bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of cannabidiol (CBD) treatment in a mouse model of Alzheimer’s disease through regulation of Interleukin‐5
Authors: Khodadadi Hesam , Salles Évila Lopes , Jarrahi Abbas , Khan MB , Yu Jack C , Morgan John C. , Hess David C , Seyyedi Mohammad , Vaibhav Kumar , Dhandapani Krishnan M , Baban Babak
Published: December 2021

Background

With the rising prevalence as the main cause of dementia, Alzheimer’s disease (AD) is emerging as one of the most important medical and social challenges for the healthcare system in both developed and developing countries. Despite significant advancement in our understanding of AD and improvement in therapeutic modalities for AD patients, however, there is currently a marked lack of definitive and effective treatment for AD. Therefore, there is an exigent need for an alternative therapy to treat the underlying causes of AD rather than its symptomatic effects. Cannabidiol (CBD) is a safe, non‐psychoactive phytocannabinoid produced by cannabis plant. Increasing evidence from our laboratory and others suggests an immunomodulatory role for CBD in a variety of inflammatory conditions, potentially including neurodegenerative diseases such as AD. Recent evidence and studies have challenged the traditional view about the role of immune system in the pathogenesis of neuroinflammatory diseases specifically AD. There are several studies indicating that Interleukin (IL)‐5, a Th2 type cytokine has the potential to alleviate the symptoms of cognitive decline in AD. Therefore, in this study we are investigating whether CBD can improve the symptoms of AD through activation of IL‐5 signaling.

Method

Age matched normal (Wild type, WT) and 5XFAD (Mouse model for familial AD) were used to evaluate their cognitive function and anxiety by using Morris water maze and Open field behavioral tests. All animals were sacrificed, and their meninges, brain and blood were collected for further flowcytometry analysis, immunohistochemistry and immunofluorescence imaging.

Result

CBD was able to modulate the level of IL‐5 expression which was associated with improvement in the behavioral and cognitive functions of AD mice.

Conclusion

Our findings suggest a possible alternative and therapeutic role for CBD in the treatment of AD. Further, these discoveries present evidence to support the beneficial role for IL‐5 as a potential biomarker in the diagnosis and treatment of AD, opening a new horizon for research to find an effective therapeutic modality for AD.
BDNF‐mediated improvements in cognition after computerized cognitive training
Authors: Nicastri Casey M , Simon Sharon Sanz , McFeeley Brittany , Ledreux Aurélie , Håkansson Krister , Granholm Ann‐Charlotte , Mohammed Abdul H. , Daffner Kirk R
Published: December 2021

Background

Evidence suggests that engagement in cognitively stimulating activities may reduce risk of cognitive deterioration and dementia. Mechanisms underlying these observations remain to be determined. Animal research indicates that brain‐derived neurotrophic factor (BDNF) plays an important role in neural plasticity, neurogenesis, synaptic growth, and cognitive performance. Working under the assumption that augmented BDNF levels benefit brain function, investigations of human subjects have focused on determining whether physical or mental activities can increase BDNF levels. Surprisingly little research has been devoted to linking alterations in BDNF to changes in cognition. This study aimed to determine whether changes in BDNF contribute to the enhancement of cognitive performance after computerized cognitive training (CCT). We have demonstrated that five weeks of CCT emphasizing working memory (WM) was associated with improvement on an untrained test of WM/processing speed, the Digit Symbol Test. Here, we investigated whether this improvement was mediated by changes in BDNF levels.

Method

Seventy‐five older adults, ages 65‐86, at two sites (USA and Sweden) were randomized to either Cogmed Adaptive (n=37) or Non‐Adaptive (active control) (n=38) CCT. Under the adaptive CCT, task difficulty was revised on a trial‐by‐trial basis to create a consistently high level of challenge. Under the active control condition, task load remained at a constant, relatively low level. CCT was performed in the homes of participants, five days per week, over five weeks. Serum BDNF levels and performance on Digit Symbol were measured pre‐ and post‐intervention.

Result

Analysis using linear mixed models demonstrated an interaction between time and intervention group for Digit Symbol score (p=.036) and BDNF level (p=.013) Only the adaptive CCT group demonstrated an augmentation of BDNF level (p=.014) and improvement in Digit Symbol scores (p<.001) after training. Mediation analysis revealed that changes in BDNF level accounted for the intervention‐related improvement in performance on Digit Symbol. Regression analysis indicated that changes in BDNF level predicted changes in Digit Symbol score (p=.010).

Conclusion

The results of this investigation suggest that increases in BDNF linked to cognitive training mediate improvement in cognitive performance. Additional research is needed to determine if these findings are specific to WM or are observed in other cognitive domains.
What do data‐driven Alzheimer’s disease subtypes tell us about white matter pathology and clinical progression?
Authors: Chen Hanyi , de Silva Eric , Sudre Carole H , Barnes Jo , Young Alexandra L. , Oxtoby Neil P. , Barkhof Frederik , Alexander Daniel C. , Altmann Andre
Published: December 2021

Background

The progression of Alzheimer’s Disease (AD) is heterogeneous with different brain regions manifesting pathology at different times during the disease. Differential sequences of grey matter (GM) volume changes, defining imaging‐based subtypes, may represent alternative disease origins, pathways or severity. Additionally, volumes of white matter hyperintensities (WMH), which increase with age, are associated with AD. In this study we used a machine learning method to estimate three types of AD trajectories and assessed their WMH load and longitudinal prognosis.

