bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retinal inhibition of glycogen synthase kinase 3 beta protects against tau phosphorylation and stabilises microtubule assembly
Authors: Chitranshi Nitin , Rajput Rashi , Garthwaite Linda , Thananthirige Kanshika Pushpitha Maha , Mirzaei Mehdi , Sheriff Samran , Godinez Angela , Gupta Veer , Graham Stuart , Gupta Vivek K. 
Published: December 2020

AbstractBackgroundThe microtubule associated protein tau is known to have several important functions like assembly and stabilisation of microtubules, axonal transport and neurite outgrowth in neurodegenerative diseases. Gsk3β, glycogen synthase kinase, plays a key role in regulating tau protein activity. There is little understanding of tau and Gsk3β association in the neurogenerative disorders affecting retina. Shp2, the mitogenic phosphatase, is associated with regulation of growth factor signalling pathways in the central nervous system. In this study we demonstrate that Gsk3β inhibition can suppress tau hyperphosphorylation and rescue the inner retinal degenerative changes induced by Shp2 overexpression (OE).MethodsAdult Sprague‐Dawley rats were subjected to intravitreal injection of adeno‐associated viral vector (AAV2) overexpressing either Shp2 or eGFP alone (3.4x1012 GC/ml; n=8). These animals were also subjected to weekly (8 weeks) intravitreal injections of Gsk3β inhibitor (10 nM) and control. Electrophysiology and positive scotopic threshold response (pSTR) (‐4.3 log cd s/m2) were measured using Phoenix Ganzfield two months following intra‐ocular injections. The amplitude of each component was measured and analysed. Immunohistochemistry (IHC) and Western blot (WB) were performed for pTau Ser404, Tau, pGsk3β Ser9, Gsk3β, Ac‐tubulin and Tyr‐tubulin.ResultsShp2OE in the rat eye significantly reduced the pSTR amplitudes (44%±3.1%) compared to PBS and GFP control. However, animals treated with Gsk3β inhibitor in Shp2OE retina demonstrated significant protection of pSTR amplitudes (81±5 % protection; n=32, p<0.05). IHC analysis demonstrated increased pTau Ser404 and decreased pGsk3β Ser9 immunoreactivity in the Shp2OE RGCs whereas pharmacological inhibition of Gsk3β for 8 weeks reversed the phosphorylation status of tau and Gsk3β in animals recieving AAV‐Shp2. We found that Shp2OE led to a markedly reduced expression of Ac‐tubulin (stable microtubules) and increased expression of Tyr‐tubulin (unstable microtubules) compared with control retina. Remarkably, the effects of Shp2OE on microtubules assembly was reversed upon Gsk3β inhibitor administration.ConclusionShp2OE in the retina led to abnormal tau hyperphosphorylation via Gsk3β activation causing deficits in RGCs visual function through the disruption of microtubular assembly. Shp2 may thus be an attractive therapeutic target to counter RGC neurodegeneration by reducing tau hyperphosphorylation in Alzheimer’s disease.
