Publications by authors named "Magda Tsolaki"

308 Publications

Memory Clinics and Day Care Centers in Thessaloniki, Northern Greece: 30 Years of Clinical Practice and Experience.

Front Neurol 2021 25;12:683131. Epub 2021 Aug 25.

1st University Department of Neurology UH "AHEPA", School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.

This review describes the diagnostic and interventional procedures conducted in two university memory clinics (established network of G. Papanikolaou Hospital: 1988-2017 and AHEPA hospital: 2017-today) and 2 day care centers (established network of DCCs: 2005-today) in North Greece and their contribution in the scientific field of dementia. The aims of this work are (1) to provide a diagnosis and treatment protocol established in the network of memory clinics and DCCs and (2) to present further research conducted in the aforementioned network during the last 30 years of clinical practice. The guidelines to set a protocol demand a series of actions as follows: (1) set the diagnosis criteria, neuropsychological assessment, laboratory examinations, and examination of neurophysiological, neuroimaging, cerebrospinal fluid, blood, and genetic markers; and (2) apply non-pharmacological interventions according to the needs and specialized psychosocial interventions of the patient to the caregivers of the patient. In addition to the guidelines followed in memory clinics at the 1st and 3rd Department of Neurology and two DCCs, a database of patients, educational programs, and further participation in international research programs, including clinical trials, make our contribution in the dementia field strong. In the current paper, we provide useful guidelines on how major and minor neurocognitive disorders are being treated in Thessaloniki, Greece, describing successful practices which have been adapted in the last 30 years.
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http://dx.doi.org/10.3389/fneur.2021.683131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425245PMC
August 2021

CSF Proteomic Alzheimer's Disease-Predictive Subtypes in Cognitively Intact Amyloid Negative Individuals.

Proteomes 2021 Aug 2;9(3). Epub 2021 Aug 2.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, 1007 MB Amsterdam, The Netherlands.

We recently discovered three distinct pathophysiological subtypes in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics: one with neuronal hyperplasticity, a second with innate immune system activation, and a third subtype with blood-brain barrier dysfunction. It remains unclear whether AD proteomic subtype profiles are a consequence of amyloid aggregation, or might exist upstream from aggregated amyloid. We studied this question in 127 older individuals with intact cognition and normal AD biomarkers in two independent cohorts (EMIF-AD MBD and ADNI). We clustered 705 proteins measured in CSF that were previously related to AD. We identified in these cognitively intact individuals without AD pathology three subtypes: two subtypes were seen in both cohorts (n = 49 with neuronal hyperplasticity and n = 44 with blood-brain barrier dysfunction), and one only in ADNI (n = 12 with innate immune activation). The proteins specific for these subtypes strongly overlapped with AD subtype protein profiles (overlap coefficients 92%-71%). Longitudinal p-tau and amyloid β 1-42 (Aβ42) CSF analysis showed that in the hyperplasticity subtype p-tau increased (β = 2.6 pg/mL per year, = 0.01) and Aβ42 decreased over time (β = -4.4 pg/mL per year, = 0.03), in the innate immune activation subtype p-tau increased (β = 3.1 pg/mL per year, = 0.01) while in the blood-brain barrier dysfunction subtype Aβ42 decreased (β = -3.7 pg/mL per year, = 0.009). These findings suggest that AD proteomic subtypes might already manifest in cognitively normal individuals and may predispose for AD before amyloid has reached abnormal levels.
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http://dx.doi.org/10.3390/proteomes9030036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396164PMC
August 2021

Measuring Impulsivity in Greek Adults: Psychometric Properties of the Barratt Impulsiveness Scale (BIS-11) and Impulsive Behavior Scale (Short Version of UPPS-P).

Brain Sci 2021 Jul 29;11(8). Epub 2021 Jul 29.

Greek Association of Alzheimer's Disease and Related Disorders (GAADRD), 54643 Thessaloniki, Greece.

Introduction: The aim of the present study was to validate the Barratt Impulsiveness Scale (BIS-11th version) scale as well as the short version of the Impulsive Behavior Scale (UPPS-P) in a population of Greek young adults. Secondly, we aimed at validating the BIS-11 in older adults.

Methods: 167 (Group 1) university students completed the Greek version of the BIS-11 (BIS-11-G) and the UPPS (UPPS-P-G) scales. Additionally, BIS-11-G was also administered to 167 (Group 2) cognitively intact older adults, to identify whether it could be used to measure impulsivity in an older adult population.

Results: Both scales had satisfactory internal reliability and test-retest reliability, as well as convergent validity in the young adult population. In regard to the factor structure, a principal component analysis (PCA) extracted two factors for the BIS-11-G in the young adult population and three factors in older adults, as well as three factors for the short UPPS-P-G in young adults.

Conclusions: The BIS-11-G and the UPPS-P-G scales can be used to measure different aspects of impulsivity in the Greek population of different ages in research and clinical practice.
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http://dx.doi.org/10.3390/brainsci11081007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394624PMC
July 2021

Human Factors and Requirements of People with Cognitive Impairment, Their Caregivers, and Healthcare Professionals for mHealth Apps Including Reminders, Games, and Geolocation Tracking: A Survey-Questionnaire Study.

