Vulnerability of neurofilament-expressing neurons in frontotemporal dementia.

Frontotemporal dementia (FTD) is an umbrella term for several early onset dementias, that are caused by frontotemporal lobar degeneration (FTLD), which involves the atrophy of the frontal and temporal lobes of the brain. Neuron loss in the frontal and temporal lobes is a characteristic feature of FTLD, however the selective vulnerability of different neuronal populations in this group of diseases is not fully understood. Neurofilament-expressing neurons have been shown to be selectively vulnerable in other neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, therefore we sought to investigate whether this neuronal population is vulnerable in FTLD. We also examined whether neuronal sub-type vulnerability differed between FTLD with TDP-43 inclusions (FTLD-TDP) and FTLD with tau inclusions (FTLD-Tau). Post-mortem human tissue from the superior frontal gyrus (SFG) of FTLD-TDP (n = 15), FTLD-Tau (n = 8) and aged Control cases (n = 6) was immunolabelled using antibodies against non-phosphorylated neurofilaments (SMI32 antibody), calretinin and NeuN, to explore neuronal cell loss. The presence of non-phosphorylated neurofilament immunolabelling in axons of the SFG white matter was also quantified as a measure of axon pathology, as axonal neurofilaments are normally phosphorylated. We demonstrate the selective loss of neurofilament-expressing neurons in both FTLD-TDP and FTLD-Tau cases compared to aged Controls. We also show that non-phosphorylated neurofilament axonal pathology in the SFG white matter was associated with increasing age, but not FTLD. This data suggests neurofilament-expressing neurons are vulnerable in both FTLD-TDP and FTLD-Tau.

Hand Motor Dysfunction Is Associated with Both Subjective and Objective Cognitive Impairment across the Dementia Continuum.

INTRODUCTION: Motor dysfunction is an important feature of early-stage dementia. Gait provides a non-invasive biomarker across the dementia continuum. Gait speed and rhythm aid risk stratification of incident dementia in subjective cognitive impairment (SCI) and are associated with cognitive domains in mild cognitive impairment (MCI) and dementia. However, hand movement analysis, which may be more accessible, has never been undertaken in SCI and rarely in MCI or dementia. We aimed to address this gap and improve understanding of hand motor-cognitive associations across the dementia continuum. METHODS: A total of 208 participants were recruited: 50 with dementia, 58 MCI, 40 SCI, and 60 healthy controls. Consensus diagnoses were made after comprehensive gold-standard assessments. A computer key-tapping test measured frequency, dwell-time, rhythm, errors, and speed. Associations between key-tapping and cognitive domains and diagnoses were analysed using regression. Classification accuracy was measured using area under receiver operating characteristic curves. RESULTS: Hand frequency and speed were associated with memory and executive domains (p ≤ 0.001). Non-dominant hand rhythm was associated with all cognitive domains. Frequency, rhythm, and speed were associated with SCI, MCI, and dementia. Frequency and speed classified ≥94% of dementia and ≥88% of MCI from controls. Rhythm of the non-dominant hand classified ≥86% of dementia and MCI and 69% of SCI. CONCLUSION: Our findings show hand motor dysfunction occurs across the dementia continuum and, similar to gait, is associated with executive and memory domains and with cognitive diagnoses. Key-tapping performance differentiated dementia and MCI from healthy controls. More research is required before recommending key-tapping as a non-invasive motor biomarker of cognitive impairment.

Development of a smartphone screening test for preclinical Alzheimer's disease and validation across the dementia continuum.

BACKGROUND: Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer's disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10-20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. METHODS: Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50-92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30-40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50-100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. DISCUSSION: This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.

Who is seeking information about traumatic brain injury? Characterizing online course participants.