Method

Subtype and Stage Inference (SuStaIn; Young et al., https://doi.org/10.1038/s41467‐018‐05892‐0) was used to estimate data‐driven disease progresion subtypes from cross‐sectional GM volumes in 795 subjects (from ADNI1/GO/2 with baseline 3T MRI scans processed with FreeSurfer 5.1 passing data quality control). Following additional quality control WMH volumes for 575 of these ADNI subjects were calculated using a Bayesian Model Selection method BaMoS (Sudre et al., https://doi.org/10.1109/TMI.2015.2419072) from three diagnostic groups: Healthy Controls (HC; n=181), Mild Cognitive Impairment (MCI; n=310) and Alzheimer’s Disease (AD; n=85). The association between SuStaIn subtypes and WMH and diagnostic conversion rates were evaluated using multiple pairwise comparisons and survival analysis, respectively.

Result

SuStaIn identified three subtypes with distinct atrophy patterns: typical (atrophy begins in hippocampus and amygdala), cortical (atrophy starts in the temporal lobe, followed by cingulate and insula) and subcortical (atrophy begins in pallidum, putamen and caudate) (Figure 1). Participants with the subcortical subtype exhibited a significantly slower rate of clinical progression to MCI or AD (Figure 2, Table 1). Furthemore, subjects with the subcortical subtype showed lower median WMH (Figure 3a), a pattern observed across the diagnostic groups (Figure 3b).

Conclusion

Participants classified as the subcortical subtype were least likely to have white matter structural changes associated with neurodegeneration and displayed the slowest rate of clinical conversion. While late hippocampal involvement in the subcortical subtype may explain less severe clinical symptoms and slower disease progression, the reason for lower WMH associated with this subtype trajectory is unknown. Further studies are needed to investigate the link between WMH and AD atrophy subtypes.
Impact of socio‐demographic features and lifestyle in cognitive performance of Peruvian adults
Authors: Vilca Brenda Chino , Zegarra‐Valdivia Jonathan Adrian , de Frutos Jaisalmer
Published: December 2021

Background

The related‐age changes are associated with a continuous process of cognitive decline. In normal aging, only 1‐2% of the population develop dementia compared with 10 to 15 % with previous mild cognitive impairment. In this line, diverse characteristics exist that act as protective factors front the disease onset and are related to better cognitive performance in the population. Our knowledge about these features can be the first step to combat dementia and reduces the impact on the elderly quality of life. The present study aimed to investigate sociodemographic characteristics and lifestyle factors affecting the cognitive function in Peruvian adults.

Method

1499 subjects (aged from 42 to 98) participated in the Interview Survey in Health Services of Primary Attention in Arequipa (Perú). The cognitive performance was evaluated with the Addenbrooke's Cognitive Examination ‐ Revised (ACE‐R). The χ2 test and multiple logistic regression models were used to define the association between cognitive impairment and socio‐demography and lifestyle variables.

Result

The multivariate analysis indicated that age, sex, single, more years of education, living in the urban area, practicing physical activities, and reading were associated with a lower risk of cognitive impairment.

Conclusion

Risk factors associated with dementia are even more visible in Latin America Countries (LAC). The wide variability in the sociodemographic characteristics and access to health care services limit early detection of the disease. The lifestyle changes could help prevent or decrease the risk of cognitive impairment and reduce the disease's impact on vulnerable environments.
Associations between neighborhood greenspaces and cognitive and brain volume measures in cognitively normal older adults
Authors: Besser Lilah M , Chang Lun‐Ching , Mitsova Diana , Renne John , Carmichael Owen T , Moulder Krista L , Morris John C , Galvin James E
Published: December 2021

Background

Living in neighborhoods with greater vegetation and park space has been associated with better brain health in older adults. While mechanisms relating greenspaces and brain health are not well understood, greenspaces may lead to better cognition and lower Alzheimer’s risk by providing social and physical activity opportunities and stress reduction, factors previously associated with Alzheimer’s disease. This study investigated associations between neighborhood greenspace types and multiple brain health measures for Alzheimer’s disease and related disorders, which has been examined little to date.

Method

Residential addresses and magnetic resonance imaging (MRI) volumes were obtained from cognitively‐normal participants who completed Uniform Data Set assessments from Knight Alzheimer’s Disease Research Center (St. Louis, Missouri). Addresses geocoded to US Census tracts were linked to National Land Cover Dataset data to identify open spaces and areas with tree canopy (hereafter termed forest). Longitudinal clinical data were obtained from the National Alzheimer’s Coordinating Center. Outcomes included CDR® Sum of Boxes, four cognitive domain z‐scores (memory, attention, executive function, and language) constructed from ten neuropsychological tests, and hippocampal and white matter hypointensity volumes (167 had T1‐weighted MRI). Multi‐level linear regression models (clustering on Census tract and participant) controlled for demographics, comorbidities, and neighborhood disadvantage and population density. Brain volume models additionally controlled for intracranial volume.

