bluuebunny/crossref_metadata_2025 huggingface dataset:
GABAergic system in Alzheimer’s disease: a systematic review with meta‐analysis
Authors: Carello‐Collar Giovanna , Bellaver Bruna , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Ramos Vanessa G. , Pascoal Tharick A , Rosa‐Neto Pedro , Zimmer Eduardo R.
Published: December 2022

Background

Cholinergic and glutamatergic dysfunctions have been widely described in Alzheimer’s disease (AD). However, the role of other neurotransmitter systems, such as the GABAergic, remains poorly understood. In fact, studies evaluating GABAergic neurotransmission in AD patients have provided contradictory results, pointing to a need for a consensus in the literature regarding the GABAergic system in AD. Thus, we aimed at examining whether the GABAergic system is altered in AD.

Method

We systematically reviewed and meta‐analyzed the literature following the PRISMA 2020 guidelines (PROSPERO #alz064082). We searched in the PubMed and Web of Science databases for studies reporting quantitative or semi‐quantitative data of GABA, and GABAergic transporters, receptors, and synthesis enzymes. The participants included were AD subjects and age‐matched cognitively unimpaired (CU) individuals. The effect sizes were determined via the standardized mean difference (SMD) using Hedge’s g method with random effects. The percentage of heterogeneity between studies was estimated using I2 test. Data are presented as SMD [95% CI], I2 %.

Result

The search identified 3,223 papers (Figure 1). Forty‐nine records met the inclusion criteria (a total of 667 AD patients, mean age 75.4, and 584 CU subjects, mean age 72.4). Here, we present results obtained in the CSF, blood, and different brain regions in which more than five studies have been meta‐analyzed. GABA levels were decreased in the CSF (‐0.42 [‐0.74, ‐0.1], p<0.0001, 0%), temporal cortex (‐0.97 [‐1.38, ‐0.55], p<0.0001, 54.6%), occipital cortex (‐1.03 [‐1.86, ‐0.2], p=0.015, 78%), and striatum (‐0.58 [‐1.09, ‐0.07], p=0.025, 0%), but not in the blood (‐0.64 [‐1.39, 0.11], p=0.092, 64.2%), frontal cortex (‐0.49 [‐1.06, 0.08], p=0.09, 73.1%), and hippocampus (‐0.39 [‐0.8, 0.03], p=0.068, 24.7%); GABA A receptor availability was decreased in the frontal (‐0.74 [‐1.44, ‐0.05], p=0.037, 50.5%) and temporal cortices (‐0.73 [‐1.15, ‐0.3], p=0.001, 7.4%), but not in the hippocampus (‐0.79 [‐1.64, 0.06], p=0.068, 66.9%). Figure 2 provides a summary of our findings.

Conclusion

Our results demonstrated a decrease of GABAergic system components in multiple brain regions and low levels of GABA in the CSF of AD subjects compared to age‐matched CU individuals, pointing to an important role played by GABAergic neurotransmission in the pathophysiology of AD.
Precision estimates of Relative and Absolute Cerebral Blood Flow in Alzheimer’s disease and Cognitively Normal individuals
Authors: Heeman Fiona , Visser Denise , Yaqub Maqsood , Verfaillie Sander C.J. , Timmers Tessa , van der Flier Wiesje M. , van Berckel Bart NM , Boellaard Ronald , Lammertsma Adriaan A. , Golla Sandeep SV
Published: December 2022

Background

Alzheimer’s disease is characterized by regional reductions in cerebral blood flow (CBF) and the gold standard for measuring CBF is [15O]H2O PET. Recently, proxies of relative CBF, derived from the early distribution phase of amyloid‐β and tau tracers, have gained attention. It has been hypothesized that relative CBF is likely to have higher precision (but not accuracy) than absolute CBF, as global variations in CBF are cancelled out. The present study assessed precision of [15O]H2O PET derived relative and absolute CBF measures, and compared them with relative CBF proxies estimated from [18F]florbetapir and [18F]flortaucipir scans.

Method

Dynamic [15O]H2O, [18F]florbetapir and [18F]flortaucipir test‐retest (TRT) PET datasets were included, consisting of eleven cognitively normal (CN) individuals for [15O]H2O, four CN and five AD participants for [18F]florbetapir, and six CN and eight AD participants for [18F]flortaucipir. [15O]H2O data were analysed using the standard single tissue compartment model and [18F]florbetapir and [18F]flortaucipir using the simplified reference tissue model (SRTM). Relative CBF (i.e. K1/K1’) was derived from absolute CBF (i.e. K1 of [15O]H2O) or estimated using SRTM (i.e. R1), in all cases using cerebellar cortex as reference tissue. CBF values were obtained for 22 cortical grey matter regions and TRT variability (eq.1) was calculated for all metrics. Differences (%) between test and retest measures were assessed using Bland‐Altman analysis and TRT variability for different tracers and between diagnostic groups were compared using Wilcoxon Signed‐Rank and Mann‐Whitney U‐tests.

Result

Average differences (M±SD) between test and retest measures were small for relative measures, [15O]H2O K1/K1’:‐2.0±7.8%, [18F]florbetapir R1:‐1.7±4.1%, [18F]flortaucipir R1:‐0.1±4.2%, but somewhat larger for [15O]H2O K1:‐5.7±14.6%,(Fig.1). In case of [15O]H2O, TRT variability was lower for K1/K1’ than for K1 (p<0.001). Furthermore, [18F]florbetapir and [18F]flortaucipir derived R1 showed lower TRT variability than [15O]H2O K1/K1’ (p<0.001). Only for [18F]flortaucipir, TRT variability was higher in the AD compared with the CN group.