Accessible, up-to-date information on traumatic brain injury (TBI) can be challenging to find and is needed to address TBI knowledge gaps and improve outcomes for people who experience a TBI. The Understanding TBI Massive Open Online Course (TBI MOOC) was developed to increase TBI knowledge across a diverse global audience. We sought to characterize the TBI MOOC participant cohort, to understand the reach of the course among this target audience. Examining the characteristics of TBI MOOC enrollees showed that participants came from a wide range of demographic backgrounds, had a variety of TBI experiences and had multiple reasons for enrolling in the MOOC. The majority of course participants shared some characteristics with other groups of health information seekers. Four distinct demographic profiles were identified among TBI MOOC participants (education seekers, TBI-aware participants, TBI care providers and retirees) using a novel approach combining chi-squared tests and network modularity. Participants assigned to the TBI-aware and retiree profiles were most likely to complete all modules of the MOOC, and the TBI-aware profile was more highly represented in more recent iterations of the MOOC. Together, these data indicate that the TBI MOOC provided information to a wide range of people, and particularly engaged participants with personal or family experience of TBI. However, engagement with this course was minimal among some hard-to-reach populations, including men and people with low levels of education, indicating that additional strategies are needed to ensure equity in health promotion.

Estimating presymptomatic episodic memory impairment using simple hand movement tests: A cross-sectional study of a large sample of older adults.

INTRODUCTION: Finding low-cost methods to detect early-stage Alzheimer's disease (AD) is a research priority for neuroprotective drug development. Presymptomatic Alzheimer's is associated with gait impairment but hand motor tests, which are more accessible, have hardly been investigated. This study evaluated how home-based Tasmanian (TAS) Test keyboard tapping tests predict episodic memory performance. METHODS: 1169 community participants (65.8 ± 7.4 years old; 73% female) without cognitive symptoms completed online single-key and alternate-key tapping tests and episodic memory, working memory, and executive function cognitive tests. RESULTS: All single-key (R2 adj  = 8.8%, ΔAIC = 5.2) and alternate-key (R2 adj  = 9.1%, ΔAIC = 8.8) motor features predicted episodic memory performance relative to demographic and mood confounders only (R2 adj  = 8.1%). No tapping features improved estimation of working memory. DISCUSSION: Brief self-administered online hand movement tests predict asymptomatic episodic memory impairment. This provides a potential low-cost home-based method for stratification of enriched cohorts. HIGHLIGHTS: We devised two brief online keyboard tapping tests to assess hand motor function. 1169 cognitively asymptomatic adults completed motor- and cognitive tests online. Impaired hand motor function predicted reduced episodic memory performance. This brief self-administered test may aid stratification of community cohorts.

Experimental laboratory models as tools for understanding modifiable dementia risk.

Experimental laboratory research has an important role to play in dementia prevention. Mechanisms underlying modifiable risk factors for dementia are promising targets for dementia prevention but are difficult to investigate in human populations due to technological constraints and confounds. Therefore, controlled laboratory experiments in models such as transgenic rodents, invertebrates and in vitro cultured cells are increasingly used to investigate dementia risk factors and test strategies which target them to prevent dementia. This review provides an overview of experimental research into 15 established and putative modifiable dementia risk factors: less early-life education, hearing loss, depression, social isolation, life stress, hypertension, obesity, diabetes, physical inactivity, heavy alcohol use, smoking, air pollution, anesthetic exposure, traumatic brain injury, and disordered sleep. It explores how experimental models have been, and can be, used to address questions about modifiable dementia risk and prevention that cannot readily be addressed in human studies. HIGHLIGHTS: Modifiable dementia risk factors are promising targets for dementia prevention. Interrogation of mechanisms underlying dementia risk is difficult in human populations. Studies using diverse experimental models are revealing modifiable dementia risk mechanisms. We review experimental research into 15 modifiable dementia risk factors. Laboratory science can contribute uniquely to dementia prevention.

Gender differences in modifiable dementia risk factors in monolingual and bilingual Australian adults.

ISSUE ADDRESSED: Gender and bilingualism are reported to influence the risk of dementia. This study examined the prevalence of self-reported modifiable dementia risk factors by gender in two samples: one that speaks at least one language other than English (LoE) and one that speaks only English. METHODS: A descriptive cross-sectional study was conducted on a sample of Australian residents aged 50 years or over (n = 4339). Participant characteristics and dementia risk behaviours were inspected using descriptive statistics in data collected via online surveys between October 2020 and November 2021. RESULTS: In both samples, men had a higher rate than women of being overweight and were classified more frequently as being at risk of dementia due to alcohol consumption, lower cognitive activity, and non-adherence to the Mediterranean-style diet. Men reported better management of their cardiometabolic health than women across both groups. Non-significant trends showed men were more often smokers but more physically active than women in the LoE group, and less often smokers but less physically active than women in the English-only group. CONCLUSION: This study found men and women reported similar patterns of dementia risk behaviours regardless of LoE or English-only status. SO WHAT?: Gender differences in risk behaviours prevail regardless of language-speaking status. The results can be used to guide future research aiming to understand and reduce modifiable dementia risk in Australia and beyond.