The Preventing Dementia Massive Open Online Course results in behaviour change associated with reduced dementia risk: The My INdex of DEmentia Risk (MINDER) study
Authors: Farrow Maree , Klekociuk Shannon Z , Bindoff Aidan , Vickers James C 
Published: December 2020

AbstractBackgroundSeveral multi‐domain dementia prevention interventions are being trialled, often involving intensive programs targeting older adults. To reach the wider population at risk of dementia, accessible and scalable interventions are also needed. The Preventing Dementia Massive Open Online Course (PD‐MOOC) aims to build knowledge of dementia risk factors, self‐efficacy in management of modifiable risk factors, and an ability to appraise evidence. Since 2016, the PD‐MOOC has attracted over 99,000 enrolments.MethodThe My INdex of DEmentia Risk (MINDER) study aimed to investigate the impact of the PD‐MOOC on risk‐related behaviour and dementia worry, and associations between the two. PD‐MOOC participants completed the short form Australian National University Alzheimer’s Disease Risk Index (ANU‐ADRI) and the Dementia Worry Scale at 3 time points: pre‐MOOC (n = 4838), immediately post‐MOOC (n = 2546), and 6 months follow‐up (n = 906). Multinomial logistic regression models were used to estimate the probability of transition from one risk behaviour state (high/intermediate/low risk) to another, based on ANU‐ADRI sub‐scales for the seven modifiable factors assessed.ResultAt 6 months follow‐up, the probability that participants in the high‐risk state for depressive symptoms at baseline had moved to the low‐risk state was 0.58 (CI: 0.49 – 0.66). Dementia worry was significantly associated with risk state transitions only for depressive symptoms; those more worried were more likely to move from the high‐ to low‐risk state. The probability that heavy alcohol drinkers at baseline transitioned to moderate drinking at follow‐up was 0.49 (CI: 0.33 – 0.64), and the probability that current smokers transitioned to former smokers was 0.15 (CI: 0.05 – 0.23). The probability of moving from the highest risk state at baseline to a lower risk state at follow‐up was 0.36 (CI: 0.11 – 0.70) for social activity, 0.35 (CI: 0.25 – 0.44) for fish consumption, and 0.20 (CI: 0.15 – 0.13) for physical activity, and just 0.02 for cognitive activity.ConclusionThese findings suggest the PD‐MOOC provides benefits beyond imparting knowledge and may contribute to self‐efficacy for sustained behaviour change. The PD‐MOOC may be considered an accessible, scalable and effective multi‐domain public health intervention for dementia risk reduction.
Cognitive reserve for memory performance is mediated by preclinical frontotemporal and limbic amyloid deposition in subjects with normal cognition in early MCI
Authors: Ali Doaa , Moga Daniela C , Khouli Riham H El , Martinez Ashley I , Abner Erin L , Jicha Gregory A 
Published: December 2020

AbstractBackgroundThe neuroanatomic substrate for cognitive reserve has been poorly elucidated. The development of antemortem biomarkers such as amyloid‐PET afford the potential to begin to explore regional pathologic burden with overt cognitive performance as well as cognitive resilience in relation to neuroanatomic distributions of pathology. The present study sought to identify the relationship between regional amyloid burden and objective measures of cognitive reserve for memory function.MethodSixty‐two subjects with normal cognition or mild cognitive impairment from the INCREASE randomized controlled trial (R01AG054130) underwent amyloid‐PET imaging with Amyvid® tracer, and regional SUVr was determined using the Siemens Syngo.via® Neurology software package. Participants underwent cognitive testing with the Montréal Cognitive Assessment (MOCA) and California Verbal Learning Test (CVLT) while challenged with 1.5mg transdermal scopolamine and four weeks later in an unchallenged state. Cognitive reserve (CR) was operationalized by subtracting the scopolamine‐challenged score from unchallenged test performance for CVLT trials 1‐5 total learning. The relationship between regional SUVr and unchallenged as well as CR cognitive test performance was analyzed using adjusted linear regression models.ResultSubjects included 39 women (63%) and 23 men (37%) with a mean age of 73.1±6.2 years, education 16.5±2.7 years, MOCA 25.8± 2.5, and CVLT 45.2± 11.6. Global amyloid‐PET SUVr ranged from 0.9‐2.0 and CVLT CR scores ranged from ‐12 to 34. While, age and education adjusted linear regression analysis demonstrated that unchallenged MOCA and CVLT scores were not significantly related to global SUVr in this sample, reduced CVLT CR was associated with increased global SUVr (p<0.05). Regional analysis demonstrated that this effect was mediated by amyloid deposition in the frontal ((p=0.009), medial temporal (p=0.019), and limbic (p=0.030) regions.ConclusionThese data demonstrate that cognitive reserve for memory functions is particularly sensitive to amyloid deposition in frontotemporal regions intrinsic or connected to the Papez circuit. While this finding is not surprising, it does provide convincing evidence that even preclinical amyloid deposition can have significant clinical consequences when neuroanatomic circuits are stressed. Further work investigating whether transient decline in memory performance at times of medical, emotional, or physical stress might be indicative of preclinical amyloid deposition is warranted.