Conclusion

Relative CBF has higher precision than absolute CBF derived from [15O]H2O PET scans. Furthermore, relative CBF proxies derived from commonly used amyloid‐β and tau tracers appear to have an even higher precision, possibly due to the compensatory effect of extraction fraction and/or the older scanner used for [15O]H2O scans.
COVID‐19‐related loneliness, social isolation and burden in informal caregivers worldwide
Authors: Chen Yaohua Sophie , Almirall‐Sanchez Arianna , Ilinca Stefania , Grycuk Emilia , Higgins Dawn , Leon Tomas , McGlinchey Eimear , Rogan Carol , Saha Sanjib , Tjin Anna , Galvin Miriam , O'Sullivan Roger , Lawlor Brian , Leroi Iracema
Published: December 2022

Background

Informal caregivers may experience high levels burden. Prior to COVID‐19, loneliness and social isolation, and especially the discordance between them, were recognized for rapid aging‐related cognitive decline. The COVID‐19 has significantly increased social isolation and loneliness in caregivers. Thus, we aimed to explore the variables that were associated with higher care burden among all caregivers and only among caregivers for people living with dementia, and whether the increased burden could be associated with a discrepancy between loneliness and social isolation.

Method

‘Comparing Loneliness and Isolation in COVID‐19’ was an online global survey of over 20,000 respondents, including 5243 caregivers across 50 countries with enduring brain or/and physical health conditions. We first used a multilevel modelling to identify risk factors associated with higher burden. Then, we defined profiles of discrepancy between loneliness and social isolation, based on the differences between standardized score on a scale of loneliness and of social connectedness and estimated the association between the discrepancy and higher burden.

Result

In our sample, 74% of caregivers were female, 44% were caring for people with dementia, and 22% for people with multiple conditions, including dementia. The most prevalent age group was 60‐69 years old. Factors significantly associated with higher care burden were being female, having poorer financial situation, worse mental health during the pandemic, caring for people with dementia or intellectual disabilities, caring in the same home, being diagnosed with COVID, and changes of care abilities. 40% of caregivers consistently reported high level of loneliness and social isolation, 38% reported consistent lower levels of both, and two groups reported discordance (low levels of loneliness and high social isolation in 13%; high levels of loneliness and mild social isolation in 12%). The latter group was at the highest risk of self‐reported increased and intense care burden.

Conclusion

This represents the largest, most widespread survey on the impact of the COVID‐19 pandemic on caregivers of people with long‐term conditions to date and reflects the importance of capturing the nuances in the relationship between loneliness and social isolation in caregivers. It will be an important resource for support agencies and to inform policy.
Experiences of English‐speaking care partners of individuals with brain health conditions during COVID‐19: a qualitative analysis
Authors: Rogan Carol , Higgins Dawn , Chen Yaohua Sophie , Grycuk Emilia , Wormald Andrew , Leroi Iracema , Galvin Miriam
Published: December 2022

Background

Public health restrictions due to the COVID‐19 pandemic have affected care partners of people living with dementia and/or mental health conditions. This qualitative study explores care partners’ ability to offer care, and changes and interruptions to care provision during the period of the COVID‐19 pandemic (2020) in English‐speaking regions worldwide.

Method

As part of an international cross‐sectional online survey, qualitative data were collected from over 1,000 English‐speaking care partners of people living with dementia and/or mental health conditions. Responses to an open‐ended question about ability to care were coded and analysed thematically. The analysis was undertaken by three independent interdisciplinary coding dyads.

Result

A number of main themes and subthemes were generated through the analysis. Reduced in‐person contact with the person with a brain health condition and restrictions in health and social care services created practical, psychological and emotional impacts for care partners. The lack of adequate information from health/social care services, deterioration in the condition of the person living with a brain health condition, and additional care hours/duties were identified. Care partners also mentioned the fear of virus transmission and increased awareness of public health measures as factors that changed or interrupted their ability to provide care.

Conclusion

The ability of care partners to provide care was changed or interrupted, and disruption to routines and services available impacted on their well‐being. These findings reflect the complexity of the care partner role and highlight the importance of supporting care partners, in particular during periods of service restrictions such as those experienced as a result of the pandemic. Findings will be of interest to policymakers and service providers.
An Analysis of Factors Influencing Dementia Study Enrollment: Focus Groups with Diverse Community Members Viewing the ACTNOW Research Registry Website
Authors: Tran Leslie , Nunnerley Michael , Gothard Sarah , Golonka Ona , Pierce Aimee , Lindauer Allison
Published: December 2022

Background

Many barriers discourage individuals from enrolling in dementia research studies, such as lack of information, web accessibility, and transportation. Research stakeholder feedback is necessary to understand these barriers. We used virtual focus groups to learn how to improve the website of our local research registry: ACTNOW (Alzheimer’s Comprehensive Treatment Network of Oregon and Washington). Local community members from diverse backgrounds interacted with the study team to provide insight on some of the roadblocks to research participation. Here, we report on findings from the focus groups and participants’ feedback related to the ACTNOW website and user engagement.