J Alzheimers Dis Rep 2021 11;5(1):497-513. Epub 2021 Jun 11.

Information Technologies Institute, Center for Research and Technology Hellas (CERTH-ITI), Thessaloniki, Greece.

Background: Mobile Health (mHealth) apps can delay the cognitive decline of people with dementia (PwD), by providing both objective assessment and cognitive enhancement.

Objective: This patient involvement survey aims to explore human factors, needs and requirements of PwD, their caregivers, and Healthcare Professionals (HCPs) with respect to supportive and interactive mHealth apps, such as brain games, medication reminders, and geolocation trackers through a constructive questionnaire.

Methods: Following the principles of user-centered design to involve end-users in design we constructed a questionnaire, containing both open-ended and closed-ended questions as well as multiple choice and Likert scale, in order to investigate the specific requirements and preferences for mHealth apps. We recruited 48 participants including people with cognitive impairment ( = 15), caregivers ( = 16), and HCPs ( = 17) and administered the questionnaire.

Results: All participants are likely to use mHealth apps, with the primary desired features being the improvement of memory and cognition, assistance on medication treatment, and perceived ease to use. HCPs, caregivers, and PwD consider brain games as an important technology-based, non-pharmaceutical intervention. Both caregivers and patients are willing to use a medication reminder app frequently. Finally, caregivers are worried about the patient wandering. Therefore, global positioning system tracking would be particularly important to them. On the other hand, patients are concerned about their privacy, but are still willing to use a geolocation app for cases of emergency.

Conclusion: This research contributes to mHealth app design and potential adoption. All three groups agree that mHealth services could facilitate care and ameliorate behavioral and cognitive disturbances of patients.
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http://dx.doi.org/10.3233/ADR-201001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293665PMC
June 2021

Extracellular GAPDH Promotes Alzheimer Disease Progression by Enhancing Amyloid-β Aggregation and Cytotoxicity.

Aging Dis 2021 Aug 1;12(5):1223-1237. Epub 2021 Aug 1.

6Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.

Neuronal cell death at late stages of Alzheimer's disease (AD) causes the release of cytosolic proteins. One of the most abundant such proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), forms stable aggregates with extracellular amyloid-β (Aβ). We detect these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of Aβ that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aβ and GAPDH and reduces Aβ-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal cells, neural degeneration, and cognitive dysfunction. In contrast, knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in Aβ-stimulated neurodegeneration. CSF from animals with enhanced GAPDH expression demonstrates increased cytotoxicity . Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of Aβ aggregates and reversed memory deficit in AD transgenic mice. These findings argue that extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, and, thus, is a promising pharmacological target for AD.
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http://dx.doi.org/10.14336/AD.2020.1230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279520PMC
August 2021

Greek High Phenolic Early Harvest Extra Virgin Olive Oil Reduces the Over-Excitation of Information-Flow Based on Dominant Coupling Mode (DoCM) Model in Patients with Mild Cognitive Impairment: An EEG Resting-State Validation Approach.

J Alzheimers Dis 2021 ;83(1):191-207

1st Department of Neurology, G.H. "AHEPA, " School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki (AUTH), Thessaloniki, Greece.

Background: Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function that could positively alter brain dynamics and the mixture of within and between-frequency connectivity.

Objective: The balance of cross-frequency coupling over within-frequency coupling can build a nonlinearity index (NI) that encapsulates the over-excitation of information flow between brain areas and across experimental time. The present study investigated for the very first time how the Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) intervention in people with mild cognitive impairment (MCI) could affect their spontaneous EEG dynamic connectivity.

Methods: Forty-three subjects (14 in MeDi, 16 in MP-EVOO, and 13 in HP-EH-EVOO) followed an EEG resting-state recording session (eyes-open and closed) before and after the treatment. Following our dominant coupling mode model, we built a dynamic integrated dynamic functional connectivity graph that tabulates the functional strength and the dominant coupling mode model of every pair of brain areas.

Results: Signal spectrum within 1-13 Hz and theta/beta ratio have decreased in the HP-EH-EVOO group in the eyes-open condition. The intervention improved the FIDoCM across groups and conditions but was more prominent in the HP-EH-EVOO group (p < 0.001). Finally, we revealed a significant higher post-intervention reduction of NI (ΔNITotal and α) for the HP-EH-EVOO compared to the MP-EVOO and MeDi groups (p < 0.0001).

Conclusion: Long-term intervention with HP-EH-EVOO reduced the over-excitation of information flow in spontaneous brain activity and altered the signal spectrum of EEG rhythms.
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http://dx.doi.org/10.3233/JAD-210454DOI Listing
January 2021

Is Depression or Apathy Playing a Key Role in Predicting Financial Capacity in Parkinson's Disease with Dementia and Frontotemporal Dementia?

Brain Sci 2021 Jun 14;11(6). Epub 2021 Jun 14.

Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54634 Thessaloniki, Greece.