Result

Participants (n=553) were on average 74 years old (standard deviation [SD]=7), 16% were Black, and 81% were White. Neighborhood percentage of open space ranged from 0 to 42% (mean=6.6%, SD=9.9) and forest ranged from 0‐16% (mean=0.2%, SD=1.4). Greater percentage of forest was associated with lower baseline episodic memory (estimate=‐0.79; 95% confidence interval [CI]=‐1.13, ‐0.46), slower annual episodic memory declines (estimate=0.069, 95% CI=0.002, 0.137), higher baseline executive function (0.15, 95% CI=0.03, 0.26), and fewer white matter hypointensities (estimate=‐3,521 mm3, 95% CI=‐6,443, ‐600). No other associations were observed.

Conclusion

Living in neighborhoods with more tree canopy was associated with lower episodic memory but higher executive function at baseline, slower annual declines in executive function, and fewer white matter hypointensities. This study suggests mixed associations between neighborhood tree canopy and brain health that will need to be replicated in larger, diverse cohorts.
Cognitive performance predictors of incident motoric cognitive risk syndrome
Authors: Ayers Emmeline , Verghese Joe
Published: December 2021

Background

Motoric cognitive risk syndrome (MCR) is a gait based pre‐dementia syndrome that builds on operational definitions of mild cognitive impairment (MCI), and is associated with increased risk for Alzheimer’s Disease and other types of dementia. Declines in cognitive function associated with risk of developing MCR have not been established. We aimed to examine the association between cognitive performance on tests of memory and executive function (EF) and related processes and risk of incident MCR.

Method

Of the 541 non‐demented participants (aged 65+) in a community‐based cohort, at baseline 22 met criteria for MCR, 58 for MCI, and 17 met criteria for both MCR and MCI, and were excluded from the analyses. Cognitive performance was measured using seven tests: the free recall score from the Free and Cued Selective Reminding Test, Figure Recall from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Story Recall from the RBANS, Category Fluency, Controlled Oral Word Association Test, Digit Symbol Substitution test and Trail Making Test part B. A confirmatory factor analysis indicated that these cognitive tests fell into two categories of cognitive function: memory and EF and related processes. Cox proportional hazard models adjusted for age, sex and education was used to examine the association between cognitive test performance and incident MCR in 444 participants. For the purpose of comparison, we also examined the association between cognitive performance and MCI.

Result

Over a mean follow‐up of 3.0 years, 37 participants developed incident MCR and 69 incident MCI. Performance on tests of EF and related processes was associated with risk for MCR (adjusted hazard ratios (aHR) ranging from 0.96 to 0.99). One memory test (free recall) was associated with risk of MCR (aHR: 0.94, 95% Confidence Interval: 0.89‐0.99). Performance on all tests of memory (aHR ranging from 0.81 to 0.92) and EF and related processes (HR ranging from 0.94 to 0.99) was associated with increased risk of MCI.

Conclusion

Cognitive performance on tests of EF and related processes are associated with increased risk of MCR. This may be indicative of a distinct underlying pathology in patients who are at risk of MCR.
Impact of brisk walking on cognitive decline in adults with and without early impairment: A FLAME analysis in the PROTECT cohort
Authors: Brooker Helen , Hayman Vincent , Aarsland Dag , Creese Byron , Ballard Clive , Corbett Anne
Published: December 2021

Background

Evidence continues to build to support the value of regular physical exercise as an affordable dementia risk reduction intervention for cognitively healthy older adults. However, the types and intensities of exercise that yield the greatest benefits are yet to be established. This study uses the recently published FLAME cognitive analysis measure to explore the impact of exercise on cognition in older adults in an online cohort.

Method

PROTECT is an innovative online study (www.protect.org.uk) in adults aged 50 and over in the UK, Participants complete annual cognitive assessment in addition to lifestyle and health measures. Participants were divided into three cohorts (Normal Cognition, Stage 2 Early AD and Stage 3 Early AD – based on the FDA framework) using baseline data from the cognitive assessment battery. Participants (n=8079) in these groups who completed the exercise questionnaire on two consecutive timepoints and within two weeks of cognitive assessment were included in this analysis. The analysis compared change in cognition from baseline using a one‐way ANOVA with physical activity type as a fixed factor and gender, age and education fitted as covariates.

Result

Composite measures of Speed of Attention [p=0.0003, d=0.26], Accuracy of Attention [p=0.0008, d=0.21], Memory [p=0.0017, d=0.11] and Executive Function [p=0.0006, d=0.09], as well as the composite FLAME measure [p=0.006, d=0.24] all showed significant benefits in participants with Normal Cognition who performed brisk walking at least twice a week, compared to indiviudals with lower levels of exercise. These benefits were also evident in participants In the stage 2 and 3 Early AD groups [Stage 2: FLAME p=0.003, d=0.13; Stage 3: FLAME p=0.006, d=0.19].

