bluuebunny/crossref_metadata_2025 huggingface dataset:
Falls and Cognition in Adults Aging with Down Syndrome
Authors: Washington Selena E , Bollinger Rebecca M. , Ances Beau , Stark Susan L.
Published: December 2023

Background

Adults with Down syndrome (DS), who are at risk, will show the neuropathological changes of Alzheimer’s Disease (AD) within their 40s, partially due to an overexpression of beta‐amyloid, which accumulates in the brain across their lifespan. The risk of developing AD in adults aging with DS increases with age and is marked by increased confusion, short‐term memory problems, and/or a loss of the ability to complete daily activities. There is limited evidence on the functional changes that happen to adults aging with DS prior to any marked AD symptoms. Growing evidence suggests that functional mobility abnormalities and an increase in falls may precede cognitive impairment and marked AD symptoms. The relationship between falls and cognition in adults with DS has not been thoroughly investigated; and could potentially serve as a less invasive method of assessment.

Method

The purpose of this study is to assess patterns of falls and functional mobility impairments that occur within an adult population aging with DS and their relationship with cognition. The participant receives an initial home visit, conducted by the PI, who completes and collects data on functional performance, fall risk(s), and the environment. The participant agrees to document any fall incidents using a calendar journal, and completes the monthly check‐in calls and/or emails initiated by the study team.

Result

We conducted a correlation analysis with the preliminary data from this cohort of 17 participants, 9 male and 8 female, with a mean age of 38.5 years (SD = 8.81). Increased falls were significantly related (p < .05) to impaired gait speed (r = .528) and balance (r = ‐.624), while cognition (r = .474, p >.05) was not associated with falls. Increased fear of falling assessment scores were correlated with impaired gait speed (r = .687), lower extremity (r = ‐.502) and mean grip strength (r = ‐.492), and balance (r = ‐.596).

Conclusion

We demonstrated that (1) participants were willing to enroll; (2) the assessment and monitoring plan were well tolerated; and (3) fear of falling scores and decreased functional mobility were similar in aging adult with DS populations to older adult (≥ 65 years of age) populations.
Social engagement and the risk of incident dementia: the Atherosclerosis Risk in Communities study
Authors: Groechel Renée C. , Liu Albert C. , Lutsey Pamela L. , Palta Priya , Kucharska‐Newton Anna M. , Koton Silvia , Sharrett A. Richey , Gross Alden L. , Walker Keenan A. , Gottesman Rebecca F.
Published: December 2023

Background

Strong psychosocial health has been linked to preserved cognition and functional independence in older adults. Associations between late‐life psychosocial health and dementia risk have been established in older adults, but it remains less clear how one’s social interactions in mid‐life may relate to dementia risk in late life. We hypothesized that social engagement in mid‐life will be negatively associated with the risk of dementia in late‐life.

Method

We included data from 13,216 dementia‐free participants at midlife (mean age: 57.0 years, SD: 5.7 years, 54.9% female, 23.8% Black) from the Atherosclerosis Risk in Communities (ARIC) cohort study. Social support and isolation were assessed via interviewer‐administered questionnaires (visit 2: 1990‐1992). Based upon categorization of both factors, participants were classified as having high, intermediate, or low mid‐life social engagement. Incident dementia cases were identified from visit 2 through December 31, 2019 with ongoing surveillance (e.g., in‐person neurocognitive testing, informant interviews, and hospitalization codes). Primary analyses used Cox proportional hazards regression models and were adjusted for demographics, APOE ε4, occupational/marital status, depressive symptoms, and vascular risk factors measured at visit 2. Secondary analyses examined whether sex and/or race modified the association between mid‐life social engagement and dementia risk with formal tests for interaction.

Result

Among 13,261 participants, 2,555 developed dementia (median follow‐up: 23.7 years). Participants with high (hazard ratio (HR): 0.77, 95% CI: 0.68 ‐ 0.86) or intermediate social engagement (HR: 0.84, 95% CI: 0.74 – 0.95) in mid‐life had a lower risk for developing dementia, compared to participants with low social engagement in mid‐life (Figure 1, Table 1). Sex modified this effect (p‐value for interaction = 0.042) whereas race did not. In males, only those with high social engagement in mid‐life had a lower risk of dementia; the association between males with intermediate social engagement in mid‐life and dementia risk was not significant (Table 2).

Conclusion

Greater social engagement in mid‐life is associated with a lower risk of dementia. This finding provides further evidence that mid‐life may be a critical time window for dementia prevention. Longitudinal studies evaluating the mechanisms by which psychosocial factors modify the likelihood of incident dementia are needed.
ApoE and immune system in the pathogenesis of tau‐mediated neurodegeneration
Authors: Chen Xiaoying
Published: December 2023

Background

Extracellular amyloid‐β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau‐mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response and their interaction with innate immune response in the presence of Aβ or tau pathology.

Method

We systematically compared the immunological milieus in the brain with amyloid deposition or tau aggregation and neurodegeneration.

Models

Three AD mouse models, including Aβ models with amyloid deposition in both parenchyma and along the vessels and tau pathology models; as well as human brain samples with different Braak scores.

Result

We found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T‐cells blocked tau‐mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN‐γ and PD‐1signaling both significantly ameliorated brain atrophy.