Decreased task‐evoked functional connectivity in the descending pain modulatory network in Alzheimer’s disease
Authors: Atalla Sebastian W. , Iversen Larkin , Moss Karen , Wright Kathy , Monroe Todd B. 
Published: December 2020

AbstractBackgroundPeople with Alzheimer’s disease (AD) may suffer from alterations in the descending pain modulatory network (DPMN). Adults with AD receive fewer analgesic pain medications and report pain less frequently than healthy controls. This study examines possible alterations in task‐evoked functional connectivity (TEFC) in response to thermal pain in several structures comprising the DPMN. We hypothesize that adults with AD will demonstrate decreased TEFC between DPMN regions.MethodThe sample consisted of 61 adults, 31 people with Alzheimer’s disease (AD; Mage = 77) and 30 healthy controls (HC; Mage = 73). The groups did not differ on socioeconomic status, current or average pain, or state or trait anxiety scores. Age and depression scores differed between groups and were controlled. Participants completed 4 pseudorandomized fMRI sessions using a passive thermal pain induction task consisting of warmth, mild pain, and moderate pain temperature thresholds. Regions of interest were selected a priori: bilateral primary somatosensory cortex (S1), bilateral anterior insula (aINS), bilateral posterior insula (pINS), anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). Psychophysiological interactions (PPI) analysis was completed using CONN v18.b. Motion correction was performed using Artifact Detection Tools and fMRI sessions for which greater than 20% of the timeseries exceeded 2 mm normalized motion were excluded from the analysis. Age and AD‐related differences in cerebral tissue volume were controlled. Contrasts for this analysis were chosen to be mild pain > warmth and moderate pain > warmth to subtract innocuous stimulus from noxious stimuli.ResultCompared to healthy controls, adults with AD exhibited decreased TEFC between the R S1 and L S1 for mild pain > warmth (T = ‐2.03, p = 0.047), and decreased TEFC between the PAG and ACC for moderate pain > warmth (T = ‐2.18, p = 0.033).ConclusionFindings suggest that in people with AD, decreased connectivity between left and right S1 may indicate altered sensory processing of neural input. Evidence of decreased connectivity between the PAG and ACC in adults with AD may indicate an inability to modulate endogenous opioid systems within the brain and may lead to increased suffering from pain.
Traumatic brain injury and dementia risk: The role of sex, insurance and race
Authors: Nuno Miriam , Ugiliweneza Beatrice , Gilsanz Paola , Peterson Rachel , Eng Chloe W. , George Kristen M. , Whitmer Rachel A. 