Method

Three 90‐minute virtual focus groups (fg) were conducted with 19 participants via videoconferencing. Inclusion criteria were ACTNOW members, African American, and low‐income and rural‐dwelling individuals combined respectively. Participants completed pre‐and post‐focus group surveys about their thoughts on the ACTNOW website and interest in dementia research. Investigators from the research team analyzed the survey data and independently coded the written transcripts from the group discussions using the Dedoose coding software.

Result

There were 19 participants overall (fg_1=8, fg_2=5, fg_3=6). The mean age was 66.9; 89.5% of the sample was female; and 57.9% were white. The analysis revealed that the participants had concerns about the readability of the website and the clarity of purpose of ACTNOW (e.g., “I look at this, and I say, whoa, wait a minute they want me to sign up for what?”). Most of the topics discussed suggested consumers did not understand the purpose of the website or ACTNOW’s promotional materials, resulting in a fear of signing up for the actual program (research registry). Survey data reported a large interest in dementia research but a need for more consumable, relevant information, such as explaining the benefits of research and requirements of being an ACTNOW member.

Conclusion

Findings demonstrate specific website usability challenges and reasons that prevent community members from signing up for dementia research. Understanding the focus group participants’ feedback is important in fostering greater diversity, appeal, and accessibility in dementia research.
The systemic disruption of P2rx7 alleviates tau pathology in P301S tau mice via inhibition of extracellular vesicle release
Authors: Abdullah Mohammad , Ruan Zhi , Bueser Katrina Rae , Ikezu Seiko , Ikezu Tsuneya
Published: December 2022

Background

P2X purinoceptor 7 (P2RX7), an ATP‐gated cation channel present abundantly in the microglia, induces membrane depolarization and extracellular vesicle (EV) secretion. Previous study demonstrated that administration of GSK1482160, a P2RX7 selective inhibitor, suppressed EVs secretion from murine microglia resulting in accumulation of Tsg101+ intraluminal vesicles (ILVs) in the hippocampus, and restored partial behavioral deficits in P301S tau mice. However, the specificity of GSK1482160 to P2RX7 has never been investigated in P301S tau mice. It is crucial to validate whether P2RX7 is a potential target for alleviating the tauopathy phenotype in P301S tau mice. The purpose of this study is to determine if deletion of P2RX7 is sufficient to recapiturate the therapeutic effect of GSK1482160 in tauopathy mouse model.

Method

Fours and nine‐months‐old P2RX7‐/‐:P301S and P301S mice were generated for the evaluation of ILV accumulation and tau pathology. Primary microglia and astrocytes from WT (C57BL/6) and P2RX7‐/‐ mice, treated with GSK1482160 and ATP for EV secretion. EVs were isolated from conditioned media via the sequential centrifugation and ultracentrifugation. Finally, EVs were quantified by nanoparticle tracking analysis and exosome specific marker CD9 ELISA. Effects of GSK1482160 on EVs secretion from astrocytes/microglia were also assessed using Western blot with EV specific markers Tsg101 and CD9.

Result

Exosome specific marker Tsg101, CD9, and tau expression levels were reduced in the hippocampus of nine‐months‐old P2RX7‐/‐:P301S mice compared to P301S mice. No significant difference between the two groups at 4 months of age was observed. Strikingly, primary cultured microglia and astrocytes showed reduction in EV secretion in both ATP stimulated or unstimulated condition from P2RX7‐/‐ group compared to WT group. Additionally, GSK1482160 pretreatment significantly reduced EV secretion from WT astrocytes and microglia, although it had no effects in P2RX7‐/‐ cells. These findings were validated by ELISA of EV marker CD9 and immunoblotting of Tsg101 and flotillin‐1 using isolated EVs.

Conclusion

Results demonstrate that P2RX7 is primarily responsible for ATP‐induced EV secretion from astrocytes and microglia, and systemic disruption of P2RX7 mimics the effect of GSK1482160 in P301S tau mice, including accumulation of ILVs in microglia and suppression of tau accumulation in the hippocampal regions.
RNA Analysis of Laser‐Captured Neurons, Microglia and Astrocyte After Intracerebroventricular Injection of Neural Stem Cell‐Derived Exosomes
Authors: Saieva Salvatore , Guptarak Jutatip , Zhang Wenru , Johnson Kathia M , Micci Maria‐Adelaide , Taglialatela Giulio
Published: December 2022

Background

Neural stem cells (NSC) and adult neurogenesis are known to modulate synaptic plasticity and cognitive function. Decreased number of NSC have been reported in Alzheimer’s Disease (AD), whereas their increase is associated with improved learning and memory. However, an increased neurogenesis does not correlate with preserved cognition, thus suggesting that other mechanisms involving increased numbers of NSC promote the preservation of memory. NSC are also known for their capacity to secrete exosomes, microvesicles containing cell‐specific cargos of biomolecules, that are taken up by other cells, thus modulating their function. We and others have shown that NSC‐derived exosomes (NSCexo) injected in brains of AD transgenic mice models ameliorated the cognitive decline and decreased the binding of toxic oligomers to synapses. The mechanisms by which NSCexo provide protection to synapse is still under investigation. Our long‐term goal is to find the specific genes modulated by NSCexo that may be responsible for the cognitive resilience and the overall improvement of CNS function. With this goal in mind, here we determine the cell‐specific (neuron vs. glia) uptake of NSCexo and subsequent cell‐specific changes in gene expression.