Association between chronic pain and risk of incident dementia: findings from a prospective cohort.

BACKGROUND: Chronic musculoskeletal pain has been linked to dementia; however, chronic pain typically occurs in multiple sites; therefore, this study was to investigate whether greater number of chronic pain sites is associated with a higher risk of dementia and its subtypes. METHODS: Participants (N = 356,383) in the UK Biobank who were dementia-free at baseline were included. Pain in the hip, knee, back, and neck/shoulder or 'all over the body' and its duration were assessed. Participants were categorised into six groups: no chronic pain; chronic pain in 1, 2, 3, and 4 sites, and 'all over the body'. All-cause dementia and its subtypes were ascertained using hospital inpatient and death registry records. Cox regression was used to investigate the associations between the number of chronic pain sites and the incidence of all-cause dementia and its subtypes. RESULTS: Over a median follow-up of 13 years, 4959 participants developed dementia. After adjustment for sociodemographic, lifestyle, comorbidities, pain medications, psychological problems, and sleep factors, greater number of chronic pain sites was associated with an increased risk of incident all-cause dementia (hazard ratio [HR] = 1.08 per 1 site increase, 95% CI 1.05-1.11) and Alzheimer's disease (AD) (HR = 1.09 per 1-site increase, 95% CI 1.04-1.13) in a dose-response manner but not vascular and frontotemporal dementia. No significant association was found between the number of chronic pain sites and the risk of incident all-cause dementia among a subsample that underwent a fluid intelligence test. CONCLUSIONS: Greater number of chronic pain sites was associated with an increased risk of incident all-cause dementia and AD, suggesting that chronic pain in multiple sites may contribute to individuals' dementia risk and is an underestimated risk factor for dementia.

Isolated rapid eye movement sleep behaviour disorder (iRBD) in the Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study: protocol and baseline characteristics.

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a sleep disorder that is characterised by dream enactment episodes during REM sleep. It is the strongest known predictor of α-synuclein-related neurodegenerative disease (αNDD), such that >80% of people with iRBD will eventually develop Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy in later life. More research is needed to understand the trajectory of phenoconversion to each αNDD. Only five 'gold standard' prevalence studies of iRBD in older adults have been undertaken previously, with estimates ranging from 0.74% to 2.01%. The diagnostic recommendations for video-polysomnography (vPSG) to confirm iRBD makes prevalence studies challenging, as vPSG is often unavailable to large cohorts. In Australia, there have been no iRBD prevalence studies, and little is known about the cognitive and motor profiles of Australian people with iRBD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study will investigate the prevalence of iRBD in Tasmania, an island state of Australia, using validated questionnaires and home-based vPSG. It will also explore several cognitive, motor, olfactory, autonomic, visual, tactile, and sleep profiles in people with iRBD to better understand which characteristics influence the progression of iRBD to αNDD. This paper details the ISLAND Sleep Study protocol and presents preliminary baseline results.

A new one-stop interdisciplinary cognitive clinic model tackles rural health inequality and halves the time to diagnosis: Benchmarked against a national dementia registry.

