bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurophysiological alterations in mice and humans carrying mutations in APP and PSEN1 genes
Authors: van Heusden Fran C , van Nifterick Anne M , Souza Bryan C. , França Arthur S.C. , Stam Cornelis J , Scheltens Philip , Smit August B. , Gouw Alida A , van Kesteren Ronald E.
Published: December 2023

Background

Studies in animal models of Alzheimer’s disease (AD) have provided valuable insights into the molecular and cellular processes underlying neuronal network dysfunction, but whether and how AD‐related neurophysiological alterations translate between mice and men remains uncertain.

Method

We characterized neurophysiological alterations in mice and humans carrying AD mutations in the APP and/or PSEN1 genes, focusing on early changes. Longitudinal local field potential recordings were peformed in 3‐12‐month‐old APP/PS1 mice and cross‐sectional magnetoencephalography recordings in pre‐symptomatic human APP and PSEN1 mutation carriers. Recordings were acquired of the left hippocampus, frontal and parietal cortex. We performed spectral activity and functional connectivity analyses and results were compared with wildtype control mice and healthy age‐matched human subjects.

Result

APP/PS1 mice showed increased aboslute power, especially at higher frequencies (beta and gamma) and predominantly between 3 and 6 months of age. Relative power showed an overall shift from lower to higher fequencies over almost the entire recording period and across all three brain regions. There was a trend for reduced peak frequency in APP/PS1 mice at 3‐4 months of age. Human mutation carriers did not show changes in power except for an increase in relative theta power in the hippocampus. Parietal cortex and hippocampal peak frequency were reduced in human mutation carriers. In both models, significant alteration in functional connectivity were detected in theta, alpha, beta and gamma frequency bands, but the exact frequency range and direction of change differed for APP/PS1 mice and human mutation carriers (Table 1).

Conclusion

In conclusion, both mice and humans carrying APP and/or PSEN1 mutations show abnormal neurophysiological activity, but several measures do not translate one‐to‐one between species. Alterations in spectral characteristics and functional connectivity in mice should be interpreted with care and may be due to overexpression of amyloid in combination with absence of tau pathology in cholinergic degeneration. Future studies should explore whether changes in brain activity in other AD mouse models provide better translation to the human AD continuum.
Early Detection of Alzheimer’s Disease using microRNAs
Authors: Heuvelman Marco , Horos Rastislav , Sikosek Tobias , Tikk Kaja , Rajakumar Timothy , Cummings Jeffrey L. , Hansen Niels , Bartels Claudia , Oberstein Timo Jan , Hausner Lucrezia , Wiltfang Jens , Frölich Lutz , Steinkraus Bruno R
Published: December 2023

Background

MicroRNAs (miRNAs) represent a class of ∼22nt short non‐coding RNAs that have been identified as a sophisticated layer of post‐transcriptional regulation, governing many cellular, inflammatory and vascular processes. Their biological importance, together with the observation that miRNAs are frequently secreted into the extracellular space and stable in blood serum/plasma and other body fluids, make them specific, robust and non‐invasive biomarkers that could augment the amyloid and tau framework. miRNAs have been used for the detection of prodromal and early Alzheimer’s disease (AD) (e.g., mild cognitive impairment (MCI) due to AD) and to improve the differential diagnosis of AD. However, to date no miRNA panel has been translated into a clinical test.

Method

In collaboration with the University of Göttingen, the University of Erlangen and Zentralinstitut für Seelische Gesundheit in Mannheim, we prospectively collected PAXgene whole blood from 225 individuals (55‐85 years of age, MMSE ≥20) phenotyped at the respective memory clinics according to state‐of‐the‐art AD diagnostics including CSF core biomarkers. Amyloid positivity as a well validated proxy of brain β‐amyloidosis was determined using a CSF ABeta42/ABeta40 threshold of 0.075. Thus, 127 individuals were ABeta(+) and 96 individuals were ABeta(‐). We deployed 100‐fold cross validation of a linear regression classifier to construct and validate small RNA feature models to evaluate their utility as biomarkers for amyloid positivity and AD diagnosis.

Result

We generated small RNA feature models and report a median diagnostic receiver operating area under the curve (AUC) of 0.66 (95% CI 0.59‐0.76) for amyloid positivity (ABeta42/ABeta40 < 0.075). We deconvolved our whole blood sRNA signature into their respective plasma or immune cell origin. We found that the predicting features largely originate from the plasma fraction of whole blood (48.8%), marking a significant increase over the unselected distribution of all features (13.1%) of 3.72‐fold (p<0.001). However, several predictive features were found to originate from peripheral immune cells, particularly of the lymphoid arm (CD4+, CD8+ and B‐cells).

Conclusion

These data suggest the potential of a small RNA‐based blood test as a viable complement to the AT(N) framework for the management of individuals at risk for AD.
Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models
Authors: Vasciaveo Valeria , Iadarola Antonella , Casile Antonino , Morello Giulia , Dante Davide , Minotta Lorenzo , Tamagno Elena , Cicolin Alessandro , Guglielmotto Michela
Published: December 2023

Background

Sleep is an important physiological process, during which extracellular metabolic wastes, such as amyloid and tau protein, are cleared via paravascular pathway. Changes in the timing and structure of sleep occur across the lifespan. Increased sleep fragmentation and reductions in slow wave sleep (SWS) represent the hallmark signs of age‐related changes in sleep. The origin of sleep disturbances in AD is thought to be multifactorial. In the aging brain, the impairment of glymphatic pathway function slows the clearance of interstitial Aβ, rendering the aging brain vulnerable to neurodegenerative disease. Several authors have independently shown that glymphatic flux depends upon the expression and perivascular localization of the astroglial water channel aquaporin‐4 (AQP4).