Conclusion

Our results thus reveal a tauopathy and neurodegeneration‐related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.
Dissection of alpha‐synuclein specific synaptic functions by gene editing
Authors: Madhivanan Kayalvizhi , Parra‐Rivas Leonardo A , Joensuu Merja , Sanders Shanley , Caballero‐Florán René , Bingham Dominic , Sharma Rohan , Jenkins Paul M , Leterrier Christophe , Meunier Frederic A , Roy Subhojit
Published: December 2023

Background

Despite almost two decades of research, the physiologic role of α‐synuclein remains unclear. Mice lacking α‐syn only show mild phenotypes, and most mechanistic studies have been done either in α‐syn over‐expressing systems, or in mice lacking all three synuclein genes (α/β/γ). However, over‐expression of proteins can induce unwanted phenotypes, and ‘triple‐knockout’ synuclein mice have structural and physiologic changes that are not specific to α‐syn – complicating interpretations.

Methods

We used CRISPR technology to systematically inactivate or activate each synuclein gene in cultured mouse hippocampal neurons, ensuring that our manipulations did not lead to compensatory changes in the non‐targeted synucleins. Gene‐editing was followed by unbiased evaluation of physiology and ultrastructure using optical synaptic vesicle (SV) recycling assays, electrophysiologic recordings, single‐molecule trafficking assays, super‐resolution imaging, and electron microscopy.

Results

Neurotransmission is maintained at a range of different activity patterns, motivating us to evaluate the role of α‐syn under basal states as well as conditions involving trains of action potentials. Elimination of α‐syn led to substantial increases in basal exocytosis. Single‐molecule trafficking of SVs in these neurons indicated an increase in mobility of reserve pool vesicles when α‐syn was absent. Increasing endogenous α‐syn levels by CRISPRa had largely reciprocal effects. Recent studies in our lab found that phosphorylation of α‐syn at the Ser129‐site is a trigger for α‐syn function at the synapse. Augmenting α‐syn functionality by constitutive phosphorylation of the α‐syn Ser129‐site also triggered clustering of distal SV‐pools, consistent with a role for α‐syn in physiologic clustering of reserve pool vesicles. However, when neuronal activity was augmented by trains of action potentials, loss of α‐syn selectively attenuated endocytosis, with no effect on exocytosis. Super‐resolution imaging revealed that α‐syn was translocated to peri‐active zones upon stimulation, suggesting that the altered localization of α‐syn under these conditions resulted in facilitation of endocytosis. Finally, mass‐spectrometry data also indicate that α‐syn binds to an endocytosis‐enriched proteome under conditions that favor neuronal activity.

Conclusion

Our data provide clarity of the repertoire of a‐syn specific functions under different physiologic conditions.
Automated analysis of letter fluency data produced by Korean and American patients with AD and MCI
Authors: Kim Jin‐Seo , Kim Seohee , Irwin David J. , Nevler Naomi , Baek Min Seok , Cho Sunghye
Published: December 2023

Background

Letter fluency task measures executive functioning and working memory in clinical settings. Previous studies have shown that both the total number of correct responses and lexical characteristics of produced words are informative in explaining patients’ performance. Yet, many previous studies analyzed fluency data in one language using manual assessments, lacking crosslinguistic validity and feasibility. We developed automated pipelines for digitized letter fluency data in Korean and English to compare patients with Alzheimer’s disease (AD) or mild cognitive impairment (MCI) and healthy controls (HC) across the two languages.

Method

We analyzed letter fluency data (English: ‘F’, Korean: ‘G’) produced by 47 Koreans (mean age = 74.1±8years, 25 females) and 40 Americans (mean age = 63.8±8.6years, 16 females) with AD (11 Koreans, 20 Americans) or MCI (16 Koreans, 7 Americans) and HCs (20 Koreans, 13 Americans) using our automated pipeline for each language. The pipelines counted the number of correct responses, rated words for frequency and length, and measured phonetic and semantic distances and pause duration between two consecutive correct responses. Linear regression models compared groups in scores and language variables, respectively, where score or speech variable was included as a dependent variable and diagnostic group as an independent variable. Education level, age, and language were co‐varied in all models. The same models were built for each language without language as a covariate.

Result

AD patients produced fewer correct responses with higher word frequency compared to HC (score: β = ‐4, p = 0.001, frequency: β = 0.63, p = 0.001) and MCI (score: β = ‐2.9, p = 0.017, frequency: β = 0.55, p = 0.008). AD patients also produced longer pauses between words and words that were less phonetically similar to its antecedent compared to HC (pause: β = 4.99, p = 0.002, phonetic similarity: β = 11.33, p = 0.011) and/or MCI patients (pause: β = 3.6, p = 0.039). The results remained similar when separate models were built for each language.

Conclusion

We demonstrated the feasibility of automated analyses of letter fluency data in different languages and validated that word frequency, pause duration and phonetic similarity were important speech characteristics in both languages. These pipelines can be adopted in other languages, which will enable large‐scale, automated crosslinguistic analyses of letter fluency data in clinical settings.
Comparison of subjective cognitive decline and polygenic risk score in the prediction of all‐cause dementia, Alzheimer’s disease and vascular dementia
Authors: Trares Kira , Stocker Hannah , Perna Laura , Beyreuther Konrad , Schöttker Ben , Brenner Hermann
Published: December 2023

Background

Subjective cognitive decline (SCD) and polygenic risk scores (PRS) have both been shown to be associated with the risk of developing dementia. However, it is of interest whether they can improve the established and well‐validated cardiovascular risk factors aging and dementia (CAIDE) model and how their predictive abilities compare.