OBJECTIVES: Unequal access to cognitive assessments is a major barrier to timely diagnosis, especially for those living in rural or remote areas. 'One-stop' cognitive clinic models are a proposed solution, but few such clinics exist. We evaluate the implementation of a new one-stop State-wide clinic model in Tasmania, Australia, where 27% of people live in rural/remote areas. METHODS: A novel single-visit protocol has been developed, comprising interdisciplinary medical and cognitive assessments, research participation, consensus diagnosis and management plan. A cross-sectional evaluation was undertaken using the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework and results benchmarked against the national Australian Dementia Network Registry. RESULTS: Over the first 52 consecutive weekly clinics: Reach: 130 adults were assessed (mean age [SD] 70.12 years [10.31]; 59.2% female) with 40 (36.8%) from rural/remote areas. EFFECTIVENESS: 98.5% (128/130) received a same-day diagnosis: 30.1% (n = 40) Subjective Cognitive Decline, 35.4% (46) Mild Cognitive Impairment, 33.1% (43) dementia and one case inconclusive. Adoption: 22.9% (156) of General Practitioners referred patients. IMPLEMENTATION: Nearly all 'ideal' diagnostic clinical practices were met and >90% of surveyed patients reported 'good/very good' clinic experience. The wait from referral to diagnosis was 2 months shorter than other national Registry clinics (78 vs. 133 days). CONCLUSIONS: This 'one-stop' model provides an interdisciplinary consensus cognitive diagnosis quickly and is well accepted; this may reduce health inequities especially for people living in rural/remote areas. This cognitive clinic model may be of relevance to other centres worldwide and also provides a rich data source for research studies.

An online, public health framework supporting behaviour change to reduce dementia risk: interim results from the ISLAND study linking ageing and neurodegenerative disease.

BACKGROUND: Unmanaged cardiometabolic health, low physical and cognitive activity, poor diet, obesity, smoking and excessive alcohol consumption are modifiable health risk factors for dementia and public health approaches to dementia prevention have been called for. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) is a dementia prevention public health study examining whether improving knowledge about modifiable dementia risk factors supports behaviour changes that reduce future dementia risk. METHODS: Residents of Tasmania, Australia, aged 50 + years who joined the 10-year ISLAND study were asked to complete annual online surveys about their knowledge, motivations and behaviours related to modifiable dementia risk. ISLAND included two knowledge-based interventions: a personalised Dementia Risk Profile (DRP) report based on survey responses, and the option to do a 4-week Preventing Dementia Massive Open Online Course (PDMOOC). Longitudinal regression models assessed changes in the number and type of risk factors, with effects moderated by exposures to the DRP report and engagement with the PDMOOC. Knowledge and motivational factors related to dementia risk were examined as mediators of risk behaviour change. RESULTS: Data collected between October 2019 and October 2022 (n = 3038, av. 63.7 years, 71.6% female) showed the mean number of modifiable dementia risk factors per participant (range 0 to 9) reduced from 2.17 (SD 1.24) to 1.66 (SD 1.11). This change was associated with the number of exposures to the DRP report (p = .042) and was stronger for PDMOOC participants (p = .001). The interaction between DRP and PDMOOC exposures yielded a significant improvement in risk scores (p = .004). The effect of PDMOOC engagement on behaviour change was partly mediated by increased knowledge (12%, p = .013). Self-efficacy enhanced the effect of knowledge on behaviour change, while perceived susceptibility to dementia mitigated this relationship. CONCLUSIONS: The ISLAND framework and interventions, a personalised DRP report and the four-week PDMOOC, work independently and synergistically to increase dementia risk knowledge and stimulate health behaviour change for dementia risk reduction. ISLAND offers a feasible and scalable public health approach for redressing the rising prevalence of dementia.

The TAS Test project: a prospective longitudinal validation of new online motor-cognitive tests to detect preclinical Alzheimer's disease and estimate 5-year risks of cognitive decline and dementia.

BACKGROUND: The worldwide prevalence of dementia is rapidly rising. Alzheimer's disease (AD), accounts for 70% of cases and has a 10-20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust 'self-testing' data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia. METHODS: Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD. DISCUSSION: This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05194787 , 18 January 2022. Retrospectively registered.

Effects of TDP-43 overexpression on neuron proteome and morphology in vitro.