Method

In this study, we performed and validated a mouse model of AD and chronic sleep fragmentation, a sleep disorder that mimics more correctly a real condition of intermittent and continuous awakening. We analyzed the effect of sleep fragmentation in wild type and 5xFAD mice. All the animals underwent to behavioral studies to analyze anxiety and spatial and working memory. We had validated sleep fragmentation and its effect through EEG and biomolecular analysis, by observing all the macro‐areas implied in sleep regulation.

Result

We noticed that sleep fragmentation induces a general acceleration of AD progression in 5xFAD mice, while in wild type mice it affects cognitive behaviors in particular learning and memory. Both these events may be correlated to AQP4 modulation, a crucial player of the glymphatic system activity. In particular, sleep fragmentation differentially affects AQP4 expression according to the stage of the disease, with an up‐regulation in younger animals, while such change cannot be detected in older ones. Moreover, in wild type mice sleep fragmentation affects cognitive behaviors, in particular learning and memory, by compromising the glymphatic system through the decrease of AQP4.

Conclusion

Nevertheless, an in‐depth study is needed to better understand the mechanism by which AQP4 is modulated and whether it could be considered a risk factor for the disease development in wild type mice. If our hypotheses are going to be confirmed, AQP4 modulation may represent the convergence point between AD and sleep disorder pathogenic mechanisms
Estimating Dementia Prevalence in Rural South Africa with Remote Consensus Diagnoses and Algorithmic Modeling
Authors: Farrell Meagan T. , Bassil Darina T. , Guo Muqi , Glymour M. Maria , Langa Kenneth M , Wagner Ryan G. , Tollman Stephen , Brickman Adam M. , Berkman Lisa F.
Published: December 2023

Background

There is limited population‐based data on dementia epidemiology from sub‐Saharan Africa, precluding deeper understanding of global dementia burden. The Health and Aging in Africa Study (HAALSI) is designed to address this evidence gap through collection of high‐quality longitudinal data on cognition, health, and everyday function in older Black South Africans. Consensus‐based diagnoses have become a gold standard for ascertaining dementia status in research settings, however, this approach is resource‐intensive and difficult to implement at scale. Here, we utilize algorithmic methods to estimate dementia prevalence and risk factors in a population‐representative cohort in rural South Africa.

Method

We utilize data from 4,176 respondents who completed assessments of health, demographics, socioeconomic conditions, cognition, and activities of daily living (ADLs) as part of HAALSI Wave 2 (2018‐2019). An enriched sub‐cohort (n = 635) later completed clinical and neuropsychological assessments and received diagnostic classification of normal cognition, mild cognitive impairment, or dementia by an expert panel. Logistic regression was used to predict dementia status in the enriched sub‐cohort using predictor variables drawn from the parent HAALSI wave. Probability cut points were selected to achieve overall prediction accuracy of at least 80%, prioritizing specificity over sensitivity. Algorithm performance was evaluated across education‐level and age subgroups. Coefficients from best‐performing algorithms were applied to the full cohort to obtain dementia probability scores and calculate dementia prevalence.

Result

When the enriched sub‐sample was reweighted to reflect the full HAALSI population, the estimated prevalence of dementia was 18%. Three models of increasing complexity were tested and showed good discrimination between dementia and non‐dementia (ROC = 0.76‐0.82). Models were generally more sensitive but less accurate in older and less educated respondents. Algorithmic estimates of dementia prevalence in the HAALSI population ranged from 15‐19%. Higher risk for dementia was associated with older age, lower education and wealth, hypertension, living alone, poor self‐rated health, widowhood, and immigration status.

Conclusion

This is one of the first studies to utilize algorithmic methods to describe dementia prevalence in South Africa, producing higher estimates than most previous reports. These efforts may provide a foundation to expand understanding of dementia epidemiology in a region of the world currently experience rapid population aging.
The Feasibility of Digital Testing using a Smartphone Application for Precision Brain Health Monitoring in the Framingham Heart Study
Authors: Sunderaraman Preeti , Karjadi Cody , Devine Sherral A. , Hathaway Lindsay , Goyal Kriti , Monteverde Jose R , Ang Ting Fang Alvin , Gurnani Ashita S , Mez Jesse B. , Au Rhoda
Published: December 2023

Background

Early detection of cognitive decline is critical to identify effective treatments for Alzheimer’s disease and related dementias. The inherent heterogeneity of behaviors associated with brain health may obscure the signals derived from a typical neuropsychological evaluation, partly because of the limited frequency of assessment with which it can be conducted. This may lead to inaccurate or poor detection sensitivity. Digital health technology using smartphone applications enables frequent assessment and, thereby, more precise monitoring of brain health. The current study sought to examine the feasibility of using smartphone application‐based tasks in community‐based participants from the Framingham Heart Study (FHS).

Method

The smartphone application consists of three blocks of assessments, lasting approximately 15‐20 minutes (Figure 1). Block 1: Participants answer questions to ensure that they can see the stimuli and hear the instructions adequately. Block 2: Participants complete a series of cognitive tasks and respond to open‐ended questions which are voice recorded. Block 3: To ensure that performance is not influenced by external factors, participants respond to questions, for example, about their experiences with using the smartphone application.