Published: December 2020

AbstractBackgroundAlthough traumatic brain injury (TBI) has been found to be associated with dementia in numerous studies, large‐scale studies of US non‐Veteran populations are scarce. The question of whether sex, insurance, and race influence the risk of dementia after a TBI is not well studied.MethodsWe analyzed data from 97,736 individuals with TBI age 55+ captured in the IBM MarketScan Commercial Claims and Encounter Database and the Medicare Supplemental Database between January 1, 2000 and December 31, 2016. Dementia diagnosis was made from inpatient or outpatient visits during this period with a “wash out” period of one year. The risk of dementia after TBI was established using Cox proportional hazard models adjusted for age, sex, insurance, diabetes, cardiovascular disease, and birth decade. We censored cases at end of enrollment or date of last claim.ResultsOver a median follow‐up of 19.2 (IQR: 6‐42) months, 6417 (5.9%) individuals developed dementia. Older age at injury was associated with a higher risk of dementia in both mild and moderate/severe cases (Age 85+ vs. 55‐64: Mild HR 13.51, 95% CI: 7.97‐22.91; Moderate/Severe HR 6.88, 95% CI: 5.37‐8.83). Women with moderate/severe TBI had a significantly higher hazard of incident dementia compared to men with the same type of injury (HR 1.14, 95% CI: 1.07‐1.21). Individuals with Medicaid and Medicare coverage had a higher risk of dementia than Commercial insurance users independent of TBI severity. The presence of diabetes (Mild: HR 1.46, 95% CI: 1.24‐1.72; Moderate/Severe: 1.28, 95% CI: 1.03‐1.58) and cardiovascular disease (Mild: HR 1.28, 95% CI: 1.03‐1.58; Moderate/Severe: 1.17, 95% CI: 1.07‐1.29) were associated with an increased risk of dementia. A reduction in dementia risk was observed among Blacks (HR 0.85, 95% CI: 0.74‐0.99), and Hispanics/Others (HR 0.63, 95% CI: 0.51‐0.78) in patients covered by Medicaid (N=13304) when compared to non‐Hispanic whites.ConclusionAge at injury, sex and insurance type were associated with increased risk of dementia after a TBI. Blacks and Hispanics/Others covered by Medicaid experienced a lower risk of dementia compared to Whites. Greater efforts to identify factors to mitigate the burden of dementia in large diverse populations are needed.
A dementia risk assessment tool to facilitate risk‐related behaviour change: The dementia risk profile
Authors: Farrow Maree , Kim Sarang , Bindoff Aidan , Doherty Kathleen , Eccleston Claire , Vickers James C 
Published: December 2020

AbstractBackgroundSeveral risk assessment tools have been developed to estimate an individual’s risk of developing dementia. These measure age, self‐report measures of risk‐related activity and health conditions, and/or physiological measures of vascular or genetic risk. An understanding of actions that one can undertake is required to facilitate individual risk reduction. We developed the Dementia Risk Profile (DRP), focusing on assessment of risk‐related behaviour rather than actual risk, with the aim of providing information to individuals to enable risk reduction.MethodThe WHO Guidelines for Risk Reduction of Cognitive Decline and Dementia recommend interventions for eight modifiable risk factors. For each of these we identified the behaviours associated with mitigating risk. We adapted relevant sections of the short form Australian National University Alzheimer’s Disease Risk Index to develop questions for the DRP and included questions to assess adherence to the Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet. Item development focused on ease of understanding and responding, provision of feedback on actions that could be taken to reduce risk, and tracking behaviour change over time.ResultThe final DRP survey measures: diagnosis, regular checks and management for blood pressure, cholesterol and diabetes; body mass index; MIND diet adherence; frequency of engagement in cognitive activities; time spent engaging in walking, moderate and vigorous physical activity; frequency and amount of alcohol consumption and smoking tobacco. Algorithms calculate an individual’s risk state for each factor and a traffic light system informs the individual of their status (e.g. red = high risk). Change within a state (e.g. still smoking but smoking less) can also be indicated, to motivate ongoing risk‐reducing behaviour change. Written feedback for each factor is provided under the headings ‘What the science says’, ‘Your status’ and ‘What can you do?’ The DRP has been implemented in a randomised controlled trial (n=414) and a population‐level public health intervention (n=3269).ConclusionInitial DRP data and user feedback will inform development to ensure its capacity to inform individuals about their risk and facilitate behaviour change that has a positive impact on their dementia risk in addition to their overall health.