TDP-43 is pathologically and genetically with associated amyotrophic lateral sclerosis and frontotemporal lobar degeneration. These diseases are characterized by significant neurite defects, including cytoskeletal pathology. The involvement of TDP-43 in the degeneration of neurons in these diseases are not yet well understood, however accumulating evidence shows involvement in neurite outgrowth, remodelling and in regulation of many components of the neuronal cytoskeleton. In order to investigate how alterations to TDP-43 expression levels may exert effects on the neuronal cytoskeleton, primary cortical neurons from transgenic mice overexpressing one or two copies of human wildtype TDP-43 under the prion promoter were examined. Label-free quantitative proteomic analysis, followed by functional annotation clustering to identify protein families that clustered together within up- or down-regulated protein groups, revealed that actin-binding proteins were significantly more abundant in neurons overexpressing TDP-43 compared to wildtype neurons. Morphological analysis demonstrated that during early development neurons expressing one copy of human TDP-43 had an increased number of neurite branches and alterations to growth cone morphology, while no changes were observed in neurons expressing two copies of TDP-43. These developmental processes require specific expression and organization of the cytoskeleton. The results from these studies provide further insight into the normal function of TDP-43 and how alterations in TDP-43 expression may impact the cytoskeleton.

Invasive experimental brain surgery for dementia: Ethical shifts in clinical research practices?

The increasing dementia prevalence worldwide is driving the testing of novel therapeutic approaches, such as invasive brain technologies, despite limited clinical evidence and the risk of accelerating cognitive decline. Our manuscript (a) reviews the NIH Clinicaltrials.gov database for deep brain stimulation, stem cell implantation, and gene therapy trials on people with dementia; (b) discusses issues on beneficence, nonmaleficence, and autonomy associated with these trials; and (c) proposes nine recommendations that build on elements from the Declaration of Helsinki. We found 49 preregistered high-risk trials from nine countries planning to or involving 11,801 people with Alzheimer's or Lewy body dementia or dementia secondary to Parkinson's or Huntington's disease. Most of the people with Alzheimer's who are in these trials are from North America and East Asia. There is substantial heterogeneity in the enrolment criteria, even for trials recruiting only those with Alzheimer's disease. Although most trials enrol people in mild to moderate stages of Alzheimer's disease, trials in China enrol people who have severe Alzheimer's. Our findings highlight a pressing need to review and refine the enrolment criteria for invasive neural trials in people with dementia, considering risks, potential benefits, and capacity for informed consent. As a multidisciplinary team from Australia, the USA, Canada, and Germany with expertise in neurology, neuroscience, and ethics, we examine how it is essential to balance the risks of invasive neural research in a vulnerable population with limited capacity to provide informed consent to help advance the body of knowledge regarding a disease with limited therapeutic options.

Consumer Access, Appraisal, and Application of Services and Information for Dementia (CAAASI-Dem): a validation study.

Objectives: The Consumer Access, Appraisal, and Application of Services and Information for Dementia (CAAASI-Dem) was developed to examine individuals' self-assessed confidence in their ability to access, appraise and use dementia services and information. The CAAASI-Dem is the only tool to date to measure this crucial component of dementia literacy. This study was designed to validate its structural validity.Method: Data was collected from 3277 participants enrolled in an on-line dementia course. The five-factor structure of the CAAASI-Dem, which was derived from a previous exploratory factor analysis, was evaluated using confirmatory factor analysis. Internal reliability, convergent and divergent validity, and known-groups validity were assessed. Results: The five-factor model demonstrated good fit with the observed data with the removal of 2 items and movement of 1 item across the factors. The resultant 24-item five-factor CAAASI-Dem showed very good sub-scale internal reliability and satisfactory convergent and divergent validity. There was good discrimination between groups of participants with different levels of care experience.Conclusion: The results provided evidence for the 24-item CAAASI-Dem as a valid and reliable five-dimensional scale. Limitations of the study are discussed, and recommendations are made for future research and practice.

Microtubule-dependent processes precede pathological calcium influx in excitotoxin-induced axon degeneration.