Result

To date, 318 FHS participants have been enrolled into the study. Of these, as of 12/09/2022, 168 participants’ first assessment period has been completed within the two week period after being enrolled in the study. Of the 168 participants, a large majority (81%; n = 136) completed all the tasks, while the remaining 32 completed partial assessment. Table 1 reveals that the overall percentage of participants who have been enrolled in the study and the percentage of those who completed their first assessment are highly similar.

Conclusion

Findings reveal that older adults from a large, community‐based study are able to successfully download and complete the first set of tasks using their smartphone application. As data collection is ongoing, the number of older adults recruited into the study is expected to increase exponentially. These results indicate that it is feasible to monitor brain health on an on‐going basis using self‐administered smartphone applications, potentially creating an effective, lower cost, and scalable approach to detect significant changes in cognitive functions earlier and more accurately in the preclinical neurodegenerative process.
Digital Cognitive Phenotyping using a Smartphone Application Among Community‐Dwelling Older Malaysians in the Transforming Cognitive Frailty in Later‐Life Self‐Sufficiency (AGELESS) Study
Authors: Tan Maw Pin , Rosli Roshaslina , Kumanan Sobiitraa , Xu Xiang‐Jiang , Low Spencer , Devine Sherral A. , Kim Nicole , Hermanto Michael , Au Rhoda
Published: December 2023

Background

The WHO’s dementia research blueprint highlighted assessment tools of cognition and function development as a strategic goal with specific need for validated tools in lower‐ to middle‐income countries (LMIC). The limited availability of such tools in LMICs is attributed to the population diversity. Malaysia is a multi‐ethnic, multi‐cultural, and multi‐religious LMIC within Southeast Asia. Challenges include cultural and educational bias and requirement for multiple translations for written tools. This study, therefore, aimed to develop and evaluate a digital tool using a smartphone application within an existing ageing cohort in Malaysia.

Method

The Transforming Cognitive Frailty into Later‐Life Self‐Sufficiency (AGELESS) study combined three pre‐existing longitudinal studies of ageing from 2013, involving individuals aged 55y recruited through electoral rolls and sampling frames. Individuals attending AGELESS health checks were invited to download a smartphone application digital protocol developed as part of a collaboration established through the Davos Alzheimer’s Collaborative. Participants were assisted in registration and assessment completion (Figure 1).

Result

Recruitment commenced in October 2022 through four mass screening activities each involving 100 participants. 141 were recruited into a pilot to test feasibility. Twenty‐three of the 141 (16.3%) completed all 10 tasks delivered in‐person (5 tasks) and remotely (5 tasks). The protocol was modified so two tasks were completed in‐person and an additional eleven tasks were completed remotely. The fourth screening recruited 53 participants of whom 22 (41.5%) completed all assessments. The basic characteristics of the participants recruited are summarized in Table 1. Issues identified were shared with the Boston University team following each session. Initially, registering or issues with starting tasks occurred with Android smartphones. Other difficulties included environmental noise and difficulties with instructions provided.

Conclusion

The recruitment and initial cognitive assessment using a smartphone application of older Malaysians appear feasible, but adaptions are required to facilitate this process. Changes in the apps Android software and protocol adjustments enhanced completion rates by 150%. Future developments will focus on processes to ensure completion of the assessment not just at baseline but also at regular follow‐up intervals.
Cognitive, functional, and neuropsychiatric correlates of regional tau in autopsy‐confirmed chronic traumatic encephalopathy
Authors: Faheem Farwa , Alosco Michael L , White Micaela , Bell Carter , Tripodis Yorghos , Yhang Eukyung , Baucom Zachary H. , Martin Brett M , Palmisano Joseph N , Goldstein Lee E , Katz Douglas I , Dwyer Brigid , Daneshvar Daniel H , Nowinski Christopher , Cantu Robert , Kowall Neil W , Stern Robert A , Alvarez Victor E. , Huber Bertrand R. , Stein Thor D. , McKee Ann C. , Mez Jesse B.
Published: December 2023

Background

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p‐tau) accumulation. The clinical features of CTE are heterogeneous and their association with CTE are unclear. We investigated the association of CTE p‐tau pathology density and location with cognitive and neuropsychiatric symptoms in brain donors with autopsy‐confirmed CTE.

Method

364 brain donors with autopsy confirmed CTE were evaluated to determine the density of p‐tau pathology in 10 cortical and subcortical regions using semi‐quantitative rating scales (score range: 0‐3). We summed ratings across 10 regions to form a global composite of p‐tau severity (score range:0‐30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF‐A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF‐A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS‐11), aggression (Brown‐Goodwin Aggression Scale), depression (Geriatric Depression Scale‐15, GDS‐15), and apathy (Apathy Evaluation Scale, AES). Multivariable linear regression analyses examined the association between global p‐tau severity and p‐tau severity in each region with each of the clinical scales, controlling for age at death, racial identity, education level, hypertension history, obstructive sleep apnea history, and substance use treatment history.

