-19 and neurocognitive disorders.

Curr Opin Psychiatry 2021 03;34(2):149-156

Cambridge Intellectual & Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge, UK.

Purpose Of Review: The COVID-19 infection results in various viral-related physical and mental health problems, joined with the long-term psychological impact of the pandemic in general. However, the accompanying neurocognitive changes remain poorly understood.

Recent Findings: We synthetize the current knowledge of viral (SARS-CoV-2) induced inflammation, mechanisms to viral entry into the central nervous system and altered neurotransmitter systems to provide an informed neurobiological explanation for the rise of neurocognitive disorders (defined as per the DSM-5 criteria).

Summary: The mild and major neurocognitive disorder symptoms due to the COVID-19 pandemic provide a unique opportunity to address the early changes underlying neurocognitive impairment at both clinical and molecular level. We discuss the utilization of the available evidence for their management and future novel therapeutic opportunities.
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http://dx.doi.org/10.1097/YCO.0000000000000687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924920PMC
March 2021

Risk factors for symptomatic HIV-associated neurocognitive disorder in adults aged 50 and over attending a HIV clinic in Tanzania.

Int J Geriatr Psychiatry 2020 10 20;35(10):1198-1208. Epub 2020 Jul 20.

Old Age Psychiatry, Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK.

Objectives: HIV-associated neurocognitive disorder (HAND), although prevalent, remains a poorly researched cause of morbidity particularly in sub-Saharan Africa (SSA). We aimed to explore the risk factors for HAND in people aged 50 and over under regular follow-up at a government HIV clinic in Tanzania.

Methods: HIV-positive adults aged 50 years and over were approached for recruitment at a routine HIV clinic appointment over a 4-month period. A diagnostic assessment for HAND was implemented, including a full medical/neurological assessment and a collateral history from a relative. We investigated potential risk factors using a structured questionnaire and by examination of clinic records.

Results: Of the cohort (n = 253), 183 (72.3%) were female and the median age was 57 years. Fifty-five individuals (21.7%) met the criteria for symptomatic HAND. Participants were at a greater risk of having symptomatic HAND if they lived alone [odds ratio (OR) = 2.566, P = .015], were illiterate (OR 3.171, P = .003) or older at the time of HIV diagnosis (OR = 1.057, P = .015). Age was correlated with symptomatic HAND in univariate, but not multivariate analysis.

Conclusions: In this setting, HIV-specific factors, such as nadir CD4 count, were not related to symptomatic HAND. The "legacy theory" of early central nervous system damage prior to initiation of anti-retroviral therapy initiation may contribute, only in part, to a multifactorial aetiology of HAND in older people. Social isolation and illiteracy were associated with symptomatic HAND, suggesting greater cognitive reserve might be protective.
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http://dx.doi.org/10.1002/gps.5357DOI Listing
October 2020

The Development of a Quality of Life Scale for Informal Carers for Older Adults.

Gerontol Geriatr Med 2020 Jan-Dec;6:2333721420920424. Epub 2020 May 14.

University of Leicester, UK.

The aim of the study was to develop a multidimensional quality of life instrument suitable for use among individuals across cultures who have an informal care role for older persons. Participants were informal carers of older adults in the United Kingdom ( = 308), United States ( = 164), and China ( = 131). We carried out exploratory and confirmatory factor analyses of 61 items derived from the eight-factor Adult Carers Quality of Life Questionnaire with newly added items to define both traditional and nontraditional informal care roles. Findings suggest a 24-item quality of life scale with a six-factor structure to caring for older adults that assesses (a) exhaustion, (b) adoption of a traditional carer role, (c) personal growth, (d) management and performance, (e) level of support, and (f) financial matters. We present a new scale to assess the multidimensional aspects of quality of life among those caring for older adults.
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http://dx.doi.org/10.1177/2333721420920424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238784PMC
May 2020

Validation of the Salzburg Dementia Test Prediction (SDTP) as a Cognitive Screening Tool in an English-Speaking Inpatient Medical Setting.

J Alzheimers Dis 2020 ;75(2):675-681

Department of Neuroscience, Behaviour and Psychology, University of Leicester, Leicester, UK.

Background: The Salzburg Dementia Test Prediction (SDTP), developed using artificial intelligence and based on the Mini-Mental State Examination (MMSE), was recently introduced as a brief cognitive screening tool for cognitive impairment.