(1) Background: Depression and apathy both affect cognitive abilities, such as thinking, concentration and making decisions in young and old individuals. Although apathy is claimed to be a "core" feature of Parkinson's disease (PD) and frontotemporal dementia (FTD), it may occur in the absence of depression and vice versa. Thus, the aim of this study is to explore whether depression or apathy better predict financial capacity performance in PD and FTD as well as in nondemented participants. (2) Methods: Eighty-eight participants divided into three groups (PD, FTD and non-demented participants) were examined with the Mini-Mental State Examination (MMSE) and the Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS)-Full and short form. The Geriatric Depression Scale informant version (GDS-15) and the Irritability-Apathy Scale (IAS) we completed by caregivers. (3) Results: The results indicated that both PD and FTD patients' general cognitive functioning and financial capacity performance is negatively influenced by apathy and not by depression. (4) Conclusions: Differences in financial capacity performance indicate that apathy should not be disregarded in clinical assessments. Further studies on larger PD and FTD populations are necessary in order to investigate the decisive role of mood factors on financial capacity impairment.
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http://dx.doi.org/10.3390/brainsci11060785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231779PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Involvement and relationship of bacterial lipopolysaccharides and cyclooxygenases levels in Alzheimer's Disease and Mild Cognitive Impairment patients.

J Neuroimmunol 2021 08 30;357:577561. Epub 2021 Mar 30.

Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; Center for Interdisciplinary Research and Innovation, Laboratory of Neurodegenerative Diseases (LND), 57001 Thermi, Thessaloniki, Greece. Electronic address:

This study reports elevated levels of bacterial lipopolysaccharides (LPSs) and cyclooxygenases (COX-1/2) in blood serum and cerebrospinal fluid (CSF) of Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) patients compared to cognitively healthy individuals, indicating LPSs as promising biomarkers, especially in serum. LPSs, in both fluids, positively correlate with COX-1/2, Αβ and tau and negatively with mental state. Furthermore, COX-2 is the main determinant of LPSs presence in serum, whereas COX-1 in CSF. These results underline the significance of microbial/ inflammatory involvement in dementia and offer novel perspectives on the roles of LPSs and COX in pathogenesis of AD.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577561DOI Listing
August 2021

Similar Theory of Mind Deficits in Community Dwelling Older Adults with Vascular Risk Profile and Patients with Mild Cognitive Impairment: The Case of Paradoxical Sarcasm Comprehension.

Brain Sci 2021 May 13;11(5). Epub 2021 May 13.

Laboratory of Neurodegenerative Diseases, Center for Interdisciplinary Research and Innovation (CIRI), Aristotle University of Thessaloniki, 57001 Thessaloniki, Greece.

Recent studies deal with disorders and deficits caused by vascular syndrome in efforts for prediction and prevention. Cardiovascular health declines with age due to vascular risk factors, and this leads to an increasing risk of cognitive decline. Mild cognitive impairment (MCI) is defined as the negative cognitive changes beyond what is expected in normal aging. The purpose of the study was to compare older adults with vascular risk factors (VRF), MCI patients, and healthy controls (HC) in social cognition and especially in theory of mind ability (ToM). The sample comprised a total of 109 adults, aged 50 to 85 years (M = 66.09, SD = 9.02). They were divided into three groups: (a) older adults with VRF, (b) MCI patients, and (c) healthy controls (HC). VRF and MCI did not differ significantly in age, educational level or gender as was the case with HC. Specifically, for assessing ToM, a social inference test was used, which was designed to measure sarcasm comprehension. Results showed that the performance of the VRF group and MCI patients is not differentiated, while HC performed higher compared to the other two groups. The findings may imply that the development of a vascular disorder affecting vessels of the brain is associated from its "first steps" to ToM decline, at least regarding specific aspects of it, such as paradoxical sarcasm understanding.
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http://dx.doi.org/10.3390/brainsci11050627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153105PMC
May 2021

Longitudinal Cognitive and Physical Training Effectiveness in MCI, Based on the Experience of the Alzheimer's Hellas Day Care Centre.

J Geriatr Psychiatry Neurol 2021 Jun 1:8919887211016057. Epub 2021 Jun 1.

Greek Association of Alzheimer's Disease and Related Disorders, Thessaloniki, Greece.

This study assesses the effectiveness of a multicomponent Longitudinal Cognitive Training (CT) program plus physical exercise (PE) for people with Mild Cognitive Impairment (MCI). 155 people with MCI, completed a 3 years (3Y) CT+PE, whilst 133 were control. Neuropsychological assessment was performed at baseline and 3 years later, whilst CT+PE had additional annual assessments. According to the results, the 3Y CT+PE outperformed control in cognitive abilities ( < 0.002), and Activities of Daily Living (ADL) ( < 0.001), stabilized their functional performances between 1st and 2nd year, but worsened in working and verbal memory between 2nd and 3 rd year ( < 0.002). Control deteriorated in cognitive functions ( < 0.001) and ADL ( < 0.001) after 3 years, whilst 1.33% of the experimental and 13.53% of the control group progressed to dementia ( < 0.001). Longitudinal CT+PE improves cognitive performance and ADL in MCI and delay the progression to dementia.
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http://dx.doi.org/10.1177/08919887211016057DOI Listing
June 2021

Ocular biomarkers and their role in the early diagnosis of neurocognitive disorders.