Method

C57Bl/6 mice received fluorescent‐labeled NSCexo via intracerebroventricular injection; after collection of brain samples, immunofluorescence on brain slices were performed to identify neurons, astrocytes and microglia. The colocalization of NSCexo with neuronal, astrocytic and microglial markers was evaluated. The single cell types were subsequently laser‐captured, and their RNA was isolated. Single‐cell RNA analysis was performed to investigate differences in RNA expression comparing not‐injected and injected animals.

Result

We found that NSCexo are taken up preferentially by neuronal cells, but also astrocyte and microglia, thus leading to the modulation of relevant gene expression. Interestingly, we also found a pronounced uptake of NSCexo in the sub‐granular area of the hippocampus dentate gyrus, likely by NSCs.

Conclusion

Our results suggest targeting of neurons (and to a lesser extent, astrocyte and microglia) by NSCexo. They also suggest important targeting of NSC themselves, in what appear to be an autocrine signaling mechanism deserving further in‐depth investigation. Collectively, these mechanisms may play a key role in the reported involvement of decreased NSC and neurogenesis in AD.
Study: A Retrospective Claims Analysis of Preventable Hospitalizations Among Wisconsin Medicaid Beneficiaries with Dementia ‐ 2016 Through 2019
Authors: Felten Kristen M. , Steinmetz Cory
Published: December 2022

Background

Older adults with Alzheimer’s Disease and Related Dementias (ADRD) are often more vulnerable to severe illness and injury than older adults without ADRD. A percentage of the causes of these hospitalizations are considered preventable with good care management. To quantify the impact of the resulting preventable hospitalizations, the Wisconsin Department of Health Services has performed an evaluation using claims data in a retrospective analysis.

Method

Using Wisconsin Medicaid claims records from the beginning of 2016 through the end of 2019, leading preventable causes of hospitalization among older Medicaid beneficiaries were identified, and rates of hospitalization for those with ADRD were compared against those without ADRD. Hospitalizations with certain diagnostic codes were considered “preventable” if timely outpatient care or simple precautions are known to resolve or avoid intensive hospital care. Direct costs to Medicaid for hospital stays were also tabulated, as well as differences by race/ethnicity and living arrangements.

Results

Preliminary aggregate results indicate higher rates of preventable hospitalization for older beneficiaries with ADRD than those without ADRD, especially for sepsis, urinary tract infections, and pneumonia. Rates of hospitalization were higher for racial and ethnic minority populations than for the white population, and an ADRD diagnosis was a larger risk factor for hospitalization in home and assisted living settings compared to a nursing home setting.

Conclusion

The cost to the health of the person with dementia, the cost to the family, and health care costs associated with a few key preventable conditions is extraordinary and unnecessary. Use of this data can drive the development of policies and practices that address risk factors for these conditions that could improve the quality of life for the person living with dementia by preventing unnecessary illness and/or injury, but could also lower unnecessary costs for families and health care systems.
Neuroimaging Findings in a Racially and Ethnically Diverse Cohort of Oldest‐Old Individuals: The LifeAfter90 Study
Authors: Corrada Maria M. , Gilsanz Paola , Tran Diana , Al‐Darsani Zeinah , Mungas Dan M. , Glymour M. Maria , Kawas Claudia H. , DeCarli Charles S. , Whitmer Rachel A.
Published: December 2022

Background

Neuroimaging biomarkers are important and widely used in dementia research. Such studies, however, are rare in the oldest‐old and essentially non‐existent in ethnically diverse oldest‐old populations where the prevalence of cognitive impairment is greatest and dementia due to multiple pathologies. Here we present initial neuroimaging findings in the LifeAfter90 Study, a racially and ethnically diverse cohort of oldest‐old individuals.

Methods

LifeAfter90 is a cohort of long‐term members of a health‐care system aged 90+ without a dementia diagnosis in their medical record at recruitment and clinical assessments every 6 months. Of the >800 participants enrolled, a subset agreed to brain imaging (MRI and amyloid PET). Hippocampal volume (HV) and white matter hyperintensities (WMH) were normalized to intracranial volume and WMH was log transformed. Amyloid burden was quantified as the mean SUVR values of 4 regions and dichotomized with an SUVR cutpoint of 1.10. Mean neuroimaging marker levels were compared between ethnoracial groups with analysis of covariance adjusting for age.

Results

To date, 99 individuals have undergone an MRI and 90 an amyloid PET scan. The average age at the time of scan was 93 years, 60% of participants were women, and 43% had college education or higher (Table 1). Unadjusted values of neuroimaging findings are in Table 1 and adjusted means in Table 2 and Figure. In our preliminary data, we see 44% amyloid positivity overall. Black individuals have the lowest proportion of amyloid positivity (32%) but among the highest WMH mean volume, whereas Latino individuals have the highest proportion of amyloid positivity (64%) and lowest WMH mean volume. Asian individuals had the highest mean hippocampal volume. Except for SUVR differences in Black vs Latino individuals (p=.04), there were no group differences in mean levels (Figure).