Objective: In the current study, we investigated whether the STDP can be used as a valid bed-side cognitive screening tool for dementia patients, in an English-speaking, medical inpatient setting.

Methods: 216 medically ill older patients who had completed the MMSE (from which the SDTP scores can be calculated), with a subsample 58 patients who had also completed the ACE-R/ACE-III scales. Diagnosis of one of four dementia types (n = 127) and socio-demographic information were also collected. MMSE, SDTP, ACE-R/ACE-III, and dementia diagnosis were used to examine the construct validity of the SDTP through assessments of the structural, concurrent, and convergent validity.

Results: The SDTP shows structural validity through demonstrating uni-dimensionality. Construct validity was demonstrated by sufficient correlation sizes with MMSE scores against a benchmark correlation size for most of the subsample, except vascular dementia. Convergent validity was demonstrated for the STDP with equivalent correlations sizes with ACE-R/ACE-III as the MMSE across all samples, though for vascular dementia the magnitude of this correlation was not as strong.

Conclusions: Our findings support using STDP as a brief assessment tool among patients who have been diagnosed with Alzheimer's disease, Lewy body disease, and mixed dementia; however, there is some statistical variability to overall MMSE scores and correlations with the ACE-R/ACE-III among patients diagnosed with vascular dementia.
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http://dx.doi.org/10.3233/JAD-200183DOI Listing
May 2021

Representation of Black, Asian and minority ethnic patients in secondary care mental health services: analysis of 7-year access to memory services in Leicester and Leicestershire.

BJPsych Bull 2020 Aug;44(4):145-152

Department of Health Sciences, College of Life Sciences, University of Leicester, UK.

Aims And Method: We aimed to explore access by Black, Asian and minority ethnic (BAME) elders to the memory services in Leicester and Leicestershire, examining any trends over time. We then compared the odds of referral by ethnicity, using observed versus expected referrals for the city of Leicester. We gathered data on a comprehensive county-wide memory clinic used by people with suspected dementia and memory problems from the Trust electronic record system during the period 2011-2017. For Leicester city, we compared referral rates for 2011-2017 and compared observed and expected referral rates with demographics from the UK Census 2011.

Results: In Leicester, there was a significant underrepresentation of referrals from the BAME population as compared with the White population in 2011, 2012 and 2013, when compared with population estimates of those aged ≥60 years from the 2011 UK Census Leicester city data. Data for the Black population were too small for comparisons. The odds of being referred to a memory clinic for the White group was double that of the Asian group in 2011 (odds ratio 2.15, 95% CI 1.52-3.02) and nearly 1.5 times in 2012 (odds ratio 1.40, 95% CI 1.01-1.93). This difference did not persist after 2014. However, this differential odds of referral changes when the age difference between the groups is accounted for. After adjusting for age, there were no differences between the two groups in their odds of referral to the memory clinic from 2011 to 2013, but from 2014 to 2017, members of the Asian group had higher odds of being referred.

Clinical Implications: The relationship between BAME and access to memory services is complex. The relative lower prevalence of Asian people among referrals to memory services in Leicester from 2011 to 2013 may partly be explained by the lower ages of the Asian population at referral. The higher prevalence of Asian people in 2014-2017 may be owing to use of denominators from the 2011 UK Census, which are likely to be disproportionately low for this group. Further studies are needed to explore any potential barriers to the access of services by BAME communities.
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http://dx.doi.org/10.1192/bjb.2020.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058817PMC
August 2020

Erythrocytes as Biomarkers for Dementia: Analysis of Protein Content and Alpha-Synuclein.

J Alzheimers Dis 2019 08;71(2):569-580

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.

Background: Discovering biomarkers for dementia is a pivotal step toward successful early diagnosis and treatment. Although plasma biomarkers have been explored, no consensus has been reached. Alpha-synuclein (AS), a 14 kDa synaptic protein associated with several neurodegenerative diseases, exists natively within erythrocytes (ERC). This protein is characteristic of Lewy body diseases, in which it aggregates into toxic Lewy bodies. As ERC are implicated in dementia, they are a potential target for future biomarkers.

Objective: The aims of this study were to assess AS levels within ERC and whether AS can be used as a peripheral biomarker to differentiate between dementia and aged matched healthy control subjects.

Methods: A total of 114 samples (60 aging controls, 36 Alzheimer's disease, 12 vascular dementia (VaD) and 6 dementia with Lewy bodies (DLB) subjects) were analyzed. We used Bradford assay to measure protein concentration, indirect ELISA to detect levels of AS, and immunoblotting to identify AS composition. Data were analyzed with nonparametric tests.