Eur J Ophthalmol 2021 May 17:11206721211016311. Epub 2021 May 17.

1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia Thraki, Greece.

Given the fact that different types of dementia can be diagnosed only postmortem or when the disease has progressed enough to cause irreversible damage to certain brain areas, there has been an increasing need for the development of sensitive and reliable methods that can detect early preclinical forms of dementia, before the symptoms have even appeared. Ideally, such a method would have the following characteristics: to be inexpensive, sensitive and specific, Non-invasive, fast and easily accessible. The ophthalmologic examination and especially the study of the retina, has caught the attention of many researchers, as it can provide a lot of information about the CNS and it fulfills many of the aforementioned criteria. Since the introduction of the non-invasive optical coherence tomography (OCT) and the newly developed modality OCT-angiography (OCT-A) that can demonstrate the structure and the microvasculature of the retina and choroid, respectively, there have been promising results regarding the value of the ophthalmologic examination in the early diagnosis of Alzheimer's disease. In this review paper, we summarize and discuss the ocular findings in patients with cognitive impairment disorders and we highlight the importance of the ophthalmologic examination to the diagnosis of these disorders.
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http://dx.doi.org/10.1177/11206721211016311DOI Listing
May 2021

A Virtual Reality-Based Screening Test for Cognitive Impairment in Small Vessel Disease.

J Alzheimers Dis Rep 2021 Mar 8;5(1):161-169. Epub 2021 Mar 8.

Department of Neurology, School of Medicine, Dokuz Eylul University, Izmir, Turkey.

Background: There is a need for new practical tools to assess the cognitive impairment of small vessel disease (SVD) patients in the clinic.

Objective: This study aimed to examine cognitive functioning by administering the Virtual Supermarket (VST) in patients with SVD with cognitive impairment (SVD-CI, N = 32), cognitively normal SVD (SVD-CN, N = 37), and age-and education-matched healthy controls (HC, N = 30).

Methods: The tablet-based VST application and comprehensive traditional pencil-and-paper neuropsychological tests assessing memory, attention, executive function, visuospatial function, and language were administered to all participants.

Results: A moderate correlation was found between the "Duration" and "Correct Quantities" variables of VST and visuospatial function and general cognitive status composite Z scores across SVD-CI patients. "Duration" and "Correct Money" variables were moderately related to memory, executive functions, and visuospatial function composite Z scores across SVD-CN patients. A combination of all VST variables discriminated SVD-CI and HC with a correct classification rate of 81%, a sensitivity of 78%, and a specificity of 84%.

Conclusion: This study is the first to evaluate cognitive functions employing the VST in SVD with and without cognitive impairment. It provides encouraging preliminary findings of the utility of the VST as a screening tool in the assessment of cognitive impairment and the differentiation of SVD patients from HC. In the future, validation studies of the VST with larger samples are needed.
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http://dx.doi.org/10.3233/ADR-200257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075552PMC
March 2021

Wearable Devices for Assessing Function in Alzheimer's Disease: A European Public Involvement Activity About the Features and Preferences of Patients and Caregivers.

Front Aging Neurosci 2021 12;13:643135. Epub 2021 Apr 12.

Center for Research and Technology Hellas (CERTH-ITI), Information Technologies Institute, Thessaloniki, Greece.

Alzheimer's Disease (AD) impairs the ability to carry out daily activities, reduces independence and quality of life and increases caregiver burden. Our understanding of functional decline has traditionally relied on reports by family and caregivers, which are subjective and vulnerable to recall bias. The Internet of Things (IoT) and wearable sensor technologies promise to provide objective, affordable, and reliable means for monitoring and understanding function. However, human factors for its acceptance are relatively unexplored. The Public Involvement (PI) activity presented in this paper aims to capture the preferences, priorities and concerns of people with AD and their caregivers for using monitoring wearables. Their feedback will drive device selection for clinical research, starting with the study of the RADAR-AD project. The PI activity involved the Patient Advisory Board (PAB) of the RADAR-AD project, comprised of people with dementia across Europe and their caregivers (11 and 10, respectively). A set of four devices that optimally represent various combinations of aspects and features from the variety of currently available wearables (e.g., weight, size, comfort, battery life, screen types, water-resistance, and metrics) was presented and experienced hands-on. Afterwards, sets of cards were used to rate and rank devices and features and freely discuss preferences. Overall, the PAB was willing to accept and incorporate devices into their daily lives. For the presented devices, the aspects most important to them included comfort, convenience and affordability. For devices in general, the features they prioritized were appearance/style, battery life and water resistance, followed by price, having an emergency button and a screen with metrics. The metrics valuable to them included activity levels and heart rate, followed by respiration rate, sleep quality and distance. Some concerns were the potential complexity, forgetting to charge the device, the potential stigma and data privacy. The PI activity explored the preferences, priorities and concerns of the PAB, a group of people with dementia and caregivers across Europe, regarding devices for monitoring function and decline, after a hands-on experience and explanation. They highlighted some expected aspects, metrics and features (e.g., comfort and convenience), but also some less expected (e.g., screen with metrics).
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http://dx.doi.org/10.3389/fnagi.2021.643135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072390PMC
April 2021

The pleiotropic beneficial intervention of olive oil intake on the Alzheimer's disease onset via fibrinolytic system.