Methods

SCD and PRS were assessed and determined in a large, population‐based cohort study. In this study, the CAIDE model was applied to a sub‐sample of 5,360 study participants and evaluated for the outcomes of all‐cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD) by calculating Akaike’s information criterion (AIC) and the area under the curve (AUC). The improvement of the CAIDE model by SCD and PRS was further examined using the net reclassification improvement (NRI) method and integrated discrimination improvement (IDI). Besides evaluations in the total sample, predictive abilities were evaluated in the mid‐life and late‐life sub‐cohort.

Results

During 17 years of follow‐up, 410 participants were diagnosed with dementia, including 139 AD and 152 VD diagnoses. Overall, the CAIDE model showed high discriminative ability for all outcomes reaching AUCs of 0.785, 0.793 and 0.789 for all‐cause dementia, AD, and VD, respectively. Adding information on SCD to the CAIDE model led to a significant increase in NRI for all‐cause dementia (4.4%, p = 0.0401) and VD (7.7%, p = 0.0095). In contrast, prediction models for AD further improved when PRS was added to the model (NRI, 8.4%, p = 0.0257). The latter became more substantial when applied to the mid‐life sub‐group (50‐64 years), achieving an NRI of 19.6% (p = 0.0075). When APOE ε4 carrier status was included in CAIDE model 2, the discriminative ability of the basic CAIDE model increased, and SCD and PRS did not further improve the prediction.

Conclusion

While PRS significantly improved the prediction of the CAIDE model for AD, information on SCD increased its discriminative ability for all‐cause dementia and VD. In contrast to PRS, information on SCD can be assessed more efficiently, and thus models including SCD can be more easily transferred to the clinical setting. Nevertheless, the two variables seem negligible if APOE ε4 carrier status is available.
When One Call Isn’t Enough: A Comparison of Alzheimer’s Association Helpline Callers
Authors: Hodgson Nancy A
Published: December 2023

Background

Family care partners of persons living with dementia (PLWD) have limited support and resources and experience high levels of stress and burden. Prior research has demonstrated that one call to the Alzheimer’s Association’s Helpline benefitted 80% of callers following a single call. However, some care partners need more support than a single call.

Method

The aim of this study was to evaluate the efficacy of offering up to two callbacks after an initial call to the Helpline. Study participants were Helpline callers who were asked if they sought additional calls due no progress towards implementing recommended action steps after a single Helpline call. Outcomes were compared at 2, 4 and 6 weeks after baseline and included PROMIS measures of self‐efficacy.

Result

Of 2504 participants, 79.92% were female, 73% were white, age = 60.31 years (± 12.59), 85.06% bachelor’s degree+, 64.42% lived with PLWD. No statistical difference were noted in demographics between single vs. +1 callers. However, +1 callers scored lower on two PROMIS items: upset (p < 0.0171) and ability to bounce back (p < 0.017). After one call, those with +1 call improved on the total PROMIS (p < 0.0001), as well as the following items: negative feelings < 0.001), stress (p < 0.0009), upset (p < 0.0145), discouragement (p < 0.006), and distress (p < 0.0001). From the first call to the second call, callers improved on the total score (p < 0.0065), upset (p < 0.0349) and ability to relax (p < 0.0213) items. Following second call, participants improved on the overall survey score (p < 0.004), as well as the following items: stress (p < 0.016), upset (p < 0.03), discouragement (p < 0.04), distress (p < 0.0066), and ability to relax (p < 0.02).

Conclusion

Further research is indicated to understand the support needs of care partners that can benefit from more than one call to a tele support program.
A study to determine the mechanisms underlying changes in synaptic vesicle glycoprotein 2A density in Alzheimer’s disease
Authors: Chang Ya Yin , King Declan , Holt Kristjan , Gladstein Scott , Horton Wesley A. , Bevis Amanda , Smith Daniel G , Zetterberg Henrik , Finnema Sjoerd J , Spires‐Jones Tara L ,   FNIH SV2A Project Team
Published: December 2023

Background

Synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane synaptic vesicle protein that regulates vesicle exocytosis and neurotransmitter release. Positron emission tomography (PET) studies reveal that the levels of SV2A are decreased in the brains of patients with Alzheimer’s disease (AD) and other brain disorders. Whether changes in SV2A PET signal are caused by a loss of synapses or a loss of SV2A protein is unclear and an impediment to developing novel treatments for neurodegenerative diseases. The goal of this study is to determine the biological underpinnings of reduced SV2A signal in individuals with AD.

Method

We examined post‐mortem brain samples from the entorhinal cortex (EC) and cerebellum (CBM) in AD patients and age‐ and sex‐matched controls without neurological conditions (EC n = 19 AD, 15 controls; CBM n = 11 AD, 12 controls). We explored differences in synaptic density and synaptic ultrastructure using array tomography and electron microscopy, and analyzed data using linear mixed‐effects models (with post‐hoc Tukey comparisons) and Spearman correlations.