Results: AS oligomers were present in dementia blood samples, whereas in controls, AS was largely monomeric. There was a significant increase in AS levels in DLB whole blood (p = 0.005; Kruskal-Wallis test), with a sensitivity and specificity of 100.0% and 93.9%. Protein concentrations in ERC isolated at pH 5.7 were significantly increased in dementia patients compared to controls (17.58 versus 40.33μg/ml; p≤0.005; Mann-Whitney test). In the VaD group, the protein concentration in the pH5.7 ERC fraction had sensitivity and specificity of 91.7% and 62.1%.

Conclusions: ERC protein concentration and AS levels have a potential for development of a novel diagnostic dementia blood test.
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http://dx.doi.org/10.3233/JAD-190567DOI Listing
August 2019

Use of herbal medicines: Pilot survey of UK users' views.

Complement Ther Med 2019 Jun 16;44:83-90. Epub 2019 Feb 16.

Department of Neuroscience, Psychology and Behaviour,University of Leicester, Leicester LE1 7RH, United Kingdom; The Evington Centre, Leicestershire Partnership Trust, Leicester General Hospital, Gwendolen Rd, Leicester LE5 4QG, United Kingdom. Electronic address:

Increasing sales of medicinal plants as supplements or health foods continue to indicate widespread self-medication. We conducted a survey on users' views on obtaining information on herbal medicines and their experiences and opinions about their use. Responses over one-year period (01.08.2015-31.07.2016) were analysed. 157 participants took part (87% aged 45-64y, and 13% >65y). 80% participants used medicinal plants for multiple health benefits [i.e. health protection (74%), disease prevention (38%) and treatment (49%]). 95% believed in the medicinal powers of plants. Information regarding use of medicinal plants was predominantly based on books (57%), the internet (53%), friends, colleagues or neighbours (51%) and health practitioners (42%). 51% of participants felt herbs were safe (51%) with less side effects (55%) than pharmaceutical medicines. 24% of medicinal plant users informed their medical doctor, with majority of informed medical professional (47%) accepting the use of medicinal plants. This pilot survey provides new and valuable information for use in designing future more comprehensive surveys to provide essential information about the use of herbal medicines by the general population and health care providers' attitudes in the UK.
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http://dx.doi.org/10.1016/j.ctim.2019.02.007DOI Listing
June 2019

Diagnosis and Management of Autism Spectrum Disorders in Russia: Clinical-Biological Approaches.

J Autism Dev Disord 2019 Sep;49(9):3906-3914

Department of Neuroscience, Psychology and Behavior, University of Leicester, Leicester, LE1 7RH, UK.

The study describes the latest recommended and adopted clinical and management practice for children and adults with autistic spectrum disorder (ASD) in Russia and discusses the most recent research work by Russian clinicians and neuroscientists in the field. The study also presents data from the first epidemiological studies on ASD prevalence and explores the latest recommendations for clinical-biological assessments for ASD diagnosis and management in Russia. The authors call for collaboration of experts in ASD field to exchange clinical and research ideas between professionals from Russia and Western European countries and expand our mutual knowledge about ASD. This should include clinical and neurobiological studies aiming to develop differential rational approaches for ASD individual management throughout lifespan of these affected individuals.
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http://dx.doi.org/10.1007/s10803-019-04071-4DOI Listing
September 2019

Delirium Stigma Among Healthcare Staff.

Geriatrics (Basel) 2018 Dec 31;4(1). Epub 2018 Dec 31.

School of Medicine and Health Institute for the Development of Education and Scholarship (Health IDEAS), Griffith University, Queensland 4122, Australia.