Exp Gerontol 2021 07 6;150:111344. Epub 2021 Apr 6.

Emeritus Professor of Hematology, Medical School, Aristotle University of Thessaloniki, Faculty of Health Sciences, Greece.

The daily consumption of Extra Virgin Olive Oil (EVOO) in Mediterranean nutrition is tightly associated with lower frequency of many diseases' appearance, including Alzheimer's disease (AD). Fibrinolytic system is already assumed to be involved in AD pathophysiology through various factors, especially plasminogen activator inhibitor-1 (PAI-1), a2-antiplasmin (α2ΑP) and tissue plasminogen activator (tPA). We, here, present a biochemical study, as a continuation of a clinical trial of a cohort of 84 participants, focusing on the pleiotropic effect of the annual EVOO consumption on the fibrinolytic factors of Mild Cognitive Impairment (MCI) patients. The levels of all these fibrinolytic factors, measured by Enzyme-Linked Immunosorbent Assay (ELISA) method, were reduced in the serum of MCI patients annually administered with EVOO, versus not treated MCI patients, as well as AD patients. The well-established AD hallmarks (Aβ1-40 and Aβ1-42 species, tau, and p-tau) of MCI patients' group, annually administered with EVOO, were restored to levels equal to those of the cognitively-healthy group; in contrast to those patients not being administered, and their AD hallmarks levels increased at the end of the year. Moreover, one of the EVOO annual consumption multimodal effects on the MCI patients focused on the levels of an oxidative stress trademark, malondialdehyde (MDA), which displayed also a visible quenching; On the other hand, an increase exhibited in the MCI patients not consuming EVOO one year after, was attributed to the lack of the EVOO anti-oxidative properties. These outcomes are exploitable towards the establishment of natural products like EVOO, as a preventive remedy fighting this neurodegenerative disorder, AD. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03362996 MICOIL gov Identifier: NCT03362996.
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http://dx.doi.org/10.1016/j.exger.2021.111344DOI Listing
July 2021

Frontotemporal dementia and financial capacity: facing the Cerberus of overestimation or underestimation?

Australas Psychiatry 2021 Apr 5:10398562211005444. Epub 2021 Apr 5.

School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Objective: This study investigates the performance of people with frontotemporal dementia (FTD) on objective assessment of financial capacity with comparison to the estimation of financial capacity by both people themselves and their caregivers.

Method: FTD patients and healthy (age/gender/education-matched) controls from Greece underwent cognitive assessment (memory, attention, executive functioning, visuospatial skills, verbal functions), emotional (anxiety, depression), and financial capacity assessment (Legal Capacity for Property Law Transactions Assessment Scale-LCPLTAS). Additionally, they self-reported on their financial performance and a third-party living with the older participants for both groups reported their estimates of financial performance and their anxiety and depression levels.

Results: Financial capacity in FTD patients is severely impaired compared to controls, but caregivers of FTD patients tend to overestimate the patients' financial performance, a finding that is not related to the caregivers' depression and anxiety levels or other demographics. FTD patients overestimate their financial capacity.

Conclusion: FTD may have significant impact on financial capacity, but people with FTD tend to overestimate their own financial capacity. This study also indicates that families and caregivers tend to overestimate financial capacity in people with FTD. This has implications for the assessment and care planning of people with FTD in clinical settings.
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http://dx.doi.org/10.1177/10398562211005444DOI Listing
April 2021

Replication study of plasma proteins relating to Alzheimer's pathology.

Alzheimers Dement 2021 Mar 31. Epub 2021 Mar 31.

Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.

Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.

Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.

Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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http://dx.doi.org/10.1002/alz.12322DOI Listing
March 2021

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 03 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

Α Virtual Reality App for Physical and Cognitive Training of Older People With Mild Cognitive Impairment: Mixed Methods Feasibility Study.

JMIR Serious Games 2021 Mar 24;9(1):e24170. Epub 2021 Mar 24.

School of Physical Education, Sport Science and Dietetics, Department of Physical Education and Sport Science, University of Thessaly, Trikala, Greece.

Background: Therapeutic virtual reality (VR) has emerged as an effective treatment modality for cognitive and physical training in people with mild cognitive impairment (MCI). However, to replace existing nonpharmaceutical treatment training protocols, VR platforms need significant improvement if they are to appeal to older people with symptoms of cognitive decline and meet their specific needs.

Objective: This study aims to design and test the acceptability, usability, and tolerability of an immersive VR platform that allows older people with MCI symptoms to simultaneously practice physical and cognitive skills on a dual task.