Result

SV2A puncta density measured with array tomography in both brain regions strongly correlates with synaptophysin puncta density, the gold standard marker for synapse density in post‐mortem brain tissue (ñ = 0.87 EC, ñ = 0.72 CBM, p<0.001 both regions). We observed lower SV2A puncta density in AD cases compared to controls in EC (p = 0.001), slightly higher SV2A puncta density in AD in CBM (p = 0.02), and no difference in the proportion of synaptophysin puncta labelled with SV2A in AD vs control (p = 0.37). Electron microscopy revealed immunogold labelled SV2A protein localized specifically to presynaptic vesicles and no difference in the number of immuno‐gold labelled SV2A particles per synapse.

Conclusion

Our data indicate that the loss of SV2A PET signal reported in vivo in patients with AD is likely caused by a loss of synapses and not the loss of SV2A protein within remaining synapses. These findings indicate that changes in SV2A PET signal are due to synaptic loss and that strategies for reversing synaptic loss or associated neuropathophysiological effects may be important to the treatment of AD and other synaptopathies. This work is part of the SV2A PET Project, a program of the FNIH Biomarker Consortium.
阿尔茨海默病和轻度认知障碍患者的外周免疫细胞与神经心理学量表、脑18 F‐FDG、18F‐AV45 PET‐CT 之间的相关性
Authors: Zhan Yu , Zhou Huiling , Kang Jian , Zhao Li , Dong Chunbo
Published: December 2023

Background

Immune dysfunction in Alzheimer’s disease (AD) was previously thought to be limited to the central nervous system, but recent studies suggest that the peripheral immune system also plays a key role. This study compared and analyzed the changes in peripheral immune cells in patients with AD and mild cognitive impairment (MCI) and their correlation with cognition, and combined 18F‐FDG PET and 18F‐AV45 PET to investigate the role of peripheral immune cells in AD pathology and the possibility as biomarkers for early clinical diagnosis and disease assessment.

Methods

The 146 participants included 70 AD patients, 26 MCI patients, and 50 controls. 34 AD patients tested with 18F‐AV45 (18F ‐Florbetapir) positron emission tomography (PET). 23 were Aβ‐positive (A+), and 11 were Aβ‐negative (A‐). All participants had a peripheral immune cell, cognitive evaluation, and detailed nervous system examination.

Results

(1) Significant differences in peripheral immune cells in AD compared with MCI and CG; (2) There was no significant correlation between NEU%, NLR, LY, and LY% and cognitive scale scores for patients in the AD and A+ groups, while there was a significant correlation with cognitive scale scores in the MCI and A‐ groups; and (3) Peripheral immune cells NEU%, NLR, LY, and LY% in A+ patients were correlated with FDG metabolism in several functional brain areas and Aβ load in some brain areas, but not with Aβ load in all functional brain areas in A‐ patients.

Conclusion

Differences in peripheral immune cells help to distinguish AD from MCI, with NLR having better diagnostic efficacy. peripheral immune cells may have a greater impact on early cognitive dysfunction; NEU%, NLR, LY, and LY% may be associated with Aβ deposition and could serve as potential biomarkers for early clinical diagnosis and disease assessment in AD.
Longitudinal AD biomarkers in monozygotic twins: genetic contribution to AD biomarker concentrations over time
Authors: Vromen Eleonora M. , Coomans Emma M. , Verberk Inge M.W. , van der Wal Mariska , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , den Braber Anouk , Tijms Betty M. , Visser Pieter Jelle
Published: December 2023

Background

Understanding the earliest pathophysiological changes in Alzheimer’s disease (AD) is important for development of therapeutic intervention strategies. Studying genetically identical twins provides unique information on genetic and environmental influences on development of AD. Here we studied change in AD biomarkers amyloid β1‐42 (aβ42), amyloid β1‐40 (aβ40), phosphorylated tau181 (p‐tau) and total tau (t‐tau) in CSF over time in a cohort of older cognitively normal monozygotic twins and tested the genetic contribution to biomarker concentrations at baseline and to change of biomarker concentrations over time.

Method

We included 103 twins (npairs = 42) from the EMIF‐AD preclinAD study with 2‐4 repeated CSF sampling available across a time period of 4.47±2 years (mean±SD age: 68.8±7 years, 54 (52%) female). We measured aβ42, aβ40, p‐tau and t‐tau using the Lumipulse platform (Fujirebio Diagnostics, Inc.). We used linear mixed models to investigate change in biomarker concentrations over time. We used twin‐pair intraclass correlation (ICC) analysis to estimate the genetic contribution to biomarker concentrations at baseline and at repeated measurements, and to annual change in biomarker concentrations.

Result

At baseline, 25 (24%) individuals had an abnormal aβ42/aβ40 ratio, 27 (26%) abnormal p‐tau and 35 (34%) abnormal t‐tau, and at last measurement respectively 34 (33%), 38 (37%) and 45 (44%). Across the group, aβ42/aβ40 decreased (β±SE ‐0.001±0, p‐value<0.001), and p‐tau and t‐tau increased over time (respectively 1.37±0.3, p‐value<0.001; 6.58±2.3, p‐value = 0.004). Increases in p‐tau levels were most pronounced in amyloid positive individuals (2.72±0.38, p‐value<0.001) compared to amyloid negative individuals (0.65±0.24, p‐value = 0.007; p‐value interaction<0.001). At baseline, the genetic contribution to biomarker concentrations was lowest for t‐tau (ICC = 0.5, p<0.001) and highest for aβ40 (ICC = 0.79, p<0.001). ICC’s remained similar at repeated measurements (table 1). Annual changes of aβ40 and p‐tau showed significant twin‐pair correlations (resp. ICC’s: 0.58 and 0.42; p‐values <0.01; Figure 1), indicating a genetic contribution to change in these concentrations over time.