Conclusions

We present neuroimaging findings from a first‐of‐its kind multi‐ethnic cohort study of oldest‐old individuals. Although too early to test for differences due to the small number of individuals, we have indications of ethnoracial differences in levels of neuropathologies consistent with those of younger elderly. Determining the utility of neuroimaging biomarkers for identifying future disease in these individuals is essential for advancing cognitive research.
The COEQUAL Registry: Creating Opportunities to Increase Health Equity & Equality for Persons at Risk for AD/ADRD
Authors: Balls‐Berry Joyce E , Mozersky Jessica , Postman Whitney , Denny Andrea , Xiong Chengjie , Kannampallil Thomas , Thompson Vetta Sanders , Hassenstab Jason J. , Gabel Matthew , Hill Carl V. , Saunders John , O'Leary Catina , Griffin Stephanie , Johnson Charis , Moulder Krista L. , Morris John C.
Published: December 2022

Background

Communities with the highest disease burden from Alzheimer’s disease and related dementias (ADRD) often experience considerable health disparities. These disparities are due to systematic and structural racism, classism, ageism, and social determinants of health, leading to distrust of and lower engagement with biomedical research. These injustices exacerbate disparities, ultimately leading to less generalizability of research findings. Therefore, we hypothesized that creating a culturally appropriate ADRD research registry called COEQUAL would increase underrepresented communities' engagement in ADRD research.

Methods

Our NIH‐funded community and patient‐engaged study aims to identify and enhance current practices to promote high‐yield engagement and retention of diverse participants in ADRD research in St. Louis, Missouri. Based at the Washington University Knight Alzheimer’s Disease Research Center, our partners include Saint Louis University, Wesley House (a social service organization), the Greater Missouri Chapter of the Alzheimer’s Association, and Health Literacy Media. We have a 20‐member Governance Board to create a culturally appropriate research registry. Before creating the COEQUAL registry, we plan to conduct a community needs assessment with listening sessions and a pre/posttest survey of n = 160 community members, patients, caregivers, and healthcare providers aged 45+. We will use direct/indirect recruitment methods like posts in the health system patient portal, social media, and emails/mailers to recruit participants. Our facilitator’s guide and a pre/posttest survey will contain validated and culturally appropriate items to gauge perceptions, practices, and knowledge related to ADRD, willingness to participate in an ADRD research registry, and ways to engage and retain diverse participants. We will oversample participants who self‐identify as Black (African American, African, African Caribbean, or African Ancestry). Findings from the community needs assessment will be used to inform recruitment, ongoing engagement with, and retention of, individuals in ADRD research.

Result

We anticipate gaining knowledge of the perceptions and practices of engaging community members, patients, and providers in creating a culturally appropriate ADRD research registry.

Conclusion

The feasibility of creating a culturally appropriate ADRD research registry in St. Louis is critical to ensure justice and generalizability in research. Moreover, using a community and patient‐engaged research approach increases the cultural appropriateness of ADRD research.
Which NODDI implementation is nicest for diffusion MRI?
Authors: Reid Robert I. , Kamykowski Michael G. , Gebre Robel K , Jack Clifford R. , Vemuri Prashanthi
Published: December 2022

Background

Neurite Orientation Dispersion and Density Imaging (NODDI) is becoming increasingly common as multiband acceleration becomes available for clinical scanning, but fitting the model can be extremely slow. Since the release of the original MATLAB implementation in 2012, three alternatives have become popular: Accelerated Microstructure Imaging via Convex Optimization (AMICO), the Microstructure Diffusion Toolbox (MDT), and the CUDA Diffusion Modelling Toolbox (cuDIMOT). They accelerate fitting through reformulation and/or using GPUs, but the implementation differences raise the question of which approach is best. To our knowledge all previous comparisons lacked knowledge of the true values and used the original implementation as the nominally correct one, with in vivo data. We remedy that using simulations with known NODDI values, in addition to in vivo scans.

Method

We created a software phantom with Neurite Density Index (NDI) values linearly increasing from 0.1 to 1.0 in x, Orientation Dispersion (ODI) from 0 to 1 in y, and Isotropic water Volume Fraction (ISOVF) from 0 to 0.9 in z. We simulated five scans using the ADNI3 advanced diffusion MRI protocol. The phantom had 20 voxels in each direction, and the fiber bundle principal direction randomly varied between the simulations. The simulations were fit by the original, AMICO, MDT, and cuDIMOT implementations, and root mean square errors were calculated as shown in Table 1. A discrepancy measure was also calculated using the brain voxels of three in vivo human scans acquired using the same protocol on a Siemens Prisma, substituting the original implementation’s values for the truth since the latter is unknown for in vivo scans.

Result

cuDIMOT had the least error (for ODI < 0.8) and was fastest. The original implementation was a close second in accuracy but much slower. cuDIMOT’s ODI underestimation can be corrected with a transfer function in the noise‐free case, but that approach fails with actual scans.

Conclusion

The original or cuDIMOT implementations should be used, with cuDIMOT the favorite when at least one CUDA‐capable GPU is available and the number of scans are large. Correcting cuDIMOT’s ODI underestimation using a different initialization or form of Dawson’s integral should be investigated.
MRI norm percentile in age‐related atrophy starts from MCI stage
Authors: Arakaki Xianghong , Butler Ryan , Kang Jimmy , Macias Thomas , Chui Helena C , Nolty Anne , Spezzaferri Mitchell , Sin Caleb , Rising Shant , Molloy Cathleen , Kloner Robert A , Fonteh Alfred N.
Published: December 2022

Background

Age related atrophy occurs in Alzheimer’s disease and related dementia (ADRD). Although atrophy was reported in early stage as mild cognitive impairment (MCI), the knowledge about earlier changes is limited. To fill this knowledge, we explored the age‐related atrophy in our pilot MRI database when participants at different stages of ADRD.