Result

The sample predominantly consisted of football players (333; 91.2%) and 140 (38.5%) had low CTE and 224 (61.5%) had high CTE (Table 1). Figures 1‐2 are Forrest plots of the estimated effects between regional p‐tau and clinical scales. Global p‐tau severity was associated with cognitive and functional scales: MI (beta = 0.46, 95% CI = 0.11‐0.81), CDS (beta = 1.08, 95% CI = 0.31‐1.85), and FAQ (beta = 0.32, 95% CI = 0.16‐0.49). After false‐discovery rate (FDR) correction, p‐tau in the frontal, inferior parietal, superior temporal cortex, and the amygdala was significantly associated with the CDS and FAQ; frontal and inferior parietal cortex and amygdala p‐tau also was significantly associated with MI. Frontal cortex p‐tau was significantly associated with the BRI. There were no significant associations with the other neuropsychiatric scales after FDR correction. Entorhinal cortex, hippocampus, and locus coeruleus showed no significant associations.

Conclusion

Accumulation of p‐tau aggregates, especially in the frontal cortex, are a driver of cognitive, function, and certain neurobehavioral symptoms in CTE.
Florbetapir amyloid PET in cognitively impaired former professional and college American football players
Authors: Stern Robert A , Trujillo‐Rodriguez Diana , Tripodis Yorghos , Pulukuri Surya V , Alosco Michael L , Adler Charles , Balcer Laura , Bernick Charles B. , Baucom Zachary H. , Marek Kenneth , McClean Michael D , Johnson Keith A. , McKee Ann C. , Stein Thor D. , Mez Jesse B. , Palmisano Joseph N , Cummings Jeffrey L. , Shenton Martha E , Reiman Eric M. ,   the DIAGNOSE CTE Research Project Investigators
Published: December 2023

Background

Repetitive head impact (RHI) exposure from the routine play of American football increases the risk of later‐life cognitive impairment and dementia from the neurodegenerative disease, chronic traumatic encephalopathy (CTE). Although neuropathological studies of CTE have found comorbid neurodegenerative and other pathologies, neuritic Aβ plaques are infrequent, particularly in early stages. However, amyloid PET imaging has not been fully characterized in cognitively impaired former American football players.

Method

In this cross‐sectional, observational cohort study from the DIAGNOSE CTE Research Project, florbetapir PET mean cortical standard uptake value ratios (SUVR) and positivity (defined by average SUVR >1.10, indicative of moderate‐to‐frequent neuritic Aβ plaques), were analyzed in 119 former professional (PRO) National Football League players, 60 former college football players (COL), and 58 men unexposed (UE) to RHI who were cognitively asymptomatic. Former players were categorized into one of four diagnostic groups: cognitively normal (CN), subjective memory complaints (SMC), mild cognitive impairment (MCI), and dementia (DEM). All participants were 45‐74 yo. Multivariable linear and logistic regressions were conducted, with race, education, age, and APOE4 genotype included as covariates. A priori power calculations demonstrated adequate power to detect significant findings

Result

No differences between the three exposure groups in average florbetapir SUVR or proportion of elevated florbetapir uptake were found. Pairwise group comparisons resulted in no differences in average SUVR between PRO and COL (‐0.01, 95% CI [‐0.033, 0.025], p = 0.95), PRO and UE (0.02, 95% CI [‐0.010, 0.029], p = 0.41), and COL and UE (0.02, 95% CI [0.0004, 0.039], p = 0.36). Analysis of covariance resulted in no differences among diagnostic groups (F = 0.94, p = 0.43). Neither years of playing football nor measures of cognition and daily functioning showed significant associations with florbetapir SUVR.

Conclusion

Former professional and college American football players with cognitive impairment and dementia did not have elevated florbetapir amyloid PET compared to a group of men without RHI exposure. Their rates of florbetapir positivity in the football players were lower than expected for a group of men this age. These findings suggest that cognitive impairment in former elite football players may not be due to Alzheimer’s disease pathology.
Sleep changes during the COVID‐19 lockdown contribute to cerebrospinal fluid phosphorylated tau and neurofilament light increases independent of β‐amyloid
Authors: Akinci Muge , Palpatzis Eleni , Sánchez‐Benavides Gonzalo , Argiris Georgette , González Escalante Armand , Deulofeu Carme , Kollmorgen Gwendlyn , Carboni Margherita , Blennow Kaj , Zetterberg Henrik , Fauria Karine , Navarro Arcadi , Gispert Juan Domingo , Suarez‐Calvet Marc , Grau‐Rivera Oriol , Arenaza‐Urquijo Eider M
Published: December 2023

Background

Previous studies reported sleep alterations during the COVID‐19 lockdown. Disrupted sleep may influence and promote Alzheimer’s disease (AD) pathologies. In cognitively unimpaired adults at AD risk, we investigated the association of sleep duration changes during lockdown in relation to pre‐ and post‐lockdown AD‐related CSF biomarkers.

Method

We included 118 adults (52‐71 years, 61.9% women) with self‐reported data on sleep duration before and during the lockdown (May–July 2020). Participants completed a questionnaire on hours of sleep per night (<7h vs. ≥7h) at both timepoints and were classified into three groups: “No change (<7h or ≥7h before and during lockdown)”, “Increased (from <7h to ≥7h during lockdown)” or “Decreased (from ≥7h to <7h during lockdown)”. All had CSF biomarkers measured with Roche NeuroToolKit or Elecsys® immunoassays before (pre‐lockdown) and after (post‐lockdown) completing the questionnaire (average time lapse: 3.4±0.4 years). During the lockdown, 117 (99.1%) participants completed an anxiety/depression assessment (Hospital Anxiety and Depression Scale). ANCOVA models adjusted by pre‐lockdown biomarker values were run to investigate differences among the three groups in post‐lockdown AD pathology (Aβ42/40 and p‐tau), neuroinflammation (sTREM2), and neuronal injury (NfL) biomarkers. Covariates included age, sex, education (years), APOE‐ε4 status, anxiety/depression levels, and time variability between the biomarker assessments. We then performed sensitivity analyses to adjust the models by pre‐lockdown Aβ42/40 levels and sleep quality (Pittsburgh Sleep Quality Index, n = 90).