Axon degeneration and axonal loss is a feature of neurodegenerative disease and injury and occurs via programmed pathways that are distinct from cell death pathways. While the pathways of axonal loss following axon severing are well described, less is known about axonal loss following other neurodegenerative insults. Here we use primary mouse cortical neuron cultures grown in compartmentalized chambers to investigate the role of calcium in the degeneration of axons that occurs following a somal insult by the excitotoxin kainic acid. Calcium influx has been implicated in both excitotoxicity and axon degeneration mechanisms, however the link between a somal insult and axonal calcium increase is unclear. Live imaging of axons demonstrated that pharmacologically preventing intracellular calcium increases through the endoplasmic reticulum or mitochondria significantly (p < 0.05) reduced axon degeneration. Live calcium-imaging with the Ca2+ indicator Fluo-4 demonstrated that kainic acid exposure to the soma resulted in a rapid, and transient, increase in calcium in the axon, which occured even at low kainic acid concentrations that do not cause axon degeneration within 24 h. However, this calcium transient was followed by a gradual increase in axonal calcium, which was associated with axonal loss. Furthermore, treatment with a range of doses of the microtubule stabilizing drug taxol, which protects against axon fragmentation in this model, prevented this gradual calcium increase, suggesting that the intra-axonal calcium changes are downstream of microtubule associated events. Biochemical analysis of taxol treated neurons demonstrated a shift in microtubule post-translational modifications, with a significant (p < 0.05) increase in acetylated tubulin and a significant (p < 0.05) decrease in tyrosinated tubulin, suggestive of a more stable microtubule pool. Together our results suggest that axonal degeneration following excitotoxicity is dependent on an increase in axonal calcium, which is downstream of a microtubule-dependent event.

Measuring consumer access, appraisal and application of services and information for dementia (CAAASI-Dem): a key component of dementia literacy.

BACKGROUND: The ability to locate, navigate and use dementia services and information, either for oneself or in providing care for others, is an essential component of dementia literacy. Despite dementia literacy being understood to be inadequate in many settings, no validated instrument exists to measure these elements. Here we describe the development and preliminary validation of the Consumer Access, Appraisal and Application of Services and Information for Dementia (CAAASI-Dem) tool. METHODS: Items were adapted from existing health literacy tools and guided by discussion posts in the Understanding Dementia Massive Open Online Course (UDMOOC). Following expert review and respondent debriefing, a modified CAAASI-Dem was administered to UDMOOC participants online. On the basis of descriptive statistics, inter-item and item total correlations and qualitative feedback, this was further refined and administered online to a second cohort of UDMOOC participants. Exploratory factor analysis identified underlying factor structure. Items were retained if they had significant factor loadings on one factor only. Each factor required at least three items with significant factor loadings. Internal consistency of factors in the final model was evaluated using Cronbach's alpha coefficients. RESULTS: From a pool of 70 initial items with either a 5-point Likert scale (Not at all confident - Extremely confident; or Strongly agree - Strongly disagree) or a binary scale (Yes - No), 65 items were retained in CAAASI-Dem-V1. Statistical and qualitative analysis of 1412 responses led to a further 34 items being removed and 11 revised to improve clarity. The 31 item CAAASI-Dem-V2 tool was subsequently administered to 3146 participants, one item was removed due to redundancy and EFA resulted in the removal of an additional 4 items and determination of a five factor structure: Evaluation and engagement; Readiness; Social supports; Specific dementia services; and Practical aspects. CONCLUSIONS: The five factors and 26 constituent items in CAAASI-Dem align with functional, critical, and communicative aspects of dementia health literacy from the perspective of the carer. As a screening tool for people living with dementia and their carers, CAAASI-Dem potentially provides a means to determine support needs and may be a key component of the dementia literacy assessment toolbox.

Communication training and its effects on carer and care-receiver outcomes in dementia settings: A systematic review.