Older people with delirium occupy more than one third of acute medical beds and require increased medical attention, as care at present is suboptimal. In addition, since delirium is undetected, it should form a target for teaching in wards. Moreover, as people with delirium are largely dependent on daily interactions and care by inpatients professional staff, it is important to address stigmatisation of these vulnerable patients. This is especially important as previous studies have shown that negative staff attitudes towards these patients undermine good care. This single center cross-sectional study was designed to determine the extent of institutional stigma among health professionals involved in the care of people with delirium. For this, professional staff working on medical wards and in communities were approached to fill in a questionnaire containing the adapted Delirium Stigma Scale and the EuroQol five dimensions (EQ-5D-5L) questionnaire. Additional demographic information concerning their education and professional and personal experience with delirium was also collected. The characteristics associated with stigma were determined from the sample. The findings of our study provide an insight into the high level of stigmatisation of delirium patients among professionals (mean 11.66/18 points). This was not related to professionals' own experiences of delirium, their educational and professional backgrounds, or them having received formal delirium education. However, working closely with people with delirium seems to have a positive impact on the de-stigmatisation of this population among health professionals. Our findings that attitudes are not influenced by formal delirium teaching need to be incorporated into the design of interprofessional educational interventions. Accordingly, we advocate more direct patient-oriented and care delivered teaching interventions.
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http://dx.doi.org/10.3390/geriatrics4010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473673PMC
December 2018

Platelets: Peripheral Biomarkers of Dementia?

J Alzheimers Dis 2018 ;63(4):1235-1259

Department of Neuroscience, Psychology and Behaviour, University of Leicester, Leicester, UK.

Dementia continues to be the most burdening neurocognitive disorder, having a negative impact on the lives of millions. The search for biomarkers to improve the clinical diagnosis of dementia is ongoing, with the focus on effective use of readily accessible peripheral markers. In this review, we concentrate on platelets as biomarkers of dementia and analyze their potential as easily-accessible clinical biomarkers for various subtypes of dementia. Current platelet protein biomarkers that have been investigated for their clinical utility in the diagnosis of dementia, in particular Alzheimer's disease, include amyloid-β protein precursor (AβPP), the AβPP secretases (BACE1 and ADAM10), α-synuclein, tau protein, serotonin, cholesterol, phospholipases, clusterin, IgG, surface receptors, MAO-B, and coated platelets. Few of them, i.e., platelet tau, AβPP (particularly with regards to coated platelets) and secreted ADAM10 and BACE1 show the most promise to be taken forward into clinical setting to diagnose dementia. Aside from protein biomarkers, changes in factors such as mean platelet volume have the potential to play a very specific role in both the dementia diagnosis and prognosis. This review raises a number of research questions for consideration before application of the above biomarkers to routine clinical setting. It is without doubt that there is a need for more clarification on the effects of dementia on platelet morphology and protein content before these changes can be clinically applied as dementia biomarkers and explored further in differentiating distinct dementia subtypes.
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http://dx.doi.org/10.3233/JAD-180181DOI Listing
June 2019

Platelet Tau Protein as a Potential Peripheral Biomarker in Alzheimer's Disease: An Explorative Study.

Curr Alzheimer Res 2018 ;15(9):800-808

Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom.

Background: Cerebrospinal fluid (CSF) measures of tau and amyloid proteins have now been largely accepted to be a diagnostic tool to aid the clinical diagnosis of Alzheimer's disease (AD), but CSF is not routinely obtained in most clinical settings. There is a need, therefore, to uncover additional readily accessible peripheral biomarkers that will enable comprehensive detection of AD-specific proteins in blood and blood derivates.

Objectives: Blood platelets contain proteins found in neuronal cell lines, including tau protein. Since tau protein is a characteristic of AD-neuropathology, platelet tau protein may be closely related to the central nervous process occurring in neurodegeneration.

Method: Platelets from 25 AD and 26 control subjects were analysed for the microtubule-binding and C-terminal region, as well as two tau phosphorylation sites (Ser202/Thr205 and Thr181).

Results: Tau protein measures did not discriminate between AD and control individuals. However, subjects with MMSE 24-27 had elevated C-terminal end tau protein (p=0.049) compared to those with MMSE >27, whereas older AD subjects (>80 years) showed higher t-tau protein in comparison to younger AD (<80 years; p=0.009) and control (<80 years; p=0.011) participants.

Conclusions: These initial findings not only confirm that platelet tau protein can be measured, but also indicate that platelet tau measures merit further study as they may be useful in indicating early stages of cognitive impairment. Further studies on larger number of participants are needed to confirm our findings.
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http://dx.doi.org/10.2174/1567205015666180404165915DOI Listing
August 2019

The therapeutic 'make-over' of dementias-an introduction.

Age Ageing 2018 05;47(3):331-333

Institute of Neuroscience, Behaviour and Psychology, MSB 332 Maurice Sharp Building, University of Leicester, University Road, Leicester LE1 7RH, UK.