Methods: On the basis of interviews with 20 older people with MCI symptoms (15 females; mean age 76.25, SD 5.03 years) and inputs from their health care providers (formative study VR1), an interdisciplinary group of experts developed a VR system called VRADA (VR Exercise App for Dementia and Alzheimer's Patients). Using an identical training protocol, the VRADA system was first tested with a group of 30 university students (16 females; mean age 20.86, SD 1.17 years) and then with 27 older people (19 females; mean age 73.22, SD 9.26 years) who had been diagnosed with MCI (feasibility studies VR2a and VR2b). Those in the latter group attended two Hellenic Association Day Care Centers for Alzheimer's Disease and Related Disorders. Participants in both groups were asked to perform a dual task training protocol that combined physical and cognitive exercises in two different training conditions. In condition A, participants performed a cycling task in a lab environment while being asked by the researcher to perform oral math calculations (single-digit additions and subtractions). In condition B, participants performed a cycling task in the virtual environment while performing calculations that appeared within the VR app. Participants in both groups were assessed in the same way; this included questionnaires and semistructured interviews immediately after the experiment to capture perceptions of acceptability, usability, and tolerability, and to determine which of the two training conditions each participant preferred.

Results: Participants in both groups showed a significant preference for the VR condition (students: mean 0.66, SD 0.41, t=8.74, P<.001; patients with MCI: mean 0.72, SD 0.51, t=7.36, P<.001), as well as high acceptance scores for intended future use, attitude toward VR training, and enjoyment. System usability scale scores (82.66 for the students and 77.96 for the older group) were well above the acceptability threshold (75/100). The perceived adverse effects were minimal, indicating a satisfactory tolerability.

Conclusions: The findings suggest that VRADA is an acceptable, usable, and tolerable system for physical and cognitive training of older people with MCI and university students. Randomized controlled trial studies are needed to assess the efficacy of VRADA as a tool to promote physical and cognitive health in patients with MCI.
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http://dx.doi.org/10.2196/24170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294639PMC
March 2021

Rationale, Design, and Methodology of a Prospective Cohort Study for Coping with Behavioral and Psychological Symptoms of Dementia: The RECage Project.

J Alzheimers Dis 2021 ;80(4):1613-1627

FERB Alzheimer Centre, Gazzaniga, Italy.

Background: Behavioral and psychological symptoms of dementia (BPSD) are quite challenging problems during the dementia course. Special Care Units for people with dementia (PwD) and BPSD (SCU-B) are residential medical structures, where BPSD patients are temporarily admitted, in case of unmanageable behavioral disturbances at home.

Objective: RECage (REspectful Caring for AGitated Elderly) aspires to assess the short and long-term effectiveness of SCU-Bs toward alleviating BPSD and improving the quality of life (QoL) of PwD and their caregivers.

Methods: RECage is a three-year, prospective study enrolling 500 PwD. Particularly, 250 community-dwelling PwDs presenting with severe BPSD will be recruited by five clinical centers across Europe, endowed with a SCU-B, for a short period of time; a second similar group of 250 PwD will be followed by six other no-SCU-B centers solely via outpatient visits. RECage's endpoints include short and long-term SCU-B clinical efficacy, QoL of patients and caregivers, cost-effectiveness of the SCU-B, psychotropic drug consumption, caregivers' attitude toward dementia, and time to nursing home placement.

Results: PwD admitted in SCU-Bs are expected to have diminished rates of BPSD and better QoL and their caregivers are also expected to have better QoL and improved attitude towards dementia, compared to those followed in no-SCU-Bs. Also, the cost of care and the psychotropic drug consumption are expected to be lower. Finally, PwD followed in no-SCU-Bs are expected to have earlier admission to nursing homes.

Conclusion: The cohort study results will refine the SCU-B model, issuing recommendations for implementation of SCU-Bs in the countries where they are scarce or non-existent.
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http://dx.doi.org/10.3233/JAD-201215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203243PMC
September 2021

4 Allele and Financial Capacity Performance in Mild Alzheimer's Disease: A Pilot Study.

J Alzheimers Dis Rep 2021 Jan 29;5(1):93-97. Epub 2021 Jan 29.

School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

This study aims to explore a little investigated topic, i.e., whether the presence of the e4 allele in patients with a diagnosis of mild Alzheimer's disease (AD) can influence financial capacity. Twenty-eight elders with mild AD carrying the 4 allele and 28 matched non-carrier patients were examined with an extensive battery of neuropsychological tests, and a specific test measuring financial capacity: Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS). The presence of the 4 allele does not differentiate the group of mild AD patients regarding a number of cognitive domains necessary for financial capacity scores as measured by LCPLTAS.
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http://dx.doi.org/10.3233/ADR-200254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903015PMC
January 2021

Editorial: Cognitive Impairment: Therapy Momentum in the Continuum of Life.

Front Pharmacol 2020 29;11:618344. Epub 2021 Jan 29.

Uehiro Research Division for iPS Cell Ethics, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.

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http://dx.doi.org/10.3389/fphar.2020.618344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878524PMC
January 2021

The Contribution of Ocular Biomarkers in the Differential Diagnosis of Alzheimer's Disease versus Other Types of Dementia and Future Prospects.

J Alzheimers Dis 2021 ;80(2):493-504

1st Neurology Department, AHEPA University Hospital, Thessaloniki, Greece.