Result

Ninety‐four participants (79.7%) reported “No change (stable)”, 10 (8.5%) “Increased” and 14 (11.5%) “Decreased” sleep duration during lockdown. Irrespective of pre‐lockdown p‐tau and NfL levels, participants transitioning to decreased sleep showed higher p‐tau and NfL post‐lockdown compared with the increased sleep group. Further, those with stable sleep duration showed higher post‐lockdown p‐tau and NfL compared with the increased group (Table 1). Results were independent of pre‐lockdown Aβ42/40 levels (Table 2) and sleep quality (Table 3).

Conclusion

Transitioning to fewer hours of sleep during the lockdown was associated with greater tau pathology and neuronal injury levels post‐lockdown. Consequently, alterations in sleep duration during the pandemic may hasten pathological processes downstream amyloid pathology. These findings suggest that pandemic‐induced lifestyle changes may increase AD prevalence in the long term.
Gut microbiome moderates the association between metabolic syndrome and the cerebrospinal fluid concentration of YKL‐40 in a cognitively unimpaired cohort
Authors: Peter Darby , Heston Margo B. , Ennis Gilda E. , Knight Rob , Kaddurah‐Daouk Rima F. , Johnson Sterling C , Asthana Sanjay , Carlsson Cynthia M. , Chin Nathaniel A. , Kollmorgen Gwendlyn , Carboni Margherita , Blennow Kaj , Zetterberg Henrik , Ulland Tyler K. , Rey Federico E. , Bendlin Barbara B
Published: December 2023

Background

Type 2 diabetes (T2D) and metabolic syndrome (MetS) are associated with increased risk of dementia, as well as altered gut microbiome composition (Ott et al., 1999; Ley et al., 2006). However, the extent to which gut microbiome alterations moderate brain pathology in these conditions remains unclear. Here, we examined the extent to which MetS associates with altered cerebrospinal fluid (CSF) biomarkers of Alzheimer’s Disease (AD), glial activation, and neurodegeneration, and whether MetS interacts with gut microbiome composition to impact brain pathology.

Method

Cognitively unimpaired adults (n = 88, Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center; Table 1) underwent fasting blood collection and lumbar puncture, and provided a stool sample. Twenty‐six percent (n = 23) of participants met MetS criteria. Fecal microbiota composition was characterized using 16S rRNA sequencing. QIIME2 was used to denoise and classify features, followed by Phyloseq to filter rare taxa, agglomerate taxa at the phylum rank, and compute relative abundances. Analyses centered on Firmicutes:Bacteroidetes, given its previously observed alterations in T2D and MetS (Stadlbauer et al., 2015). CSF biomarkers were quantified using a robust prototype assay as part of the Roche NeuroToolKit research platform. Multiple regression models were used to determine associations between MetS and CSF biomarkers in addition to Firmicutes:Bacteroidetes, and any MetS by Firmicutes:Bacteroidetes effects on CSF biomarkers. Results are reported as significant when p < 0.05, uncorrected.

Result

A significant negative association between MetS and CSF YKL‐40 was observed (Figs. 1a, 1b), but no significant association between MetS and Firmicutes:Bacteroidetes (Fig 1c), nor associations with other CSF biomarkers (Table 2). MetS showed a significant interaction with Firmicutes:Bacteroidetes on YKL‐40 (Fig. 1d), as control participants with a higher ratio showed increased YKL‐40.

Conclusion

In a cognitively unimpaired cohort, MetS was associated with lower CSF YKL‐40 (a marker of astrocytic activation) and moderated the relationship between Firmicutes:Bacteroidetes and CSF YKL‐40. While the direction of the findings was unexpected, T2D is associated with inhibition of astrocyte activation (Jing et al., 2013), and astroglial function is modulated by gut microbiota. Follow‐up studies are currently testing how gut microbiome modulates neuroimmune function in the context of AD.
Acceptability of a Balance Rehabilitation Program Delivered via a Tele‐Remote Platform Among a Thai MCI Cohort
Authors: Utoomprurkporn Nattawan , Limkitisupasin Patcharaorn , Tundiew Noppawan , Magauina Gulnaz , Tunvirachaisakul Chawit , Tangwongchai Sookjaroen
Published: December 2023

Background

Patients with mild cognitive impairment can have a decline in overall motor function and balance which are more severe than the normal older adult population. Balance rehabilitation should be offered consistently to maximize its effect. Telerehabilitation programs are emerging as a possible solution for customized balance exercises for older adults at home.

However, the acceptability of such programs among cognitive decline cohorts should be explored. Modification may be needed to tailor to the need of this population. We conducted a public involvement and engagement session with the MCI cohort according to the user‐centred design approach to gather feedback from the cohort to better improve the platform to suit the cognitive decline of older adults' needs, especially in ASIAN culture.

Method

Twenty MCI and carer volunteers from the memory clinic were invited to attend the session. The augmented reality equipment, sensors and telerehabilitation platform were shown to the group. Their opinions and feedback about the system were collected.

Result

Volunteers were keen to adopt new technology. The user experience and system usability were collected along with additional feedback from the cohort to ease the use of the platform for the cognitively impaired population.