Conclusion

These findings contribute further evidence that regular participation in exercise of at least moderate intensity offers benefit to major aspects of cognitive function in both healthy aging individuals and those at the pre‐clinical stages of cognitive decline.
Spontaneous blinking and brain health: Can blink‐related oscillations capture brain changes in aging?
Authors: Liu Careesa C. , Meltzer Jed A. , Keerthi Prerana , Pappas Chloe , Sekuler Allison B. ,   Cambridge Centre for Aging and Neuroscience (Cam‐CAN)
Published: December 2021

Background

Blink‐related oscillations (BROs) are recently discovered neurophysiological responses that follow spontaneous blinking, and represent environmental monitoring and awareness processes as the brain evaluates new visual information after eye reopening. BROs strongly activate the precuneus which is one of the earliest brain regions impacted by Alzheimer’s disease (AD) neuropathology, and as such may provide an important avenue for assessing and monitoring brain health in aging. In this study, we conducted the first investigation of BRO effects in normal aging to determine whether these responses can capture aging‐related brain changes.

Method

This research used data from the Cambridge Centre for Aging and Neuroscience (Cam‐CAN) repository, which comprises magnetocenphalography (MEG) and structural magnetic resonance imaging (MRI) from 700 healthy adults aged 18‐88. The MEG paradigm consists of a target detection task with simultaneous auditory and visual stimulation. MEG data were first denoised using independent component analysis, then BRO responses were derived by segmenting the cleaned data into 3s epochs time‐locked to spontaneous blinking. Participants were divided into 4 age groups comprising the youngest (18‐30), middle‐young (31‐50), middle‐old (51‐70), and oldest (71‐90), and analyses were performed using global field power (GFP) and minimum norm estimates to examine BRO effects at the sensor‐ and source‐levels, respectively.

Result

Results showed that BRO responses were present in all age groups. GFP amplitude increased with age during intervals spanning post‐blink BRO peaks, but not the pre‐blink baseline (p<0.05). BROs also activated brain regions spanning the occipital, temporal, and parietal cortices in all age groups (p<0.05 FWE), with the extent of activation increasing with age. Moreover, the activation extent of precuneus and hippocampus regions showed inverted U‐shape with age, increasing towards the middle‐old group but decreasing in the oldest.

Conclusion

These results demonstrate for the first time that BRO responses can capture brain changes in normal aging, with increased neural activation for processing blink‐related information as one ages. Results suggest that BROs may represent a simple yet powerful avenue for measuring aging‐related brain function changes, providing a potential tool for early detection of neurodegeneration – particularly with respect to the precuneus and hippocampus regions highly implicated in AD.
Comparison between face‐to‐face and remote language assessment with the Minilinguistic State Examination
Authors: Pistolesi María Agustina , Martínez‐Cuitiño Macarena , Vivas Leticia , Manoiloff Laura , Paolantonio Patricia , Fernández‐Zaionz Axel , Ortells Tobias , Geraldine Reimundo , Montero Lucía , Nieto Mayda , Romero Nicolás , Castaño Federico , Sanchez María Victoria
Published: December 2021

Background

The COVID‐19 pandemic had an impact on neuropsychological assessment and implied an adjustment in the settings of evaluation. To continue providing clinical assistance to patients, it was necessary to adapt previously developed tools for face‐to‐face evaluation for a remote format. To know the effectiveness of this way of administration, it becomes necessary to identify whether this new modality differs significantly from the face‐to‐face one. With the pandemia some researcher started to make this comparisons. Identify these possible differences using short tools makes it easy to access this information. The Minilinguistic State Examination (MLSE) is a recently developed tool for assessing acquired language difficulties that is being adapted and validated in various languages.

Objective: The aim of this work is to identify possible differences in the performance of control subjects by comparing the face‐to‐face and remote clinical evaluation using the MLSE Argentinean version.

Method

Two groups of healthy subjects were assessed: 23 face‐to‐face and 31 remotely. All were native Spanish speakers with middle to high educational level. A Mann‐Whitney´s U test was performed between groups comparing the scores on each of the subtests of the MLSE (except sentence repetition because it was subtly changed for the remote version).

Result

There were no significant differences in any of the aforementioned tasks concerning both modalities (p > .005) but only in the comprehension part of repeat and point (U = 310; p = .004), where better performance was observed for the remote group. Additionally, within modality (face‐to‐face and remote), comparisons were performed considering age and educational level and there were no statistically significant differences (p > .005).

Conclusion

The remote modality of this version of the MLSE could be a good option to perform a language screening. The better performance observed in the remote group in one comprehension task could be explained by the higher cultural level of that group. That can be a bias when considering samples that access computer mediated evaluations. Thus, additional sample must be collected including lower educated participants. Also, further studies are necessary to assess the utility of the remote modality for patients with aphasia.
The Asian Cohort for Alzheimer’s Disease (ACAD) study
Authors: Wang Li‐San , Tee Boon Lead , Gu Yian , Li Clara , Vogel Briana , Reyes‐Dumeyer Dolly , Faber Kelley , Hsiung Ging‐Yuek Robin , Rosen Howard J , Schellenberg Gerard D , Varma Rohit , Foroud Tatiana M , Kukull Walter A , Henderson Victor , Lee Haeok , Yu W Haung , Peavy Guerry M , Feldman Howard , Mayeux Richard , Chui Helena C , Jun Gyungah R , Park Van Ta , Chow Tiffany W ,   The Asian Cohort for Alzheimer’s Disease Study
Published: December 2021

Background

Asian Americans and Asian Canadians (ASACs) are the fastest growing minority group in the US and Canada. Roughly 21% of ASACs will be 65 years or older by 2060, underscoring the importance to understand how dementia and Alzheimer’s disease (AD) affect these large sectors of the populace. By comparison, ASACs are under‐sampled in AD research. Culturally appropriate, community‐based approaches to recruit these understudied communities are urgently needed.