Conceptualizing the relationship between parental education and own cognition in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study
Authors: Eng Chloe W , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , DeCarli Charles , Whitmer Rachel A 
Published: December 2020

AbstractBackgroundFew studies have considered how parental education influences late‐life cognition; those that have often focus on maternal and not paternal influences or as part of a broader SES index, which does not allow us to understand the functional form of the relationship between parental education and cognition. We assessed whether mother’s education dichotomized at 8th grade, a commonly used cutoff among similarly aged older adults to our sample, sufficiently captured effects of parental education by systematically evaluating conceptualizations of parental education.MethodsKaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study baseline participants, aged 65 years plus (n=1,633), self‐reported own and parents’ education at baseline. Parental education was operationalized separately as (1) mother’s only, (2) father’s only, (3) mother and father together; each operationalization was considered as categorical (missing, <=8th grade, incomplete high school, high school diploma, postsecondary education), as >8th grade (with missingness indicator and with missing included in “low”), and as high school completion (with and without missingness indicator). Parental (4) concordance (both high, high mother, high father, both low), (5) highest parental level, and (6) lowest parental level were also evaluated. Verbal episodic memory (VEM), semantic memory (SEM), and executive functioning (EF) from the Spanish and English Neuropsychological Assessment Scales (SENAS) were considered separately in covariate‐adjusted linear models. The lowest Bayesian Information Criterion (BIC) model was considered to provide the best fit.ResultsAcross all parental education operationalizations, 8th grade cut‐offs performed best; categorical (5‐level) parent education performed the worst. Semantic memory was best predicted by the referent measure of mother’s education >8th (B̂: 0.33; 95% CI: 0.25, 0.42); however verbal memory was best predicted by mother’s education >8th grade (B̂: 0.14; 95% CI: 0.03, 0.24) plus missing indicator (B̂: ‐0.24; 95% CI: ‐0.37, ‐0.10) and executive function by both mother’s (B̂: 0.22; 95% CI: 0.12, 0.31) and father’s (B̂: 0.18; 95% CI: 0.09, 0.28) >8th together.ConclusionThe preferable performance of parental education as >8th grade likely reflects historical education trends when KHANDLE participants’ parents were educated; whether preference for dichotomized measures over full categories reflects uncertainties in recall of parental education remains unclear.
The diffusion of dementia risk education
Authors: Fair Hannah , Eccleston Claire , Doherty Kathleen , Klekociuk Shannon Z , Farrow Maree 
Published: December 2020

AbstractBackgroundThe Preventing Dementia Massive Open Online Course (PD‐MOOC) is one of several initiatives aiming to increase dementia risk knowledge and promote risk‐reducing behaviour. These initiatives primarily reach advantaged individuals, increasing health inequities. Previously, thematic analysis of PD‐MOOC participant feedback identified frequent reports of sharing dementia risk information with others. Interpersonal communication often introduces information to people from a broader demographic and may increase the impact of dementia risk education. This study investigated the diffusion of dementia risk reduction knowledge and behaviour beyond PD‐MOOC participants.MethodThe PD‐MOOC attracted over 99,000 enrolments from 2016 to 2019. Responses to surveys completed by participants before (demographics) and after (course feedback) the PD‐MOOC were analysed. Qualitative statements were characterised using key word filtering and subsequent thematic analysis. Chi‐squared tests of homogeneity with Bonferroni adjustments for multiple comparisons were used to determine significant information sharing patterns.ResultOlder people, females, health sector workers and people with a post‐secondary education were over‐represented among PD‐MOOC participants. Participants expressed an eagerness to share the MOOC with others, with 98.8% of respondents agreeing they “would recommend the MOOC to others”. 25% of responding participants discussed sharing PD‐MOOC information in their response to the question “If you have already applied your MOOC learning, please tell us how”. Among those who reported sharing information with specific people, family members were mentioned most frequently, followed by friends and colleagues. Significantly more responses discussed sharing information with males than females (p < 0.001) and with people outside the health sector than within (p < 0.001). Some participants reported sharing information about specific risk domains; physical activity was mentioned most frequently, followed by cognitive stimulation and diet. Additionally, some reported that the person with whom they shared information altered their behaviour; increased physical activity was most commonly reported, followed by a general improved lifestyle and a change in diet.ConclusionInformation sharing transmits dementia risk information to, and promotes behaviour change among, people who are demographically less represented in the PD‐MOOC, extending the reach and impact of this educational intervention. The PD‐MOOC enables dementia risk reduction beyond those educated.