Conclusion

The volunteer feedback promoted the customization of the platform to be more user‐friendly. Balance rehabilitation programs delivered via tele‐remote platform at home can be a potential solution among the MCI population in ASIA.
Feasibility, reliability and predictive validity of digital cognitive assessments in a diverse cohort of community‐residing older adults
Authors: Katz Mindy J. , Garza Angel Garcia De La , Roque Nelson A , Derby Carol A. , Sliwinski Martin J. , Lipton Richard B. , Wang Cuiling
Published: December 2023

Background

Digital cognitive assessments repeated over multiple days improve reliability compared to “single‐shot” assessments due to within person variability in function. Further, digital assessments are possible when clinic visits are not. We show the utility of digital approaches using data from the Einstein Aging Study (EAS) diverse cohort of community‐dwelling older adults.

Method

Participants were administered conventional and ambulatory digital assessments annually. The later consisted of a 2‐week burst of digital cognitive and behavioral/exposure measures obtained 6 times/day. Digital cognitive assessments included three tests (processing speed (Symbol Match), visual short‐term memory binding (Color Shape), and spatial working memory (Grid Memory)). Exposure assessment included daily stress, pain, and subjective sleep quality. Feasibility was measured as compliance defined as proportion of completed assessments. Frequency of annual assessments completed was evaluated throughout the COVID‐19 pandemic. For digital measures, reliability was calculated using intraclass correlations (ICCs) across days within a burst and across annual visits. ICCs for conventional measures across annual visits were also computed. To assess predictive validity, we used Cox proportional hazard models to examine whether mean and variability of performance on the 3 digital cognitive tasks predicted incident MCI.

Result

Compliance rates overall were 88% and were ≥ 85% in strata based on MCI status, age, race/ethnicity, education or prior experience with smartphones (Table 1). Data collection was maintained throughout the pandemic (Figure 1). ICCs for the digital cognitive measures was consistently high (>0.93). The same was true for exposure measures of stress, subjective sleep and pain (>.88). ICCs across annual follow‐up for digital measures ranged from 0.87 to 0.96 compared to 0.51 to 0.87 for conventional cognitive measures. Regarding predictive validity, worse mean performance in all three digital cognitive measures and higher within‐person variability (SD) in symbol search and color shape were associated with higher risk of incident MCI.

Conclusion

Digital assessments are feasible to administer, have high reliability and show predictive validity for MCI. They may provide useful tools in observational studies and clinical trials due to improved classification of cognitive status and feasibility in situations where in person assessments are not possible.
Cognitive lapses reported by daily digital diary, and not by recall‐based questionnaires, predict future MCI in a demographically diverse cohort of community‐dwelling older adults
Authors: Rabin Laura , Mogle Jacqueline , Wang Cuiling , Nester Caroline O. , Derby Carol A. , Garza Angel Garcia De La , Lipton Richard B. , Katz Mindy J.
Published: December 2023

Background

Although cognitive lapses are a daily occurrence for many older adults, widely used self‐reports of cognitive function ask respondents to recollect lapses occurring over months or years. We used daily diaries to capture memory and other cognitive difficulties close in time to their occurrence and determined whether daily reports predicted concurrent and/or new cases of mild cognitive impairment (MCI) in the next year (i.e., at annual follow‐up).

Method

In the Einstein Aging Study, daily digital diary indicators of cognitive lapses were assessed each evening over a two‐week period (82% of diaries completed). Conventional recall‐based indicators were the Cognitive Change Index total score and a single item capturing worsening memory (with/without worry), both assessed at each annual visit. Using time‐dependent lagged models with generalized estimating equations (GEE) to correct for within person correlation, we evaluated the association of current cognitive lapses with the probability of being MCI at the current or next annual visit among those diagnosed with MCI after baseline (n = 31 new cases).

Result

In 307 community‐dwelling participants (Mage = 77.05, SD = 4.95; 67% female, 47% White) who were free of MCI at baseline, higher numbers of daily problems significantly predicted the likelihood of being diagnosed with MCI at the next annual visit (average number of visits = 2.72, range 1‐6 years). For every additional daily cognitive lapse, there was a 5% greater odds of being classified at the next visit (OR = 1.05, 95% CI: 1.01‐1.09). By contrast, conventional indicators did not significantly predict transition to MCI at the next visit (ps = .48 and .62, respectively). However, the single item regarding worsening memory was related to concurrent MCI diagnostic status (p<.01). Sensitivity analyses examining the first 3 days or first 7 days to determine the number of daily reports required to identify new MCI cases indicated that both 3 and 7 days significantly predicted future MCI (OR = 1.34, 95% CI: 1.12‐1.61; OR = 1.07, 95% CI: 1.00‐1.14, respectively).

Conclusion

A brief daily diary assessment of cognitive lapses predicted new cases of MCI. The combination of daily and conventional methods may represent complementary approaches that offer the optimal approach for capturing self‐perceived cognitive deficits associated with current and future MCI.
Investigating the Genetics of Sporadic Early‐Onset Alzheimer’s Disease
Authors: Nudelman Kelly N. H. , Jackson Trever , Rumbaugh Malia C. , Eloyan Ani , Pentchev Julian V. , Faber Kelley M. , Snoddy Casey , Foroud Tatiana M. , Carrillo Maria C. , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G. ,   the LEADS Consortium
Published: December 2023

Background

Only a small percentage of early‐onset Alzheimer’s disease (EOAD) participants are known to carry autosomal dominant pathogenic variants in the amyloid beta precursor protein (APP) gene or in presenilin 1 or 2 (PSEN1/2); more research is needed to identify additional causative genetic variants. This study presents results of the initial genetic analyses in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) and planned next steps.