Method

The Asian Cohort for Alzheimer’s Disease (ACAD) will be the first large dementia genetics cohort to examine genetic/non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history, experience and leadership in AD research. The National Institute on Aging (NIA) has resourced our study, which will leverage national AD research resources and facilitate collaborations with international cohorts.

Result

ACAD consists of 8 recruiting sites (6 US and 2 Canada), a coordinating site, an analysis site, and 4 active workgroups. ACAD has developed a data collection packet (DCP) and pre‐screening/sample collection procedures. The Data Management Workgroup has implemented them into a central REDCap database. The Outreach Workgroup has translated the forms and are conducting an outreach campaign into Chinese (Mandarin and Cantonese), Vietnamese and Korean. The Training Workgroup has developed a training curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment. We will recruit cases of dementia, mild cognitive impairment, subjective cognitive complaint, and controls without cognitive impairment in collaboration with community partners, clinics, and nursing homes that serve Asian communities. We will collect saliva or blood for DNA/genetics and biomarker studies.

Conclusion

After launching ACAD in November 2020, we built foundation materials to initiate recruitment in Spring 2021. ACAD will provide guidance for future studies to explore ASAC risk factors for AD and related dementias. In collaboration with ongoing consortium efforts in Alzheimer’s Disease Genetics Consortium, trans‐ethnic insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD. Our long‐term goal will be to extend ACAD to South Asians, Filipinos, and Japanese.
Increased brain rewiring in patients with mild cognitive impairment
Authors: Li Yong , Butz‐Ostendorf Markus
Published: December 2021

Background

Depending on disease progression, differentiation of patients with mild cognitive impairments from those with Alzheimer disease from structural MRI is often difficult as grey matter (GM) loss is not yet present in MCI patients. Therefore, we re‐assessed WM densities at the initial and changes between two measurements in 22 randomly chosen MCI patients from the ADNI3 cohort [Weiner MW et al. 2017] and compared them to 25 matched controls.

Method

We computed full brain probabilistic tractography by MrTrix3 [Tournier et al. 2019]. ROI to ROI connectivity (HCP MMP 1.0 brain atlas) was compared between groups for Superior Longitudinal Fasciculus (SLF) and Occipital Cortex networks in two longitudinal DTI scans with one year interval by the help of NICARA (www.nicara.eu) [Kopetzky, Butz‐Ostendorf, 2018].

Result

Surprisingly, MCI patients showed an increase in brain connectivity of the SLF that was associated with an increased brain rewiring, which we did not observe in matched controls. By contrast, we did not find a similar pattern in WM connections of the visual cortex. This observation was seen in about 40% of MCI patients and did not correlate with age, nor with disease onset. Patients with increased connectivity did not show a decrease in MMSE scores over time whereas patients with a loss in connectivity were more likely to decrease in MMSE score.

Conclusion

This study is the first that reports a pronounced brain [Van Ooyen, Butz‐Ostendorf 2017 (eds)] rewiring in association with WM hyperconnectivity [Delli Puzzi et al. 2019] in MCI patients. Phases of pronounced brain rewiring could be an expression of a compensatory response aiming at functional reorganization of brain networks. Our findings point to the urgent need for including longitudinal DTI tractographies in routine brain scans and clinical trials.
Mixed methods used in the refinement of an Alzheimer’s study registry to optimize recruitment of Latinx and Black individuals
Authors: Aggarwal Raj , Stowell Carter , Plant Aaron , Creech Deborah Neffa , George Sheba , Williams Emily , Fiore Nora , Langbaum Jessica B
Published: December 2021

Background

Alzheimer’s disease (AD) disproportionately affects Latinx and Black individuals, yet they are underrepresented in AD studies. Recruitment challenges for these populations limit generalizability of findings. The purpose of this 2020 study was to improve an existing online AD participant registry to optimize recruitment of Latinx and Black individuals. Refinements were geared toward recruitment on mobile devices, as research suggests mobile‐first approaches may be more successful within these populations.

Method

We used an iterative, mixed methods approach to improve the registry with 45‐75‐year‐old Latinx and Black individuals who self‐reported no mild cognitive impairment, dementia, or AD diagnoses. Strategies included (in order): four focus groups (n=39); an online survey to assess attitudes and acceptability toward the existing registry (n=677); usability testing of existing registry (n=40); development of a refined registry prototype; qualitative (n=24) and quantitative (n=392) usability testing of refined prototype; a final online survey to assess attitudes and acceptability toward refined prototype (n=769). To assess acceptability of registry improvements, quantitative and qualitative data from the initial and final surveys were compared.