With dementia becoming increasingly prevalent, there is a pressing need to become better equipped with accurate diagnostic tools that will favorably influence its course via prompt and specific intervention. The overlap in clinical manifestation, imaging, and even pathological findings between different dementia syndromes is one of the most prominent challenges today even for expert physicians. Since cerebral microvasculature and the retina share common characteristics, the idea of identifying potential ocular biomarkers to facilitate diagnosis is not a novel one. Initial efforts included studying less quantifiable parameters such as aspects of visual function, extraocular movements, and funduscopic findings. However, the really exciting prospect of a non-invasive, safe, fast, reproducible, and quantifiable method of pinpointing novel biomarkers has emerged with the advent of optical coherence tomography (OCT) and, more recently, OCT angiography (OCTA). The possibility of analyzing multiple parameters of retinal as well as retinal microvasculature variables in vivo represents a promising opportunity to investigate whether specific findings can be linked to certain subtypes of dementia and aid in their earlier diagnosis. The existing literature on the contribution of the eye in characterizing dementia, with a special interest in OCT and OCTA parameters will be reviewed and compared, and we will explicitly focus our effort in advancing our understanding and knowledge of relevant biomarkers to facilitate future research in the differential diagnosis between Alzheimer's disease and common forms of cognitive impairment, including vascular dementia, frontotemporal dementia, and dementia with Lewy bodies.
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http://dx.doi.org/10.3233/JAD-201516DOI Listing
September 2021

The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease.

Alzheimers Dement 2021 07 25;17(7):1145-1156. Epub 2021 Jan 25.

Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Introduction: This study investigated the diagnostic and disease-monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals.

Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants.

Results: Phosphorylated-tau181 (P-tau181), neurofilament light, amyloid-β (Aβ42/40), Total-tau and Glial fibrillary acidic protein were altered in AD dementia but P-tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P-tau181 was increased in MCI converters compared to non-converters. Higher P-tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P-tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals.

Discussion: P-tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P-tau181 as a non-invasive and cost-effective diagnostic and prognostic biomarker in AD.
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http://dx.doi.org/10.1002/alz.12283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359457PMC
July 2021

Setting Up a Cognitive Training Service for Egyptian Older Adults.

J Alzheimers Dis 2021 ;79(4):1673-1682

School of Medicine, Aristotle University of Thessaloniki, Greece.

Background: With greying of nations, dementia becomes a public health priority. The rising dementia prevalence escalates both health care expenses and burden, placing the entire healthcare system and caregivers under huge stress. Cognition-oriented interventions have been shown to enhance the overall cognitive performance among healthy and cognitively impaired older adults.

Objective: This article is assumed to be a steppingstone for the introduction and establishment of cognition- oriented interventions in Egypt. In addition, it aims to offer provisional guidance for health care providers in Arab speaking countries in a stepwise approach in order to establish cognition-oriented intervention services and help them to evaluate and monitor their efficacy.

Methods: Aconsortium of Egyptian and Greek specialists developed a protocol for the operations of the Ain Shams Cognitive Training Lab and the provision of cognition-oriented interventions. This protocol is based on a previous successful protocol that has been implemented in Greece for more than 10 years and is co-designed to fit the needs of older adults in Arabic speaking countries.

Results: The types of services offered, their objectives, recruitment of participants, delivery of interventions, measurement of outcomes and privacy policy are all outlined in the policy.

Conclusion: Establishing the appropriate framework in which cognitive training strategies can be adapted and implemented in Arabic population, constitutes an inevitable achievement in healthy ageing and can be also assumed as a dementia prevention strategy. Moreover, setting up the first cognitive laboratory in Egypt older adults, can be a model of good practice across the Arabic countries.
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http://dx.doi.org/10.3233/JAD-201278DOI Listing
September 2021

Mild Alzheimer Disease, Financial Capacity, and the Role of Depression: Eyes Wide Shut?

Alzheimer Dis Assoc Disord 2021 Jan 11. Epub 2021 Jan 11.

School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

The aim of this study was to assess whether comorbid depression in patients with mild Alzheimer disease (AD) can influence financial capacity. The sample comprised 109 participants divided into 4 groups: mild AD with and without depressive symptoms, and cognitive normal elderly with and without depression. Participants were examined using a number of neuropsychological tests, with an emphasis on the Mini-Mental State Examination, the 15-item Geriatric Depression Scale, and the Legal Capacity for Property Law Transactions Assessment Scale. Financial capacity ascertained as performance in the Legal Capacity for Property Law Transactions Assessment Scale in the group of mild AD patients was severely impaired when depression coexisted, thus clearly differentiating the mild AD group from mild AD with comorbid depression.
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http://dx.doi.org/10.1097/WAD.0000000000000427DOI Listing
January 2021

Pathophysiological subtypes of Alzheimer's disease based on cerebrospinal fluid proteomics.

Brain 2020 12;143(12):3776-3792

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC - Location VUmc, The Netherlands.