Methods

Whole exome sequencing (WES) is being performed for all cognitively impaired participants, including individuals with EOAD or frontotemporal dementia. Sequencing data is processed using GATK best practices and all variants for APP, PSEN1/2, progranulin (GRN), and microtubule associated protein tau (MAPT) are reviewed for previously reported pathogenic variants. C9ORF72 is also assessed for pathogenic repeat expansions. WES was analyzed with CANOES and CoNIFER for copy number variants (CNVs). WES data has been reviewed for reported pathogenic variants in other neurodegenerative disease‐associated genes. Gene burden testing is being done for the LEADS cases and age‐matched controls from the Parkinson’s Progression Markers Initiative for rare variants in these genes.

Results

To date, WES has been generated for 301 cases, and GWAS for 384 participants (290 cases, 89 controls). Reported pathogenic variants or repeat expansions in C9ORF72, PSEN1, GRN, and MAPT were identified in 2% of cases for the six screened genes. No CNVs were detected in APP, PSEN1/2, GRN, or MAPT. Review also identified individuals with pathogenic variants or CNVs in genes linked with diseases including Parkinson’s disease and Niemann‐Pick disease, including reported or predicted pathogenic variants in GBA, LRRK2, and SMPD1. Surprisingly, results do not show enrichment of functional TREM2 variants compared to population frequency.

Conclusions

Initial results indicate that LEADS is strongly enriched for novel genetic risk and/or causative factors, as only 2% have a reported pathogenic variant or repeat expansion in APP, PSEN1/2, GRN, MAPT, or C9ORF72. Review of reported pathogenic variants in other neurodegenerative disease‐associated genes indicates that while a small portion of disease etiology may be explained by these variants, more research is needed to identify additional causative and risk factors contributing to EOAD.
Exploring specialist dementia nursing models and their impact on people living with dementia and their family: A systematic review
Authors: Brown Pat C , Burton Alexandra , Ayden Jordan , Harrison‐Dening Karen , Hoe Juanita , Cooper Claudia
Published: December 2023

Background

Evidence that brings together the attributes, specialist knowledge, skills, and competencies required by specialist dementia nurses to fulfil their role is currently lacking, making it difficult to assess the effectiveness of specialist nurse‐led interventions. We systematically reviewed the evidence for specialist dementia nursing to determine how it is defined in terms of key skills, models of delivery, and the impact on families and people living with dementia

Method

We searched for papers using three databases (MEDLINE, CINAHL, PsycINFO), grey literature (EThOS), and the National Institute for Health and Care Excellence (NICE) evidence search. Search terms related to ‘specialist nursing’ and ‘dementia’ were used. We screened titles and abstracts of identified articles and conducted forward searches for additional relevant studies. Two authors independently rated study quality. Findings were synthesised narratively.

Result

31 studies were included in the review; 26 were conducted in the UK or USA using a range of methodologies. Role titles varied to include “Admiral Nurses”, “Nurse Practitioners” and “Clinical Nurse Specialists”. We found limited evidence comparing the knowledge, skills, and competencies required by specialist nurses except Admiral Nursing where these were described in three studies. In RCTs (n = 2), specialist nursing did not improve donepezil adherence; and personalised emails to family carers from a nurse specialist did not increase carer self‐efficacy when compared to less intensive interventions. In non‐randomised studies, a USA Nurse Dementia Care Manager service was associated with fewer emergency room and hospital admissions; there were no differences in clinical or cost outcomes in an Admiral Nursing service; and training inpatient specialist nurses in a behavioural intervention increased use of pain‐ relief medication and reduced patient length of stay. Of the 31 studies, 4 reported high carer satisfaction with specialist nursing.

Conclusion

We identified only one framework defining specialist dementia nursing competencies, and limited evidence for effectiveness of specialist nursing dementia services on families affected by dementia, despite care received being highly valued. No RCT has measured the impact of specialist nursing on family carer and client outcomes relative to less specialist care.
Modeling Alzheimer’s Disease: DNA damage response and MAPK‐DLK signaling in wild‐type tau‐induced neurodegeneration
Authors: Li Sanming , Roy Ethan , Watkins Trent , Cao Wei
Published: December 2023

Background

Despite the well‐established link between tau aggregation and clinical progression of Alzheimer’s disease (AD), the major pathways driven by tau elevation to intrinsically damage neurons are incompletely understood. Vast majority of AD patients harbor wild‐type MAPT gene, a contrast to primary tauopathy conditions that are driven by mutant tau.

Method

To model AD‐relevant neurodegeneration compelled by tau, we overexpressed wild‐type full‐length human tau in mouse primary neurons and examined the morphological, cellular, and molecular changes after. We also treated the cells with selective inhibitors to examine the involvement of MAP kinase signaling pathway.

Result

We observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau‐expressing neurons. Gene profiling analysis revealed significant alterations in the MAP kinase pathway; moreover, inhibitors of DLK and JNK were effective in alleviating wild‐type human tau‐induced neurodegeneration. In contrast, mutant P301L human tau elicited less cytotoxicity in primary neurons than wild‐type tau, despite producing a comparable DNA damage response.