Method

MRI data are analyzed using NeuroQuant. We studied MRI data in cognitively healthy (CH, n=74) individuals when their cerebrospinal fluid (CSF) amyloid/tau ratios were normal (CH‐NATs, n=18) or pathological (CH‐PATs, n=41), in participants with impaired or MCI (n=9), and Alzheimer’s disease (AD, n=6), and other dementia (OD, n=6). We explored age, gender‐corrected norm percentiles for atrophy analysis in age‐related structures – (including hippocampal occupancy score (HOC, percent of hippocampi volume relative to inferior lateral ventricle volume), hippocampi, entorhinal cortex, and inferior lateral ventricles) and whole brain, cerebral white matter. We compared the data between CH, MCI, AD, and OD, compared between CH‐NATs and CH‐PATs, and compared between CH with cerebrospinal fluid (CSF) amyloid pathology (ChA+, n=15) and CH without CSF pathology (ChA‐T‐N‐, n=13) based on CSF Aβ42, phosphor‐tau (p‐tau), and total tau (t‐tau). Bonferroni correction was used for Multiple comparisons.

Result

Analysis of MRIs collected at HMRI show neuro‐quantitative data in CH participants compared to MCI, AD, or OD, and MCI to AD and OD. Compared to CH, MCI have decreased HOC and larger superior lateral ventricle (Table 1, Figure 1), AD have decreased HOC, hippocampi, whole brain, and cerebral white matter, and larger lateral ventricles, OD have similar changes except hippocampi (no change). No significant changes observed between MCI and AD or OD. No significant changes were observed between CH‐NATs and CH‐PATs, or between ChA+ and ChA‐T‐N‐.

Conclusion

Despite sample size limitation, these results suggest: 1) norm percentile is sensitive to age‐related atrophy at impaired stages, consistent with known changes; Whole brain volume decreases in AD and OD, only AD observed decreased hippocampal atrophy; 2) No apparent age‐related changes were observed in CH stage. Overall, MRI age‐ and gender‐corrected norm percentile for age‐related atrophy analysis is informative in individuals as early as MCI stage.
Sex differences in the protective effects of cognitive reserve
Authors: Chooi Cheyenne K , Gavett Brandon E , Weinborn Michael , Rainey‐Smith Stephanie
Published: December 2022

Background

Cognitive reserve is the term used to describe the apparent ability of one’s cognitive processes or neural networks to adapt in response to neuropathology and brain injury. This protective ability is proposed to account for individual differences in age‐associated cognitive decline and Alzheimer’s disease (AD) risk, where higher levels of cognitive reserve are associated with more preserved cognitive functioning and delayed onset of AD dementia. Women have a higher prevalence of AD than men, and account for two‐thirds of AD diagnoses. Sex differences in the protective ability of cognitive reserve may account for differences in Alzheimer’s disease prevalence between men and women, but few studies have explored this possibility. This study evaluates sex as a moderator of the relationship between cognitive reserve and brain volume effects on executive function.

Method

The study used archival data from 997 older adult participants in the Australian Imaging, Biomarkers, and Lifestyle(AIBL) Flagship Study of Ageing (see Table 1 for descriptives). Structural equation modelling was used to estimate a proxy for cognitive reserve and to run the analytical model. Cognitive reserve was defined as the variance in episodic memory not explained by demographics (e.g., education) and brain integrity (i.e., the residual reserve index; Reed et al., 2010). Executive functioning intercept and slope – derived from up to 7 study visits (18‐month follow‐up intervals) – were regressed onto the main and interaction effects of the residual reserve index, brain integrity (i.e., the combination of grey matter, hippocampal, and white matter hyperintensity volumes), and sex, plus covariates (e.g., number of apolipoprotein alleles; age).

Result

A significant three‐way interaction was observed between cognitive reserve, brain integrity, and sex; Women benefitted more than men from the protective effects of cognitive reserve at comparably low levels of brain integrity. Further analyses also showed that women, on average, have higher levels of cognitive reserve as reflected by the residual reserve index.

Conclusion

Sex differences in cognitive reserve highlight a potential sex‐related mechanism by which cognitive reserve confers protection against cognitive decline in the face of low brain integrity. These findings further our understanding of potential factors that maximise the protective effect of cognitive reserve.
Neuropsychiatric symptoms impact associations between plasma neurofilament light and cognition in individuals with Lewy body pathology, but not in Alzheimer’s disease.
Authors: Ortiz Gema , Weigand Alexandra J. , Cooper Shanna , Smirnov Denis S. , Salmon David P. , Galasko Douglas R. , Bangen Katherine J. , Thomas Kelsey R.
Published: December 2022

Background

Lewy body disease (LBD) is one of the most prevalent causes of dementia following Alzheimer’s disease (AD). Plasma neurofilament light chain (NfL) is a marker of neuroaxonal degeneration associated with cognitive decline in LBD, AD, and other neurodegenerative disorders. Neuropsychiatric symptoms are often present in both LBD and AD and can affect quality of life and cognitive performance. Therefore, we investigated whether the association between plasma NfL and cognition was moderated by the severity of neuropsychiatric symptoms in LBD and AD.