Result

There was an increase between the surveys in the percentage of Latinx and Black respondents who agreed that: they would likely sign up for the registry (48.2% to 54.1% and 42.1% to 53.4%); the registry was designed with people like them in mind (54.4% to 63.0% and 50.1% to 61.2%); and most of their family and friends would relate to the registry (41.2% to 51.9% and 36.8% to 49.4%). Survey participants responded favorably to specific content in the refined registry (e.g., discussing challenges of recruiting Latinx and Black individuals for AD studies and showing diversity of program staff). Qualitative responses in the final survey included that the refined registry was easy to understand and navigate, and was trustworthy. Nearly half of respondents (49.4%) said they would be likely to sign up for the registry using their smartphone or tablet.

Conclusion

Refinements to an online study recruitment registry aimed at improving participation among traditionally underrepresented populations were successful at increasing acceptability and sign‐up intentions. These findings have important implications regarding reaching underrepresented populations for participation in AD studies.
The impact of novel Xe delivery on Alzheimer‐related gene regulation
Authors: Yin Xing , Booher Keith , Peng Tao , Morales Rodrigo , Claypool Jonathan , McPherson David , Huang Shaoling
Published: December 2021

Background

Effective treatments for Alzheimer’s disease (AD) are classically designed to canonical disease players (e.g., misfolded proteins, neurodegeneration, and brain inflammation). Importantly, treatments must be able to cross the blood‐brain barrier (BBB) to cause meaningful therapeutic effects. Sufficient evidence has demonstrated that xenon (Xe), a bioactive gas, has profound neuroprotective effects with advantages of rapid diffusion across the BBB into hypoperfused brains without side effects. For chronic use, a long‐term and effective Xe delivery method is needed. Here, we present novel Xe formulations with effective cerebral delivery strategies for extended endogenous neuroprotection and neurorestoration.

Method

Orally deliverable Xe cyclodextrin (Xe‐CD) and intravenous deliverable Xe‐liposome were prepared. Xe‐CD was orally administrated in aged (10 months old) ApoE knockout mice fed with high‐fat diet for 6 weeks. The brain and blood amyloid‐β (Aβ) levels were measured by ELISA. To extend therapeutic effects, Xe‐liposomes were intravenously administrated using an intermittent repetitive administration strategy in a rat stroke model. Xe effects on epigenetic regulation were evaluated in this rat stroke model using Whole‐genome bisulfite sequencing (WGBS) and gene pathway enrichment analyses. Neurocognitive recovery was also evaluated.

Result

Aged (10 months old) ApoE knockout mice fed with high‐fat diet for 6 weeks developed high Ab expression levels in the brain and blood. However, Xe oral administration for 6‐week prevented the high‐fat diet‐induced Aβ elevation. Repetitive intermittent administration of Xe formulations extended the protective effects over time as long‐term memory restoration post stroke was observed. Whole‐genome bisulfite sequencing (WGBS) and gene pathway enrichment analyses revealed enrichment of differential methylation in multiple biologic pathways associated with growth factor response, memory consolidation, synaptic plasticity, and brain aging in the hippocampus. Of interesting, Xe regulated endogenous β‐secretase (BACE1), and low‐density lipoprotein receptor‐related protein 1 (LRP1), both of which are known to be associated with Ab. Xe also regulated memory and age related genes such as Gadd45b, DMNT3a, and HDAC9; and growth factor related genes NTrK2 and NGF. Gadd45b and PFAa also regulate long‐term memory consolidation.

Conclusion

We have developed a novel Xe formulation and delivery strategy for long‐term neuroprotection that stabilizes the brain through multiple pathways.
A 10‐year behavioral and social sciences research agenda for ADRD: Reflections on a new national academies report
Authors: Powell Patricia , Yaffe Kristine , Mor Vincent , Checksfield Molly
Published: December 2021

Background

The National Academies of Sciences, Engineering, and Medicine was charged with developing a ten‐year agenda for research in the behavioral and social sciences that would substantially contribute to reducing the burden of ADRD.

Method

The report was developed by a committee of individuals with expertise across a range of disciplines and fields, including dementia research. The committee was charged with assessing the role of the social and behavioral sciences in reducing the burden of dementia. The committee held several evidence‐gathering sessions, reviewed published literature, commissioned several papers, and engaged individuals living with dementia and caregivers as a part of an Advisory Panel to the committee.

Result

The committee’s report will be published in spring 2021, after undergoing the National Academies' rigorous review process. The report will include conclusions and recommendations about the following topics: (1) research using the methods of behavioral and social sciences on the burden of AD/ADRD on individuals, families, medical and long‐term care systems; (2) challenges associated with AD/ADRD care; (3) intervention development for persons with dementia and their caregivers at different stages of illness; (4) cognitive and AD/ADRD epidemiology; (5) factors affecting AD/ADRD prevention, leveraging basic and translational research on behavioral and social pathways to AD/ADRD and cognitive decline; (6) detection of AD/ADRD‐related change; (7) causes and consequences of AD/ADRD health disparities; and (8) AD/ADRD data infrastructure needs.