Conclusion

In this sample of older cognitively normal monozygotic twins, we found that AD biomarkers became increasingly abnormal over time. Our unique twin design further indicates that these very early pathophysiological changes are under moderate to high genetic influence, which also indicates a role of environmental factors.
Mind over memory: reducing fear and avoidance of memory loss (REFRAME) study in older adults
Authors: An Hosanna , Marquez Melissa , Regan John , O'Loughlin Patricia , Pavithra Pavithra , Taddeo Michelle , Knight Rachel , Bennett Marc P , Lenaert Bert , Griffith James W , Farina Francesca R
Published: December 2023

Background

Fear of Alzheimer’s disease and related dementias (ADRD) is a growing concern among older adults. High levels of fear are associated with poorer health outcomes, lower levels of psychological well‐being, and the perpetuation of harmful cognitive‐behavioral cycles that can potentially hasten cognitive decline. Interventions that disrupt these cycles could bring both immediate and long‐term benefits for reducing ADRD‐related fears. Given the projected increase in the number of people living with ADRD and accompanying fears, effective interventions are needed to address the emotional needs of older adults. We evaluated a brief psychological intervention aimed at promoting adaptive coping in older adults with heightened ADRD‐related fear and examined its effects on broader health outcomes.

Method

Eighty‐one older adults experiencing heightened ADRD‐related fear were recruited to participate in a 3‐week online intervention aimed at reducing fear (primary outcome) and improving secondary health‐related outcomes (i.e., anxiety, depression, social function). Participants were randomly assigned to REFRAME or active comparison group. Both groups completed psychoeducation and mindfulness activities designed to reduce fear. The REFRAME group completed an additional behavioral activation module designed to disrupt patterns of avoidant behavioral coping. Participants completed measures at baseline, weeks 1‐3 of the intervention, post‐intervention, and 4‐week follow‐up. Outcomes were analyzed using linear mixed effects models.

Result

Participants ranged from 55 to 90 years, (M = 65.4, SD = 7.1). Intervention adherence was high (>75%) across both groups. ADRD‐related fear decreased significantly over time in both groups. Anxiety, depression, and self‐reported memory failures also decreased significantly in both groups, while social function and well‐being improved. The REFRAME group exhibited a greater reduction in depression compared to the control group.

Conclusion

Our brief psychological intervention had positive effects on ADRD‐related fear among older adults. However, further research is needed to determine the long‐term benefits and their effectiveness in at‐risk populations (e.g., people with a family history of dementia), as well as the acceptability of this intervention in clinical settings. These findings highlight the potential benefits of disrupting harmful cognitive‐behavioral cycles, as this may encourage older adults to stay engaged in healthy behaviors for longer, ultimately improving their quality of life.
Cognitive Testing in Diverse Populations to Further the Objective and Clinical Understanding Study ‐ FOCUS
Authors: Galvin James E
Published: December 2023

Background

One of the great challenges facing clinical trial recruitment is to have a representative sample reflective of the diversity of the US population. While racial and ethnic minorities compromise 39% of the United States population, they only account for 2%‐16% of clinical trial participants.1 The aim of the FOCUS study was to collect cognitive testing data from a diverse population and develop normative ranges for Cognivue, the first FDA‐cleared computerized cognitive assessment device based on modern cognitive neuroscience. Cognivue Thrive provides a 5‐minute cognitive screen while Cognivue Clarity provides a 10‐minute comprehensive assessment, allowing both physicians and non‐physician clinicians to objectively and quantitatively access brain health beyond traditional paper and pencil cognitive tests.

Method

Cognivue partnered with Velocity Clinical Research to lead the recruitment efforts for the FOCUS study. The enrollment goal included an objective to enroll a group resembling the racial, ethnic, gender, and educational makeup recorded in the 2020 U.S. census data. Study subjects were recruited through local community outreach, participant referrals, and advertising. Recruitment was stopped once goals for specific sub‐groups were reached, to model real‐world outcomes. Cognivue Thrive and Clarity were administered to assess scoring and normative ranges and compared against performance on other neuropsychological test batteries within the diverse study cohort.

Result

The Cognivue/Velocity partnership resulted in recruitment of more than 1,500 subjects from 14 sites in 11 states with a mean age of 50.2±16.3y (range 18‐89), 59.2% female, and 51.8% with 12 years or less of education. Over 28% of subjects identified their race as Black or African American, American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander, or other non‐white, and over 12% of participants identified as Hispanic or Latino.

Conclusion

Working in collaboration with Velocity, a clinical research partner with study sites throughout the United States, Cognivue was able to reach a 37% research participation rate of historically underserved and underrepresented populations in the national FOCUS study.