Method

Participants from the UCSD Shiley‐Marcos Alzheimer’s Disease Research Center with data for the informant‐reported Neuropsychiatric Inventory (NPI), plasma NfL, and AD and/or LBD neuropathology at autopsy were included (n = 204). General linear models examined whether the influence of neuropsychiatric symptoms on the association between plasma NfL and cognition at the last assessment prior to death varied by neuropathology. Participants with LBD only (n = 22), LBD+AD (n = 59) and AD only (n = 123) were included. Covariates included: age, education, sex, APOE ε4 carrier status, cognitive classification (unimpaired, MCI, or dementia), and time from last assessment to death. Given similar patterns of results for the LBD and LBD+AD pathology groups, they were combined for the final analyses. The Dementia Rating Scale (DRS) was used as the cognitive outcome measure.

Result

The three‐way NfL x NPI x pathology interaction was significant (p = .019, η p 2 = .029). In the LBD+AD group, neuropsychiatric symptoms moderated the relationship between plasma NfL and DRS total score (p = .013, η p 2 = .084) such that higher NPI scores had a more negative association between NfL and DRS (total score as well as attention, initiative/perseveration, and memory subscales). Although there was an association between NfL and DRS total score in the AD‐only group, this was not moderated by NPI score (p = .460, η p 2 = .005).

Conclusion

These results highlight the importance of considering neuropsychiatric symptoms when examining the relationship between NfL and cognition, particularly in patients with suspected LBD pathology. Neuropsychiatric symptoms differ in LBD and AD, so future work will examine whether specific symptoms that are more prevalent in LBD, such as apathy, are driving the observed relationships.
The pharmaceutical potential of AR‐65, a novel Alzheimer’s disease drug targeting the immunoproteasome
Authors: Park Ji Eun , Bhattarai Deepak , Park Yujin , Lee Min Jae , Son Sumin , Kim Dong‐Eun , Kim Kyung Bo
Published: December 2022

Background

Previously, we reported that inhibition of the immunoproteasome (iP), which is upregulated in reactive glial cells near amyloid‐β (Aβ) deposits in the brains of patients with Alzheimer’s disease (AD), leads to improved cognitive function in an AD mouse model of Aβ amyloidosis (Tg2576) via suppression of microglia‐mediated inflammation, independent of Aβ accumulation.

Method

Here, we investigated the pharmaceutical properties of our lead iP inhibitor (AR‐65), a macrocyclic peptide epoxyketone, selected based on in vitro and cellulo iP inhibitory activities and cell‐based anti‐inflammatory efficacy. Specifically, the metabolic stability of AR‐65 was assessed using pooled human liver microsomes. In addition, the flux rate of AR‐65 was measured to evaluate the permeability across Caco‐2 monolayers over‐expressing ABCB1 and ABCG2, two major efflux drug transporters present in the human brain.

Result

The macrocyclic AR‐65 displayed improved metabolic stability (6‐fold increased half‐life), permeability, and solubility (in an injectable pharmaceutical buffer system with no cyclodextrin) compared to the FDA‐approved linear peptide epoxyketone proteasome inhibitor, carfilzomib (Kyprolis®). Finally, pilot PK studies performed using ICR mice confirmed that AR‐65 is metabolically more stable than carfilzomib and can cross the blood‐brain barrier to inhibit the brain iP.

Conclusion

Taken together, the results suggest that AR‐65 may hold great potential to be further investigated in clinical settings.
Interest in and perceived benefits and risks of Alzheimer’s disease clinical and biomarker results disclosure among diverse participants and care partners
Authors: Feldman Sara J , Lesniak Mary , Milliken Marie , Sadaghiyani Shima , Roberts J. Scott , Hampstead Benjamin M. , Rahman‐Filipiak Annalise
Published: December 2022

Background

Alzheimer’s disease (AD) biomarker disclosure is a potential avenue for tailoring person‐centered care for patients and families and targeting known health disparities. However, disclosure cannot take a one‐size‐fits‐all approach. It is critical to understand whether older adults with and without cognitive impairment (i.e., mild cognitive impairment (MCI)) and their care partners are interested in engaging in biomarker disclosure, and what perceived benefits and risks exist, as a function of race, social determinants, and clinical status.

Method

57 participant‐care partner dyads [participants: 56.1% female; 36.8% Black, 74.3±5.98 years, 42.1% with MCI; partners: 79.0% female; 33.3% Black, 66.9±10.9 years] completed a semi‐structured interview assessing demographic factors, healthcare access, economic stability, social support, and perspectives on AD biomarker disclosure. Fisher’s exact tests were used to assess participant and partner characteristics associated with interest in, and perceived benefits and risks of the participant engaging in results disclosure. Differences in participant and care partner responses were evaluated using two‐sample t‐tests.