Conclusion

The report will include conclusions and recommendations to guide behavioral and social science research in the coming decade that could reduce the burden of ADRD.
Increasing fasting glucose is associated with Alzheimer’s disease–related neuropathological and structural decline in older adults
Authors: Honea Robyn A. , Greene Zachary D. , John Casey S. , Kueck Paul J. , Kamat Ashwini , Taylor Matthew K. , Lepping Rebecca , Vidoni Eric D. , Burns Jeffrey M. , Morris Jill K.
Published: December 2021

Background

Research on risk factors for dementia and in preclinical populations has shown that glucose regulation may be involved in amyloid synthesis, cognitive processing, and neurodegeneration; however, the extent to its involvement is unclear. Fasting glucose is a straightforward measure that could be a window into metabolic changes either associated with or preceding dementia.

Method

We sought to test whether a change in fasting glucose over one year was related to multi‐modal brain imaging measures of neuropathological changes in the brain associated with dementia. We leveraged longitudinal biospecimens and neuroimaging measures collected during the Alzheimer’s Prevention through Exercise (APEX) trial (n=109) to examine the longitudinal relationship between change in fasting glucose and change in neurodegeneration and cerebral amyloid over 1 year of follow‐up.

Result

The group of individuals with stable or improving fasting glucose (n=65) exhibited less atrophy and regional amyloid accumulation compared to the group whose fasting glucose worsened over 1 year (n=44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus, reduced diffusion in limbic white matter, and increased amyloid accumulation in the precuneus cortex. Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by APOE4 carrier status. Increasing fasting glucose may reflect changes in cellular bioenergetics associated with Alzheimer’s disease neuropathophysiology.

Conclusion

Dysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine if treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.
Inhibitory control deficits in vascular cognitive impairment revealed using the Multi‐Item Localization (MILO) task
Authors: Richards Emma V , Thornton Ian M , Bayer Antony , Tales Andrea
Published: December 2021

Background

Reaction time (RT) in Vascular Cognitive Impairment (VCI) is particularly slowed when assessed using tests of executive function, however, these tests do not reveal the integrity of specific functional subcomponents of information processing related to RT that are affected by VCI, thus limiting understanding of behavioural change, symptoms and disease progression. Pathological changes in white matter can be ‘silent’, on routine neuroimaging, and not all clinical tests may be sensitive to such effects, highlighting the importance of using of a wider range of tests than may be used at present. The Multi‐Item Localization (MILO) task is used to characterise the performance of mild/moderate VCI and is designed to explore the temporal context of visual search, in addition to measuring overall completion time, it provides a profile of serial reaction time (SRT) patterns across all items in a sequence. MILO assesses how well participants plan ahead during search, and whether items that have already been located can be effectively ignored (i.e., inhibited) identifying deficits in inhibitory control during search.

Method

Participant groups: VCI patients (n =26); cognitively healthy (CH) older adult control group (n=23); young adults (n=26). The MILO iPad app consisted of the digit sequence 1‐8, presented as red/white pool balls. Participants were required to tap each ball in consecutive order, quickly and accurately. In the Vanish condition, items were removed from the screen following the response. In the Remain condition, items were unaffected when touched and the set size were the same throughout a trial. Participants completed two blocks of 20 correct trials, one block of Vanish trials followed by one block of Remain trials.

Results

The performance of VCI participants was characterised by overall slowing, increased error rates, and crucially, a compromised ability to use inhibitory tagging. Performance was compromised when items remained visible and have already been responded to, resulting in detrimental slowing of processing.

Conclusion

The MILO task could be a useful tool for identifying non‐age‐related changes in behaviour with patient populations, and clearly hints at a specific inhibitory deficit in VCI.
Tau pathology mediates the effects of amyloid on cerebral blood flow and propagation of tau
Authors: Bilgel Murat , Wong Dean F. , Resnick Susan M.
Published: December 2021

Background

Amyloid is associated with greater tau pathology and is thought to facilitate the spread of tau from the medial temporal lobe (MTL) to the neocortex. The extent to which amyloid versus MTL tau is involved in propagating tau remains unclear. Given the potential role of cortical tau in early neurodegeneration, understanding the contributors to its spread might inform preventative strategies.

Method

We acquired 18F‐flortaucipir (FTP) PET scans to measure tau pathology in 113 non‐demented Baltimore Longitudinal Study of Aging participants. To assess if amyloid facilitates the spread of tau from the MTL to the neocortex, we investigated whether amyloid moderates the association between tau in the entorhinal cortex (EC) and the inferior temporal gyrus (ITG). To quantify the involvement of amyloid versus MTL tau in propagating tau, we investigated whether EC tau mediates the association between amyloid and ITG tau. Finally, we investigated the local relationship between ITG tau and cerebral blood flow (CBF), an indicator of neurodegeneration, quantified as the relative radiotracer delivery parameter R1
computed from dynamic Pittsburgh compound B (PiB) PET scans. We used robust linear regression for all statistical models to mitigate the influence of the few outlying tau data points on the estimates, and included age, sex, race, and education as covariates.

Result

Amyloid positive (A+) participants had higher FTP‐SUVR in the EC and ITG. Higher FTP‐SUVR in the EC was associated with higher FTP‐SUVR in the ITG. This association was steeper among A+ individuals (amyloid and EC FTP‐SUVR interaction β=0.269, p=0.023). EC FTP‐SUVR mediated the association between amyloid and ITG FTP‐SUVR (indirect effect=0.136, p=0.043).