1Clin Pharmacol Ther. 2015 Mar;97(3):263‐73. https://doi.org/10.1002/cpt.61.
Poor objective sleep quality is associated with worse cognition cross‐sectionally and longitudinally in cognitively unimpaired adults
Authors: Stankeviciute Laura , Tort‐Colet Núria , Fernández‐Arcos Ana , López‐Martos David , Sánchez‐Benavides Gonzalo , Minguillon Carolina , Fauria Karine , Holst Sebastian C , Garces Pilar , Mueggler Thomas , Arqueros Aurora , Iranzo Álex , Suarez‐Calvet Marc , Gispert Juan Domingo , Molinuevo Jose Luis , Grau‐Rivera Oriol
Published: December 2023

Background

Sleep disturbances are prevalent in Alzheimer’s disease (AD), with sleep quality being impaired already in the preclinical stages. Specifically, reduced sleep efficiency and sleep fragmentation have been cross‐sectionally associated with poor cognition in healthy older adults. However, there is limited knowledge of how objectively measured sleep features relate to cognitive change. We aimed to investigate the relationships of actigraphy‐measured sleep with both cross‐sectional and longitudinal cognition in a cohort of cognitively unimpaired (CU) adults at increased risk of AD.

Method

This study included 123 CU adults from the ALFASleep project (mean age 63.9 years, 60.2% females, 50.4% APOE‐ε4 carriers) without sleep medication use (Table 1). Correlates of sleep quality were measured using actigraphy (Actiwatch2®, Philips Respironics) for two weeks. We used separate multivariate linear regressions to assess the association between actigraphy‐derived sleep parameters: total sleep time (TST), sleep efficiency, sleep latency, wake after sleep onset (WASO), and cognitive composite outcomes: Preclinical Alzheimer’s Cognitive Composite (PACC), and executive, memory and attention composites. We corrected all models for age, sex, APOE‐ε4, status, education and the time difference between cognitive and sleep assessments. Furthermore, we performed analyses on cognitive change from a previous visit (performed on average 3 years before) additionally adjusting by the time difference between two cognitive assessments.

Results

In cross‐sectional analyses, shorter TST was associated with lower PACC (p = 0.049) and executive composite (p = 0.039) scores. Also, lower sleep efficiency and higher WASO (indicating more nocturnal awakenings) were associated with lower performance on executive tasks (p = 0.015; p = 0.026) (Table 2). In longitudinal analyses, shorter TST was associated with poorer longitudinal performance in PACC and executive composite scores (p = 0.020).

Conclusions

Objectively measured indicators of poorer sleep quality are associated with poorer cognitive outcomes, both cross‐sectionally and longitudinally, in middle‐aged CU adults. Importantly, the executive function seems to be the most vulnerable to sleep impairment. Further research to unravel the underlying mechanisms using multi‐modal neuroimaging and CSF biomarkers of AD pathology is undergoing.
Sleep fragmentation is associated with lower cerebral structural integrity in females
Authors: Stankeviciute Laura , Tort‐Colet Núria , Fernández‐Arcos Ana , Garcia Marina , Minguillon Carolina , Fauria Karine , Holst Sebastian C , Garces Pilar , Arqueros Aurora , Iranzo Álex , Suarez‐Calvet Marc , Mueggler Thomas , Gispert Juan Domingo , Molinuevo Jose Luis , Grau‐Rivera Oriol
Published: December 2023

Background

Sex is a risk factor for Alzheimer’s disease (AD), with females accounting for two‐thirds of all cases. Epidemiological evidence showcases that sleep disturbances also increase AD risk, with females reporting more disrupted sleep in ageing compared to males. However, little is understood about how objective measures of sleep are associated with brain structural integrity, especially regarding the role of sex. We explored associations between actigraphy‐measured sleep and regional cortical thickness in middle‐aged cognitively unimpaired (CU) adults at risk of AD.

Methods

We included 151 CU adults from the ALFASleep project (mean age 64.6 years, 64.2% females) (Table 1). Correlates of sleep quality were measured using actigraphy (Actiwatch2®, Philips Respironics) for two weeks. The cortical thickness (CTh) of the “Alzheimer’s disease (AD) signature” composite region of interest (ROI) was calculated using FreeSurfer v6.0. We performed separate general linear models with CTh as the dependent variable, and actigraphy‐derived sleep parameters [total sleep time (TST), sleep efficiency, sleep latency, wake after sleep onset (WASO) and sleep fragmentation] as the predictors of interest. All models were corrected for age, sex, APOE‐ε4 status, sleep medication use and the time difference between MRI and actigraphy data acquisition. To investigate whether sex modified these associations we performed interactions between each actigraphy measure and sex. Finally, we performed stratified analyses to understand which group was driving any significant effects.

Results

Higher sleep fragmentation was associated with lower CTh (p = 0.006) in the whole group (Figure 1). Results remained significant after correction for sleep medication use. Significant interactions were found between sex and sleep efficiency, WASO and sleep fragmentation (Table 2, Figure 2). Stratified analyses showed that, among females, lower sleep efficiency (p = 0.003), higher WASO and higher fragmentation were significantly associated with lower CTh (p<0.001), without any significant associations among males.