The online themed collection of 15 papers recently published provides an update on the advances of pharmacological and non-pharmacological interventions in dementia over the last 15 years. The published studies reflect the efficacy of the current anti-dementia treatments, preventive treatments of cardio and cerebrovascular incidents (known to be risk factors for dementia), alongside the use of antidepressant medication and non-pharmacological interventions for treatment of behavioural and psychopathological symptoms of dementia. We also address the future preventative steps and therapeutic strategies currently in development to combat the devastating consequences of dementia.
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http://dx.doi.org/10.1093/ageing/afy019DOI Listing
May 2018

Electrochemical Detection of Plasma Immunoglobulin as a Biomarker for Alzheimer's Disease.

Sensors (Basel) 2017 Oct 27;17(11). Epub 2017 Oct 27.

School of Chemical Engineering and Advance Materials, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.

The clinical diagnosis and treatment of Alzheimer's disease (AD) represent a challenge to clinicians due to the variability of clinical symptomatology as well as the unavailability of reliable diagnostic tests. In this study, the development of a novel electrochemical assay and its potential to detect peripheral blood biomarkers to diagnose AD using plasma immunoglobulins is investigated. The immunosensor employs a gold electrode as the immobilizing substrate, albumin depleted plasma immunoglobulin as the biomarker, and polyclonal rabbit Anti-human immunoglobulin (against IgA, IgG, IgM) as the receptor for plasma conjugation. The assay showed good response, sensitivity and reproducibility in differentiating plasma immunoglobulin from AD and control subjects down to 10 dilutions of plasma immunoglobulin representing plasma content concentrations in the pg mL range. The newly developed assay is highly sensitive, less time consuming, easy to handle, can be easily modified to detect other dementia-related biomarkers in blood samples, and can be easily integrated into portable devices.
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http://dx.doi.org/10.3390/s17112464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713623PMC
October 2017

Exploring Erythrocytes as Blood Biomarkers for Alzheimer's Disease.

J Alzheimers Dis 2017 ;60(3):845-857

Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.

Peripheral biomarkers for dementia are few and far between. Despite research into blood plasma/serum biomarkers for dementia diagnostics, there is a lack of information on erythrocytes and their vast proteomes as potential biomarkers. This review identifies a number of relevant and potentially promising erythrocyte biomarkers for various subtypes of dementia. These include erythrocyte morphology, oxidative stress, and erythrocyte membrane proteins such as the glucose transporter (GLUT-1), amyloid-β, IgG, Hsp90, calpain-1, and band 3 protein. Of those proteins identified Hsp90, amyloid-β, calpain-1 and band 3 show the most promise as pre-clinical biomarkers. However, the most intriguing aspect of erythrocytes is their changed morphology in dementia. The altered morphology not only could be used as a diagnostic biomarker but may be crucial in early pathogenesis of the disease. Further work must be done to establish the pathological connection between the periphery and central disease processes.
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http://dx.doi.org/10.3233/JAD-170363DOI Listing
May 2018

Silent lives: why do we fail community-dwelling people with dementia?

Age Ageing 2017 05;46(3):341-343

Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.

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http://dx.doi.org/10.1093/ageing/afx028DOI Listing
May 2017

Current and Future Perspectives of Liaison Psychiatry Services: Relevance for Older People's Care.

Geriatrics (Basel) 2016 Mar 3;1(1). Epub 2016 Mar 3.

Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE4 5PL, UK.

A large number of people admitted to medical wards have co-morbid mental health problems, and these predominantly include depression, dementia and delirium. An additional one third of medically ill patients remain in hospitals with undetected and, therefore, undiagnosed mental health problems. The comorbidity of mental and physical illnesses leads to poor health outcomes, prolonged inpatient stays and use of inpatient resources, involvement of various affiliated health services, introduction of medications and discharge to long-term facilities, including residential and nursing 24-h care, increased both readmission rates and mortality. The establishment of Liaison psychiatry services to meet the needs for people with mental health problems admitted to medical wards is a priority for many acute health Trusts. This has an economical background in terms of cost-savings, especially in relation to the older adults, with decreasing readmission rates and quicker hospital discharges. In the current review, we address the latest policies regarding Liaison psychiatry services; especially those for older people with dementia and delirium, and discuss their future shaping.
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http://dx.doi.org/10.3390/geriatrics1010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371160PMC
March 2016

Multiplex analyte assays to characterize different dementias: brain inflammatory cytokines in poststroke and other dementias.

Neurobiol Aging 2016 Feb 30;38:56-67. Epub 2015 Oct 30.

Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK. Electronic address:

Both the inflammatory potential and cognitive function decline during aging. The association between the repertoire of inflammatory biomarkers and cognitive decline is unclear. Inflammatory cytokines have been reported to be increased, decreased, or unchanged in the cerebrospinal fluid and sera of subjects with dementia. We assessed 112 postmortem brains from subjects diagnosed with poststroke dementia (PSD), vascular dementia, mixed dementia, and Alzheimer's disease (AD), comparing those to poststroke nondemented (PSND) subjects and age-matched controls. We analyzed 5 brain regions including the gray and white matter from the frontal and temporal lobes for a panel of cytokine and/or chemokine analytes using multiplex-array assays. Of the 37 analytes, 14 were under or near the detection limits, 7 were close to the lowest detection level, and 16 cytokines were within the linear range of the assay. We observed widely variable concentrations of C-reactive protein (CRP) and serum amyloid A at the high end (1-150 ng/mg protein), whereas several of the interleukins (IL, interferon-gamma and tumor necrosis factor) at the low end (1-10 pg/mg). There were also regional variations; most notable being high concentrations of some cytokines (e.g., CRP and angiogenesis panel) in the frontal white matter. Overall, we found decreased concentrations of several cytokines, including IL-1 beta (p = 0.000), IL-6 (p = 0.000), IL-7 (p = 0.000), IL-8 (p = 0.000), IL-16 (p = 0.001), interferon-inducible protein-10 (0.044), serum amyloid A (p = 0.011), and a trend in IL-1 alpha (p = 0.084) across all dementia groups compared to nondemented controls. IL-6 and IL-8 were significantly lower in dementia subjects than in nondemented subjects in every region. In particular, lower levels of IL-6 and IL-8 were notable in the PSD compared to PSND subjects. Because these 2 stroke groups had comparable degree of vascular pathology, the lower production of IL-6 and IL-8 in PSD reaffirms a possible specific involvement of immunosenescence in dementia pathogenesis. In contrast, CRP was not altered between dementia and nondementia subjects or between PSD and PSND. Our study provides evidence not only for the feasibility of tracking cytokines in postmortem brain tissue but also suggests differentially impaired inflammatory mechanisms underlying dementia including AD. There was a diminished inflammatory response, possibly reflecting immunosenescence and cerebral atrophy, in all dementias. Strategies to enhance anti-inflammatory cytokines and boost the immune system of the brain may be beneficial for preventing cognitive dysfunction, especially after stroke.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759608PMC
February 2016

Relevance of 123I-FP-CIT SPECT brain scans in routine clinical settings.

Br J Psychiatry 2015 Oct;207(4):364

Elizabeta B. Mukaetova-Ladinska, MD, MMedSci, PhD, MRCPsych, Newcastle Liaison Team for Older Adults, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, and Institute for Ageing and Health, Newcastle University, Wolfson Research Centre, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK. Email: Ann Scully, MRCPsych, Newcastle Liaison Team for Older Adults, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1192/bjp.207.4.364DOI Listing
October 2015

Behavioural and psychiatric symptoms in people with dementia admitted to acute hospitals.

Br J Psychiatry 2015 Feb;206(2):166

Elizabeta B. Mukaetova-Ladinska, Senior Lecturer in Old Age Psychiatry, Institute of Neuroscience, Newcastle University, Newcastle University Institute for Ageing and Newcastle Liaison Team for Older Adults, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne. Email: Ann Scully, Consultant in Old Age Psychiatry, Newcastle Liaison Team for Older Adults, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne.

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http://dx.doi.org/10.1192/bjp.206.2.166DOI Listing
February 2015

Tau proteins in the temporal and frontal cortices in patients with vascular dementia.

J Neuropathol Exp Neurol 2015 Feb;74(2):148-57

From the Institute of Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, United Kingdom (EBM-L, ZA-A, ESM, ML, LJLC, AEO, RNK); and Institute of Mental Health, University of British Columbia, Vancouver, British Columbia, Canada (WGH).