Alzheimer's disease is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. CSF contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether Alzheimer's disease biological subtypes can be detected in CSF proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 911 tested) proteins differed between Alzheimer's disease (defined as having abnormal amyloid, n = 425) and controls (defined as having normal CSF amyloid and tau and normal cognition, n = 127). Using these proteins for data-driven clustering, we identified three robust pathophysiological Alzheimer's disease subtypes within each cohort showing (i) hyperplasticity and increased BACE1 levels; (ii) innate immune activation; and (iii) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals were labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, and 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for Alzheimer's disease (all P > 0.01). Additional pathological comparisons that were available for a subset in ADNI suggested that subtypes showed similar severity of Alzheimer's disease pathology, and did not differ in the frequencies of co-pathologies, providing further support that found subtypes truly reflect Alzheimer's disease heterogeneity. Compared to controls, all non-demented Alzheimer's disease individuals had increased risk of showing clinical progression (all P < 0.01). Compared to subtype 1, subtype 2 showed faster clinical progression after correcting for age, sex, level of education and tau levels (hazard ratio = 2.5; 95% confidence interval = 1.2, 5.1; P = 0.01), and subtype 3 at trend level (hazard ratio = 2.1; 95% confidence interval = 1.0, 4.4; P = 0.06). Together, these results demonstrate the value of CSF proteomics in studying the biological heterogeneity in Alzheimer's disease patients, and suggest that subtypes may require tailored therapy.
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http://dx.doi.org/10.1093/brain/awaa325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805814PMC
December 2020

Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer's disease.

Alzheimers Res Ther 2021 01 9;13(1):20. Epub 2021 Jan 9.

UK Dementia Research Institute, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK.

Background: Both serotonergic signalling disruption and systemic inflammation have been associated with the pathogenesis of Alzheimer's disease (AD). The common denominator linking the two is the catabolism of the essential amino acid, tryptophan. Metabolism via tryptophan hydroxylase results in serotonin synthesis, whilst metabolism via indoleamine 2,3-dioxygenase (IDO) results in kynurenine and its downstream derivatives. IDO is reported to be activated in times of host systemic inflammation and therefore is thought to influence both pathways. To investigate metabolic alterations in AD, a large-scale metabolic phenotyping study was conducted on both urine and serum samples collected from a multi-centre clinical cohort, consisting of individuals clinically diagnosed with AD, mild cognitive impairment (MCI) and age-matched controls.

Methods: Metabolic phenotyping was applied to both urine (n = 560) and serum (n = 354) from the European-wide AddNeuroMed/Dementia Case Register (DCR) biobank repositories. Metabolite data were subsequently interrogated for inter-group differences; influence of gender and age; comparisons between two subgroups of MCI - versus those who remained cognitively stable at follow-up visits (sMCI); and those who underwent further cognitive decline (cMCI); and the impact of selective serotonin reuptake inhibitor (SSRI) medication on metabolite concentrations.

Results: Results revealed significantly lower metabolite concentrations of tryptophan pathway metabolites in the AD group: serotonin (urine, serum), 5-hydroxyindoleacetic acid (urine), kynurenine (serum), kynurenic acid (urine), tryptophan (urine, serum), xanthurenic acid (urine, serum), and kynurenine/tryptophan ratio (urine). For each listed metabolite, a decreasing trend in concentrations was observed in-line with clinical diagnosis: control > MCI > AD. There were no significant differences in the two MCI subgroups whilst SSRI medication status influenced observations in serum, but not urine.

Conclusions: Urine and serum serotonin concentrations were found to be significantly lower in AD compared with controls, suggesting the bioavailability of the neurotransmitter may be altered in the disease. A significant increase in the kynurenine/tryptophan ratio suggests that this may be a result of a shift to the kynurenine metabolic route due to increased IDO activity, potentially as a result of systemic inflammation. Modulation of the pathways could help improve serotonin bioavailability and signalling in AD patients.
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http://dx.doi.org/10.1186/s13195-020-00741-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797094PMC
January 2021

Effects of a Person Centered Dementia Training Program in Greek Hospital Staff-Implementation and Evaluation.

Brain Sci 2020 Dec 12;10(12). Epub 2020 Dec 12.

School of Medicine, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece.

People with Dementia (PwD) are frequently admitted in general hospitals. However, health care professionals have lack of dementia knowledge, negative attitudes toward dementia, and lack of confidence in caring those patients. The aim of this study is to develop, implement and evaluate a dementia staff training program in Greek general hospitals. It was a repeated-measures research design. Fourteen (14) two-day workshops were conducted, consisting of six targeted and interactive modules. Staff members (N = 242) attended the program and were assessed according to (1) individual performance: questionnaires about attitudes towards dementia, confidence in care, knowledge about dementia and anxiety before, immediately after the training and three months later, (2) an overall training evaluation immediately after the training and (3) an evaluation of training implementation three months later. Positive attitudes towards dementia, improvement of confidence in care and decrease of feeling of anxiety as a trait, were sustained over time. Knowledge about dementia also increased after the training and sustained, with, however, a slight decrease over time. A well applied training program seems to provide the basis of a better care in PwD during hospitalization. However, changes in the organizational level and a transformation of care culture are necessary for training sustainability over time.
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http://dx.doi.org/10.3390/brainsci10120976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763588PMC
December 2020
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