Conclusions

In CU, higher sleep fragmentation is associated with reduced cortical thickness in areas vulnerable to early AD‐related neurodegeneration. Importantly, in females, lower sleep efficiency, as well as higher WASO and sleep fragmentation are associated with lower integrity in AD‐vulnerable regions. These results suggest that females in the preclinical stages of AD are more vulnerable to the effects of sleep fragmentation.
Strategy for Creating Evidence‐based Educational Programs
Authors: Stratton Lauren
Published: December 2023

Background

To address the challenges of caregiving, the Alzheimer’s Association offers a range of educational programs, both in‐person and virtual, on a variety of topics, including understanding Alzheimer’s disease and related dementias, communication and dementia‐related behaviors, and financial literacy. The Association has a concerted effort to offer programs that meet the needs of their constituents, while also ensuring the programs are evidence‐based. The Association has developed a strategy for proving the evidence‐base of their educational programs and are systematically conducting studies on these programs.

Method

This strategy includes creating an academic collaboration with an expert researcher in the field. Additionally, collaborations are created with community partners to aid with recruitment and implementation. Recruitment is another important aspect of the strategy that must be individualized depending on the program; however we have the benefit of using our caregiving network. The methodology also is thought through carefully, including the program ‘dose’, outcomes, and the inclusion of data collection periods.

Result

Additionally, in the process of the creation and evaluation of a program, it is important to consider the generalizability and application of the program, which must then be integrated into the research design. For the Association, this approach includes developing programs that are scalable and accessible, including multiple modes of delivery, engaging diverse and underserved communities, creating Spanish versions, including all types of caregivers (including both dementia and non‐dementia caregivers). To accomplish this, caregivers are engaged throughout the entire process and the Association’s chapter network of 70 local chapters is utilized on the ground‐level to recruit and disseminate the program through community educators and community partnerships.

Conclusion

Overall, during this session, the strategy behind building an evidence‐base for educational programs will be discussed in‐depth and we will examine the balance that is needed to fill the need within the target population and community, ensure the program is interactive and engaging, and create a scientifically‐sound methodology.
Success and Challenges of Evaluation and Research within the Alzheimer’s Association
Authors: Clifford Kristen
Published: December 2023

Background

Caregivers of people living with dementia often experience increased stress, depression, and isolation during their caregiving journey. The Alzheimer’s Association offers the live, 24/7 helpline, which provides support, resources, and information by trained staff to help offset the struggles caregivers experience. Also through the helpline, care consultations are provided, which aim to help caregivers navigate through difficult times and decisions associated with the disease.

Method

To better understand the impact of care consultations, randomized control studies were designed to be implemented in a live call center, which presented both challenges and successes.

Result

A research team was established and protocols put in place to effectively manage randomization, pre‐survey, intervention, and post‐surveys.

Conclusion

This presentation will discuss challenges and successes of conducting research in a live call center, as well as implications for further research.
Moderating effects of physical activity on the relationship between arterial stiffness and amyloid deposition in cognitively unimpaired older adults
Authors: Kim Geon Ha , Kim Bori.R. , Jeong Jee Hyang
Published: December 2023

Background

Arterial stiffness is linked to age and cardiovascular risk factors and is associated with cognitive decline and dementia in older adults. The moderating effects of physical activity (PA) on the relationship between arterial stiffness and amyloid deposition have not been established. This study investigates this interaction effect.

Methods

94 cognitively unimpaired older adults underwent cognitive function tests, brain MRI, and 18F‐florbetaben (FBB) PET to quantify amyloid deposition. Arterial stiffness was measured by brachial‐ankle pulse wave velocity (baPWV). PA was assessed using the International Physical Activity Questionnaire. Participants were divided into tertiles by MET‐hour/week values, and the correlation between baPWV and amyloid deposition was compared in the lowest and highest PA groups.

Results

Participants were mostly female (76.6%) with a mean age of 72.5 and 10.6 years of education. There was a significant positive correlation between baPWV and amyloid deposition (r = 0.3, P = 0.04). In the lowest PA group, there was a significant positive correlation between baPWV and amyloid deposition (r = 0.48, P = 0.037), but not in the highest PA group (r = 0.11, P = 0.61).

Conclusion

PA has a moderating effect on the relationship between arterial stiffness and amyloid deposition, suggesting that higher PA may attenuate this link.
The role and mechanism of TPK‐SENP1 signaling axis in regulating Aβ deposition in Alzheimer’s disease
Authors: Zeng Yeting , Xu Yangqi , Zhong Chunjiu
Published: December 2023

Background

Numerous studies have demonstrated that SUMOylation plays an important role in the development of Alzheimer’s disease (AD). However, there has been no research on how key neural signals regulate the dynamic balance of target SUMOylation/deSUMOylation in AD. Therefore, further investigation is needed to explore important SUMOylation/deSUMOylation homeostatic regulatory targets and their mechanisms in AD.

Method

Alterations in neurons, glia, and apoptosis were evaluated using immunofluorescence staining. The expression of related proteins was investigated using western blotting. Aβ40 and Aβ42 levels were measured using ELISA. An AAV carrying the Syn‐eGFP‐SENP1 construct was injected into the ventricles of mice. Behavioral assessments, including the Y maze and Rotarod tests, were performed to evaluate cognitive and motor function.

Result

Our findings indicate that the expression of thiamine pyrophosphokinase (TPK) is significantly diminished in the brains of AD patients. The conditional ablation of TPK in the brains of adult mice results in the emergence of a range of AD‐like pathological features. Additionally, we observed a significant decrease in the expression of SUMO‐specific protease 1 (SENP1), suggesting that TPK may play a role in regulating SENP1 expression. The overexpression of SENP1 was able to ameliorate the AD‐like pathological features observed in TPK knockout mice. Furthermore, we found that levels of APP, BACE1, and Aβ were elevated in SENP1flox/flox; Camk2α‐Cre mice relative to control mice, providing further evidence for the critical role of SENP1 in AD pathogenesis.