Result

When asked to select the main benefit and disadvantage of knowing AD risk (out of 9 benefits and 10 disadvantages), participants and partners described varied benefits. Participants and partners both endorsed having the opportunity to engage in Alzheimer’s disease treatments and/or clinical trials (23.2% v. 29.8%), followed by having the opportunity to inform long‐term care plans (14.3% v. 17.5%) and learning more about the participants’ health (12.5% v. 15.8%) as primary motivators for engaging in biomarker disclosure. In contrast, the majority of participants (80.8%) and partners (82.1%) endorsed no perceived disadvantages of learning the participants’ biomarker information for risk of dementia‐Alzheimer’s Type. Nearly all dyads endorsed moderate to strong interest in cognitive test results (96.5% participants; 93.0% partners), structural neuroimaging (94.8%; 89.4%), genotyping (94.8%; 87.7%) and protein biomarker disclosure (98.3%; 87.7%). Interest was not associated with diagnosis, race, or social determinants of health.

Conclusion

Participants and care partners endorse almost universal interest, varied benefits and few disadvantages of learning the participant’s AD biomarker results. Pre‐disclosure education and decisional‐capacity assessment are needed to ensure informed decision‐making. Further data on how social determinants may influence motivations for, reactions to, and risks of AD biomarker disclosure are needed.
African Americans' intentions to share their Alzheimer’s preclinical biomarker results with loved ones in a hypothetical vignette: the importance of support persons
Authors: Ketchum Fred B , Erickson Claire M , Chin Nathaniel A. , Gleason Carey E. , Clark Lindsay R.
Published: December 2022

Background

Literature on factors influencing the decision to enroll in Alzheimer’s biomarker research increasingly indicates that study partners are important to this decision. Limited research suggests participants are comfortable sharing their biomarker results within close relationships in the context of clinical trials. It is unknown how participants feel about sharing results in non‐clinical trial studies, which may be similar to future clinical settings in which risk information may be shared without an available clinical trial. Our objective was to understand whether and why prospective participants in preclinical AD biomarker studies intend to share their results. Because most preclinical biomarker research lacks adequate representation of African American and other racially and ethnically minoritized individuals, we focus our analysis on African Americans.

Methods

We enrolled African Americans (N = 145) between 46‐85 years of age from the Wisconsin Alzheimer’s Disease Research Center Clinical Core or the Wisconsin Registry for Alzheimer’s Prevention. After hearing a vignette describing a hypothetical biomarker research study, participants indicated how likely they would be to share their biomarker results with loved ones using a 5‐point Likert scale, and then provided open‐ended responses. Using qualitative content analysis, we identified themes that motivated and discouraged sharing results.

Results

72% of participants were either ‘very’ or ‘extremely’ willing to share their biomarker results with loved ones. The most common reasons motivating sharing results were so that their loved ones could support them and they could prepare together; so that their loved ones could monitor participants and understand cognitive changes they might experience; and to share important information about health. 16% would share the information selectively, and 12% were ‘not at all’ or ‘a little’ willing to share, for reasons including to avoid worrying their loved ones or concern about being treated differently.

Conclusion

Most participants wanted to share their biomarker results within close relationships. Increased understanding of motivations for sharing results may enable stronger support for both sides of this dyad. This in turn may suggest ways to increase participation in biomarker research and inform future research aimed at preparing to translate testing and disclosure into clinical practice, particularly among African Americans.
Participant education and preparedness in learning personal β‐amyloid PET results: Preliminary findings from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Erickson Claire M , Jonaitis Erin M. , Basche Kristin E , Chin Nathaniel A. , Johnson Sterling C. , Clark Lindsay R.
Published: December 2022

Background

Earlier detection of Alzheimer’s disease (AD) coupled with improved accessibility of testing means more adults may learn their biomarker results. To reduce potential negative psychosocial impacts and promote autonomy to act on the AD risk information to make lifestyle and advanced care planning changes, it is imperative that individuals understand the meaning of their results. The Wisconsin Registry for Alzheimer’s Prevention is disclosing β‐amyloid (Aβ) PiB‐PET results to a subsample of cognitively unimpaired older adult participants and assessing the impact of Aβ‐PET disclosure on psychological well‐being, health behaviors, and long‐term planning.

Method

Prior to learning Aβ‐PET results, participants (n = 64,age = 71.4±4.6) engaged in an education session. Participants were assessed on their baseline knowledge of AD and meaning of Aβ‐PET results utilizing a 15‐question quiz with multiple choice and true/false questions. Next, participants were guided through a 20‐minute interactive presentation describing AD and potential Aβ‐PET results. The same quiz was administered again to ensure adequate understanding. We assessed within‐person differences on pre‐ and post‐education quiz scores using paired t‐tests. The Views and Perceptions of Amyloid Imaging questionnaire surveyed reasons participants wanted to learn their Aβ‐PET results. Upon study completion, participants provided feedback on their experience and satisfaction with different elements of the education session.

Result

The most common reasons participants reported wanting to learn their Aβ‐PET results included to contribute to AD research (88.9% very‐extremely important) and to inform potential preventative measures (85.2% very‐extremely important). Post‐education quiz scores were on average two points higher than baseline scores (t = 10.2, df = 62, p<0.0001). Of those that have completed 6‐month follow‐up, over 90% agreed they understood the meaning of elevated and non‐elevated results and 73% agreed the educational materials were useful.

Conclusion

Even in this highly educated and research‐involved group, an education session improved knowledge about AD risk and amyloid PET results. As research further elucidates the relationship between preclinical biomarker accumulation and AD dementia risk, it will be important to effectively communicate findings with individuals who learn their AD biomarker results. Returning results can promote transparency and potentially goodwill with participants. However, responsible return of results must incorporate intentional efforts to ensure understanding of such information.