Higher ITG FTP‐SUVR was associated with lower PiB‐R1
(β=‐0.277, p=0.039). The direct association between amyloid and PiB‐R1
was not statistically significant (direct effect=‐0.366, p=0.192), but there was an indirect effect via ITG FTP‐SUVR (indirect effect=‐0.14, p=0.015).

Conclusion

Our findings suggest that both amyloid and MTL tau pathology are involved in the spread of tau into the neocortex. Tau accounted for 28% of the amyloid‐CBF relationship, indicating its role in early neuronal hypoactivity. Therapeutics may need to target both amyloid and tau early to prevent neocortical involvement.
Gamma frequency sensory stimulation prevents brain atrophy, improves sleep and memory in probable mild Alzheimer’s patients
Authors: Chan Diane , Suk Ho‐Jun , Jackson Brennan L , Milman Noah , Stark Danielle , Fernandez Vanesa , Banerjee Arit , Kitchener Erin , Klerman Elizabeth B , Boyden Edward S , Brown Emery N , Dickerson Brad C. , Tsai Li‐Huei
Published: December 2021

Background

Non‐invasive gamma frequency light and sound stimulation at 40Hz reduced Alzheimer’s disease (AD) pathology and improved performance during behavioral testing in mouse models of AD (Iaccarino et al., Nature, 2016; Martorell et al., Cell, 2019; Adaikkan et al., Neuron, 2019). Sensory stimulation inducing 40Hz entrainment reduced amyloid and hyperphosphorylated tau burden and prevented brain atrophy in different mouse models of AD. Performance on tasks testing short‐term memory and spatial learning improved after 6 weeks of daily 40Hz stimulation. We therefore hypothesized that translation of gamma entrainment with light and sound can be used as a disease‐modifying therapeutic for AD.

Methods

We conducted a placebo‐controlled, randomized control trial (n = 15) in volunteers with probable mild AD to use our light and sound device at home for one hour daily (NCT 04042922). Control devices delivered constant light and white noise while devices with the active setting produced patterned and synchronized light and sound at 40Hz. Electroencephalogram (EEG) was used to evaluate for safety and entrainment when using the 40Hz stimulation. Weekly phone questionnaires were used to assess safety. Magnetic resonance imaging was used to evaluate brain structure and actigraphy was used to record sleep. Face‐name association delayed recall was done to assess changes in cognition.

Results

We report interim results after 3 months of daily 40Hz stimulation. Mild AD patients were highly compliant with usage in both the control and active groups. EEG data show that our novel light and sound device safely and effectively induced 40Hz entrainment in subjects with mild AD. After 3 months of daily stimulation, 40Hz entrainment prevents both hippocampal atrophy and ventricular enlargement and the extent of ventricular change differs between groups (p = 0.034, p = 0.024, p = 0.043, respectively). Circadian rhythmicity also improved with 40Hz stimulation (p = 0.03). Performance on the face‐name association delayed recall test improved in accuracy (p = 0.004).

Conclusions

Gamma frequency light and sound stimulation can be used safely daily for 3 months and prevents AD‐related degeneration. Induced entrainment using sensory stimulation at 40Hz shows promise as a novel disease modifying therapeutic for Alzheimer’s dementia.
Preliminary diagnostic criteria for prodromal behavioral variant frontotemporal dementia: Mild behavioral and/or cognitive impairment
Authors: Barker Megan S , Gottesman Reena T , Manoochehri Masood , Forsberg Leah K. , Heuer Hilary W. , Boeve Bradley F. , Boxer Adam L. , Rosen Howard J. , Cosentino Stephanie , Rascovsky Katya , Huey Edward D. ,   ALLFTD Consortium
Published: December 2021

Background

At present, no research criteria exist for the diagnosis of prodromal behavioral variant frontotemporal dementia (bvFTD). Leveraging data from carriers of pathogenic genetic mutations as a proxy for frontotemporal lobar degeneration pathology, we sought to develop and test a proposed set of research criteria for prodromal bvFTD, termed “Mild Behavioral and/or Cognitive Impairment in bvFTD” (MBCI‐FTD).

Method

Participants included 68 carriers of a pathogenic mutation in microtubule‐associated protein tau (MAPT), or progranulin (GRN), or a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), with mild behavioral and/or cognitive changes. Based on extensive clinical workup, the prodromal mutation carrier group was divided into a Development Group (N=22) and a Test Group (N=46). The Development Group was selected to be the subset of the prodromal mutation carriers for whom we had longitudinal evidence of conversion to a bvFTD phenotype, and were used to develop the criteria. The Test Group was the remainder of the prodromal mutation carriers (e.g., single visits only) and was used to validate the criteria. Familial non‐carriers were included as controls (N=165).

Result

Frequencies of behavioral and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in prodromal mutation carriers and non‐carrier controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate‐severe dysphoria, behavioral disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviors (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioral changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of Possible MBCI‐FTD; Probable MBCI‐FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI‐FTD criteria correctly classified 95% of the Development Group of prodromal mutation carriers, and 41% of the Test Group, with a false positive rate of <10%.

Conclusion

We present the first diagnostic criteria for prodromal bvFTD. Future research should prioritize establishing generalizability to non‐genetic cases, and testing the specificity of these criteria against psychiatric, neurologic and other neurodegenerative diseases.