We previously reported that, in the brains of older patients with vascular dementia (VaD), there is a distinctive accumulation of detergent-extractable soluble amyloid-β, with a predominance of Aβ42 species. It is unclear, however, if tau proteins also accumulate in the brains of older VaD subjects. Using antibody-specific immunoassays, we assessed concentrations of total tau (t-tau) and phosphorylated tau protein, measured at 3 phosphorylated sites (i.e. Thr181, Ser202/Thr205, and Ser262), as well as synaptophysin in the temporal and frontal cortices of 18 VaD, 16 Alzheimer disease (AD), and 16 normal age-matched control subjects. There was selective loss of t-tau protein in VaD compared with controls and AD subjects (p < 0.021 and p < 0.001, respectively). In contrast, phosphorylated tau levels were similar to controls in VaD in both regions, but they were increased in the temporal lobes of patients with AD (p < 0.01 and p < 0.0001 for Ser202/Thr205 and Ser262 phosphorylated sites, respectively). The reduced t-tau in the VaD group was unrelated to any low-level neurofibrillary or amyloid pathology or age at death. These findings suggest that breaches of microvascular or microstructural tissue integrity subsequent to ischemic injury in older age may modify tau protein metabolism or phosphorylation and have effects on the burden of neurofibrillary pathology characteristic of AD.
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http://dx.doi.org/10.1097/NEN.0000000000000157DOI Listing
February 2015

Molecular imaging biomarkers for dementia with Lewy bodies: an update.

Int Psychogeriatr 2015 Apr 22;27(4):555-77. Epub 2014 Dec 22.

Newcastle University,Newcastle upon Tyne,UK.

Background: Dementia with Lewy body (DLB) is considered to be the second most common form of neurodegenerative disorders after Alzheimer's disease (AD), affecting as many as 100,000 people in the UK and up to 1.3 million in the USA. However, nearly half of patients with DLB remain undiagnosed thus depriving many of them from an early and adequate treatment of their distressing symptoms. Accurate and early diagnosis of DLB is important for both patients and their caregivers, since the neuropsychiatric symptoms require specific management.

Methods: In the current study, we review the most recent developments in the field of molecular nuclear imaging to diagnose DLB.

Results: The review addresses, the neurotransmitter based (dopaminergic, cholinergic, and glutamatergic) nuclear imaging techniques, role of the autonomic dysfunction and its visualization in DLB with myocardial sympathetic imaging and vesicular catecholamine uptake, as well as the use of amyloid polypeptides and glial markers as molecular imaging probes in the clinical diagnosis of DLB.

Conclusions: Most of the above nuclear imaging methods are restricted to highly specialized clinical centers, and thus not applicable to a large number of patients requiring dementia (e.g. DLB) diagnosis in routine clinical setting. Validating them against more readily accessible peripheral biomarkers, e.g. CSF and blood biomarkers linked to the DLB process, may facilitate their use in wider clinical settings.
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http://dx.doi.org/10.1017/S1041610214002555DOI Listing
April 2015

Liaison services for older adults.

Br J Psychiatry 2014 Jun;204(6):491-2

Elizabeta B. Mukaetova-Ladinska, Institute for Ageing and Health, Newcastle University Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK. Email: Ann Scully, Centre for Health of the Elderly, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1192/bjp.204.6.491DOI Listing
June 2014

Plasma and platelet clusterin ratio is altered in Alzheimer's disease patients with distinct neuropsychiatric symptoms: findings from a pilot study.

Int J Geriatr Psychiatry 2015 Apr 12;30(4):368-75. Epub 2014 Jun 12.

Institute for Ageing and Health, Newcastle University, Newcastle, UK.

Background: Clusterin protein in plasma has been found to differentiate between people with and without cognitive changes. However, these findings are not conclusive, despite the clusterin gene variations repeatedly being linked to increased risk for dementia, in particular Alzheimer's disease (AD).

Method: We analysed the level of clusterin in platelet and plasma in 25 subjects with a clinical diagnosis of AD and 26 subjects with no cognitive impairment.

Results: In the current study, we report that the levels of both plasma and platelet clusterin are similar between AD and cognitively intact individuals. Clusterin plasma and platelet levels, as well as the plasma/platelet clusterin ratio, were not affected by age, gender, cognitive impairment and/or overt behavioural symptomatology, including presence of hallucinations and delusions, as well as depression. However, the plasma/platelet clusterin ratio was positively associated in with the Neuropsychiatric Inventory measures of agitation, apathy, irritability and motor aberrant behaviour in AD subjects.

Conclusion: Previous inconsistencies in reported blood clusterin levels may be a result of underlying non-cognitive symptoms in people with AD. Our findings need now to be replicated in larger group of dementia subjects.
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http://dx.doi.org/10.1002/gps.4145DOI Listing
April 2015
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