Conclusion

We have established a cellular tauopathy model highly relevant to AD and identified coupled DNA damage response and MAPK‐DLK pathway in the neuronal degenerative process induced by wild‐type human tau.
Association Between Neuroimaging Biomarkers, Plasma NfL, and Memory Performance in Adults With Down Syndrome With and Without Dementia
Authors: Queder Nazek , Adams Jenna N. , Keator David B. , McMillan Liv , Sathishkumar Mithra , Taylor Lisa M. , Doran Eric , Nguyen Dana , Hom Christy , Krinsky‐McHale Sharon J , Price Julie C , Lai Florence , Rosas H. Diana , Petersen Melissa , O'Bryant Sid E. , Brickman Adam M. , Head Elizabeth , Mapstone Mark , Schupf Nicole , Silverman Wayne , Lott Ira T , Yassa Michael A.
Published: December 2023

Background

Down syndrome (DS) is associated with early development of Alzheimer’s disease pathology. Both the severity of tau pathology and the increase of neurofilament light chain (NfL) protein are correlated with cognitive decline in the neurotypical populations. Here, we assessed whether tau accumulation in the hippocampus and entorhinal cortex and plasma NfL concentrations were associated with memory performance in adults with DS.

Method

We used 18F‐AV‐1451 (FTP) positron emission tomography (PET) to assess tau accumulation in 44 participants enrolled in the multi‐site Alzheimer’s Disease in Down syndrome (ADDS) study (age 50.72 + 6.21). FTP‐PET scans were partial volume‐corrected, and weighted standardized uptake value ratio (SUVR) were calculated for each of the following regions of interests (ROIs): entorhinal cortex, hippocampus, and the precentral gyrus (control). Participants' plasma NfL concentration (in pg/mL) was measured on a single plex plate using the ultra‐sensitive single molecule array (Simoa) technology platform HD‐X. Memory performance was measured with the modified Cued Recall Test. We evaluated the relationship between FTP SUVRs, NfL, and memory performance using linear regression analysis. Sex and site were used as covariates.

Result

Increased FTP SUVR in the hippocampus and entorhinal cortex were associated with lower scores on free recall (hippocampus: r2 = 0.53, p <0.001; entorhinal: r2 = 0.35, p <0.001) and total recall (hippocampus: r2 = 0.46, p <0.001; entorhinal: r2 = 0.29, p <0.01). As expected, no association between FTP SUVRs and memory performance was found in the precentral gyrus. Additionally, higher plasma NfL concentrations were associated with lower free recall (r2 = 0.35, p <0.001) and total recall (r2 = 0.29, p <0.01). Further, increased levels of plasma NfL were associated with increased FTP SUVRs in the hippocampus (r2 = 0.38, p <0.001), entorhinal cortex (r2 = 0.28, p<0.01), and precentral gyrus (r2 = 0.19, p<0.05).

Conclusion

Increased levels of both in‐vivo tau in medial temporal ROIs and NfL in plasma were associated with worse memory performance, consistent with observations in the neurotypical population. Future work will investigate the impact of tau accumulation and NfL concentration on longitudinal cognitive decline in older adults with DS.
Prognostic utility of plasma p217+tau vs amyloid and tau PET in the Alzheimer’s continuum
Authors: Feizpour Azadeh , Dore Vincent , Doecke James D , Saad Ziad S. , Triana‐Baltzer Gallen , Krishnadas Natasha , Fowler Christopher J , Ward Larry , Martins Ralph N , Masters Colin L , Villemagne Victor L , Fripp Jurgen , Kolb Hartmuth C. , Rowe Christopher C
Published: December 2023

Background

We evaluated the association of plasma p217+tau with longitudinal cognition and its comparative performance to amyloid‐β (Aβ) and tau PET in predicting prospective cognitive decline.

Method

153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) participants underwent baseline p217+tau SIMOA assay, 18F‐MK6240 tau‐PET and 18F‐NAV4694 Aβ‐PET with neuropsychological follow‐up (MMSE, CDR‐SB, AIBL‐PACC) over 2.4 ± 0.8 years. The association of baseline biomarkers with cognitive decline was evaluated. Sample size to detect a 30% slowing in cognitive decline in a 2‐year trial and selection cost using p217+tau (pT+) were compared to Aβ‐PET (A+) and tau‐PET (T+) with and without p217+tau pre‐screening.

Result

In the CI, plasma p217+tau predicted change in MMSE (β = ‐0.55, p < 0.001) and CDR‐SB (β = 0.61, p < .001) with effect size larger than Aβ Centiloid (MMSE β = ‐0.48, p = 0.002; CDR‐SB β = 0.43, p = .004) but smaller than tauMetaT SUVR (MMSE: β = ‐0.62, p < .001; CDR‐SB: β = 0.65, p < .001). In the CU, only tauMetaT SUVR predicted change in AIBL‐PACC (β = ‐0.22, p = 0.008). Screening CI for pT+ led to 24% reduction in sample size compared to screening with PET for A+ and 6‐13% compared to T+ (different regions). This translated to an 80% biomarker test cost‐saving assuming p217+tau costed one‐fifth of PET. In a trial requiring PET T+ or A+, pT+ pre‐screening followed by PET would cost more in the CI group with AD prevalence of 70%, compared to ∼35% cost‐saving in the CU group with preclinical AD prevalence of 25%.

Conclusion

Substantial cost reduction can be achieved using p217+tau alone to select participants with CI for a trial, compared to selection by PET. Pre‐screening with p217+tau followed by PET provides cost‐saving in preclinical AD trials but is questionable in MCI/AD trials.