Conclusion

Modulation of SENP1 expression by TPK may regulate pathological features associated with AD, suggesting that SENP1 may be an important target for the development of AD drugs.
Neuronal targeting of tau using a mRNA‐encoded tau‐specific antibody fragment
Authors: Wongsodirdjo Patricia , Caruso Alayna C , Vella Laura J , Hung Ya Hui , Götz Jürgen , Nisbet Rebecca M
Published: December 2023

Background

A promising target for the treatment of Alzheimer’s disease and related tauopathies is intraneuronal tau. We have generated conventional tau‐specific monoclonal antibodies, as well as engineered antibody fragments, and demonstrated their ability to reduce tau pathology in the brains of tau transgenic mice (Nisbet et al., Brain 2017, Bajracharya, Brici et al., ANC 2021, Bajracharya et al. JCR 2022). Therapeutic efficacy is limited, however, by the inability of these antibodies to readily cross the blood‐brain barrier (BBB) and neuronal membrane to target intraneuronal tau. The SARS‐CoV‐2 pandemic revealed the potential of mRNA technology as an accessible and affordable strategy for delivering exogenous proteins, such as antibodies, to cells. The aim of this study was to explore the potential of utilizing mRNA to improve the intraneuronal delivery of our lead‐candidate tau‐specific monoclonal antibody in a single chain variable fragment (scFv) format.

Method

The cDNA encoding the tau scFv was cloned into an expression plasmid with a T7 promotor. The plasmid DNA was linearized, and in vitro transcription was conducted. The resulting mRNA was capped at the 5’ end with anti‐reverse cap analogue (ARCA), and possessed a 3’ poly (A) tail. The mRNA was then loaded into synthetic and biological nanoparticles and cellular uptake of the encapsulated mRNA and expression of the scFv was determined using mouse primary hippocampal neurons and human neuroblastoma SH‐SY5Y cells. Finally, binding of the expressed scFv to cytoplasmic tau was determined using a GFP‐pulldown assay.

Result

Highly‐pure synthetic mRNA encoding a tau scFv was successfully generated and encapsulated into synthetic and biological nanocarriers. Upon treatment of cells with the encapsulated mRNA in vitro, the tau scFv was expressed and capable of engaging intracellular tau.

Conclusion

Collectively, our results validate the use of mRNA encoding tau‐specific antibodies as an effective and economic alternative to conventional antibodies for specific targeting of intracellular antigens such as tau.
Regulation of pro‐inflammatory cytokine release by purinergic signalling in a human monocyte‐derived microglial model
Authors: Cowley Jamie , Harrison Neale , Morano Ines , Chan Hujo , Li Zhi , Pegg Ashley , Corsi‐Zuelli Fabiana , Jinks Elizabeth , Ali Haleema , Stevens Andrew , Belli Antonio , Upthegrove Rachel , Brady Catherine , Gordon John , Qureshi Omar , Barnes Nicholas
Published: December 2023

Background

Neuroinflammation is generally accepted as a major feature of Alzheimer’s disease (AD) with genetic evidence linking ‘myeloid’ associated genes (e.g. TREM2, CD33, ABCA7 and CR1) with AD risk and supporting a role for microglia (and infiltrating monocytes) in mediating pathology. The excitatory P2×7 receptor, expressed by microglia in the brain, upon activation by pathological concentrations of ATP drives a pro‐neuroinflammatory response primarily through the release of IL‐1β and IL‐18. In contrast P2Y receptor signaling has been associated with anti‐inflammatory effects such as reduction in TNFa release. The present study investigated the role of purinergic signalling in the modulation of cytokine release from human microglia derived from monocytes (iMDM).

Method

Human microglia (iMDM) were differentiated from human peripheral blood monocytes by culture in a cocktail of CNS‐associated cytokines over 5‐10 days. The immuno‐phenotype of the iMDM versus the originating monocytes were assessed by immuno‐cytochemistry. iMDM were primed with LPS before stimulation of purinergic receptors with selected agonists and antagonists to investigate cytokine release. Findings were extended using human brain slices.

Result

iMDM displayed an upregulation of microglial phenotypic markers (e.g. TMEM119, IBA1, CX3CR1, P2YR12 and TREM‐2). Following priming of iMDM with LPS, the P2×7 receptor agonist, BzATP, evoked a concentration‐dependent release of pro‐inflammatory cytokines (including IL‐1α, IL‐1β and IL‐18) that was prevented in a concentration‐dependent manner by P2×7 receptor antagonists and NLRP3 inhibitors. Although the P2×7 receptor was the major driver of IL‐1β release, TNFa release (evoked by LPS) and sensitivity to NLRP3 inhibitors, was modulated by purinergic agonists suggestive of a role for P2Y receptors in this system. The importance of P2×7‐receptor in mediating IL‐1β release was further confirmed by the use of human brain slices.

Conclusion

Modulation of purinergic signalling has the potential to regulate neuroinflammation and the ability of P2×7 receptor antagonists to suppress a pro‐inflammatory response by microglia suggests this pharmacological action may offer benefit to patients with AD.