AIMS AND OBJECTIVES: To review communication interventions that aim to improve regular care interactions between people with dementia and their carers in various settings; and to examine the impact of such interventions on both carer and care-receiver outcomes. BACKGROUND: Effective communication is imperative to ensure quality of care for people living with dementia. Due to neurodegenerative changes, people with dementia encounter ongoing and progressive difficulties in both understanding and expressing themselves. This in turn creates challenges for carers, which highlights the need for equipping them with necessary communication skills to respond to the specific communication needs of people with dementia. DESIGN: Systematic review and meta-analysis. METHOD: Medline, Embase, CINAHL, ProQuest and PsycINFO databases were searched for eligible interventions with any date of the publication. Hand searching was also conducted through reviewing the reference lists of relevant articles. The screening and selection of studies were based on the inclusion/exclusion criteria for eligibility and the methodological quality assessment checklist. Random-effects meta-analyses were conducted on comparable quantitative data. The review is reported following the PRISMA reporting guidelines. RESULTS: Seventeen studies were included in the final review, including 12 randomised controlled trials (RCTs), three nonrandomised controlled trials (NRCTs) and two controlled before-after interventions. The intervention designs, settings and outcome measures were varied. The findings suggest that the communication training had a positive impact on both carer and care-receiver outcomes, albeit to different degrees. The intervention effects were found to be strongest on carer communication skills and knowledge. CONCLUSION: There is solid evidence for the positive impact of communication training on the skills and knowledge of carers. More research is needed regarding the effects of such educational interventions on carer physio-psychological outcomes and care-receiver neuropsychiatric symptoms. It is important to establish best practices in training design, develop validated outcome measures and adopt consistent reporting approaches. RELEVANCE TO CLINICAL PRACTICE: The increasing global prevalence of people with dementia manifests across clinical and community contexts. The profound impact of dementia on communication and associated care raises the imperative for enhanced health worker and carer communication skills to meet the needs of this particular client group. The findings of this review indicate that educational interventions incorporating face-to-face and diverse instructional delivery methods in dementia communication showed positive outcomes for communication skills in all carer groups and warrant inclusion as strategies in dementia training.

How is palliative care understood in the context of dementia? Results from a massive open online course.

BACKGROUND: A palliative approach to the care of people with dementia has been advocated, albeit from an emergent evidence base. The person-centred philosophy of palliative care resonates with the often lengthy trajectory and heavy symptom burden of this terminal condition. AIM: To explore participants' understanding of the concept of palliative care in the context of dementia. The participant population took an online course in dementia. DESIGN: The participant population took a massive open online course on 'Understanding Dementia' and posted answers to the question: 'palliative care means …' We extracted these postings and analysed them via the dual methods of topic modelling analysis and thematic analysis. SETTING/PARTICIPANTS: A total of 1330 participants from three recent iterations of the Understanding Dementia Massive Open Online Course consented to their posts being used. Participants included those caring formally or informally for someone living with dementia as well as those with a general interest in dementia Results: Participants were found to have a general awareness of palliative care, but saw it primarily as terminal care, focused around the event of death and specialist in nature. Comfort was equated with pain management only. Respondents rarely overtly linked palliative care to dementia. CONCLUSIONS: A general lack of palliative care literacy, particularly with respect to dementia, was demonstrated by participants. Implications for dementia care consumers seeking palliative care and support include recognition of the likely lack of awareness of the relevance of palliative care to dementia. Future research could access online participants more directly about their understandings/experiences of the relationship between palliative care and dementia.

Repeat propofol anesthesia does not exacerbate plaque deposition or synapse loss in APP/PS1 Alzheimer's disease mice.

BACKGROUND: There is increasing interest in whether anesthetic agents affect the risk or progression of Alzheimer's disease (AD). To mitigate many of the methodological issues encountered in human retrospective cohort studies we have used a transgenic model of AD to investigate the effect of propofol on AD pathology. METHODS: Six month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic AD mice and control mice were exposed to 3 doses of propofol (200 mg/kg) or vehicle, delivered at monthly intervals. RESULTS: There was no difference in the extent of ß-amyloid (Aß) immunolabeled plaque deposition in APP/PS1 mice in vehicle versus propofol treatment groups. We also detected no difference in plaque-associated synapse loss in APP/PS1 mice following repeat propofol exposure relative to vehicle. Western blotting indicated that there was no difference in post-synaptic density protein 95, synaptophysin or glutamic acid decarboxylase 65/67 expression in control or APP/PS1 mice subjected to repeat propofol treatment relative to vehicle. CONCLUSIONS: These data suggest that repeat propofol anesthesia may not exacerbate plaque deposition or associated synapse loss in AD. Interestingly, this data also provides some of the first evidence suggesting that repeat propofol exposure in adult wild-type mice does not result in robust long-term alterations in the levels of key excitatory and inhibitory synaptic markers.