bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Functional Mobility Performances of People with Alzheimer’s Disease, Mild Cognitive Impairment, and Cognitively Healthy Individuals
Authors: Menengiç Kübra Nur , Ovacık Uğur , Güngör Feray , Bülbül Nazlı Gamze , Çınar Nilgün , Yeldan İpek
Published: December 2023

Background

One of the important factors that make it difficult to carry out activities of daily living independently is the decrease in functional mobility. Mobility‐related disability is a major public health issue that reduces the quality of life and increases the need for care, the burden, and the cost of care. However, in the early stages of dementia, the deterioration in motor skills is often overlooked. This study aimed to compare the mobility performance of healthy individuals and people with Mild Cognitive Impairment (pwMCI) and Alzheimer’s disease (pwAD).

Method

Cognitive level was measured with Montreal Cognitive Assessment (MoCA) and mobility performance was measured using Timed Up and Go Test (TUG) and 5 Times Sit to Stand Test (5XSTST). Statistical analysis was performed using One Way ANOVA in SPSS v.26 and the level of significance was accepted as p<0.05.

Results

36 pwAD (Age: 74.90±9.25, 53.12% Female), 14 pwMCI (Age: 63.82±12.55 years, 52.6% Female), and 10 cognitively healthy individuals (Age: 60.25±10.23 years, 82% Female) were included the study. The mean of MoCA scores were 12.62±6.36, 22.25±3.04 and 28.5±0.5; TUG results were 15.34±11.83 sec, 7.47±1.41 sec and 6.86±1.98 sec; 5XSTST results were 16,31±7.75 sec, 11.06±1.98 sec and 9.34±2.37 sec. A significant difference was found between the three groups in terms of TUG and 5XSTST results (p = 0.027, p = 0.015, respectively).

Conclusion

In pwAD and pwMCI, the decrease in cognition appears to be accompanied by impairment in functional mobility. Motor skills should be evaluated not only in AD diagnosis but also during the prodromal stage to provide early intervention for loss of motor function. Improving motor function should be added to rehabilitation goals before impaired functional mobility begins to affect activities of daily living.
Cognitive Training with Neurofeedback using fNIRS is Associated with Improved Cognition in Older Adults
Authors: Acevedo Bianca P , Collins Nancy , Ageiwa Kota , Kinoshita Mika
Published: December 2023

Background

This study examined the effects of a 4‐week cognitive training program with neurofeedback (CT‐NF) using fNIRS among 86 healthy, older adults.

Method

Participants were randomized to either a treatment (app‐based ABC games) or control (Tetris) group, and they all completed seven cognitive assessments, pre‐ and post‐intervention. Also participants received live feedback of their brain activity (neurofeedback using fNIRS) while doing their exercises.

Result

The treatment (ABC) group showed significant improvements in memory and composite cognitive function, while the control group did not. Cortical brain activity (measured during CT‐NF) was associated with both cognitive and game performance.

Conclusion

These findings suggest that CT‐NF and specifically ABC exercises, confer improved cognition in the domains of memory and overall cognitive function in healthy, older adults.
A biological age biomarker based on circadian rest‐activity rhythms and risk of dementia
Authors: Li Peng , Gao Lei , Sun Haoqi , Gao Chenlu , Cai Ruixue , Rutter Martin K , Hu Kun
Published: December 2023

Background

Circadian function is altered with aging, leading to changes in the ∼24‐h rhythms of behavior and physiology. Based on circadian rest‐activity rhythms (CRAR), we previously constructed a biological age biomarker to characterize the aging profile of circadian function—circadian age (CircAge)—in older adults (>65 years) and showed its association with risk of Alzheimer’s dementia. Here, we constructed CircAge in middle‐to‐older‐aged adults and tested whether it predicts all‐cause dementia.

Method

Participants from the UK Biobank with valid actigraphy data were studied (n = ∼97,000; 42‐78 years old). We developed a machine‐learning‐based regression model with 23 CRAR features derived from actigraphy (using cosinor, nonparametric, uniform‐phase‐empirical‐mode‐decomposition, and detrended‐fluctuation analyses). The fitting target was chronological age (ChrAge), and the prediction output was defined as CircAge. Model parameters were optimized using cross validation on 47,234 participants not performing shift work and without mental/behavioral or nervous system diseases. The optimized model was applied to all dementia‐free participants with valid CRAR (n = 80,805) to obtain their CircAge.

Result

CircAge was 1.03±0.01 years older per one‐year older in ChrAge that explained ∼25% of the variance of CircAge (p<0.0001). Male sex, European ethnicity, or having mental/behavioral/nervous system diseases were associated with a greater CircAge (all p<0.0001). We compared CircAge of current shift workers (n = 6,389) with that of matched non‐shift workers to examine whether CircAge captures CRAR perturbations and found that CircAge of current shift workers was 1.1±0.2 years greater (p<0.0001) than non‐shift workers. We then associated the difference between CircAge and ChrAge (DCC, = CircAge‐ChrAge) to incident all‐cause dementia using a Cox proportional hazards model adjusting for ChrAge, sex, ethnic groups, mental/behavioral diseases, and nervous system diseases. Results showed that greater DCC predicted higher adjusted risk of all‐cause dementia (n = 451): each decade higher DCC corresponding to a 1.10‐fold higher risk (95% CI: 1.02‐1.18; p = 0.009).

Conclusion

CRAR patterns can be translated into a biological aging biomarker for circadian function (CircAge), and greater CircAge than ChrAge is independently associated with risk of dementia in middle‐to‐older‐aged adults. Future studies are warranted to examine the use of CircAge (and/or in combination with other risk markers) for identifying at‐risk individuals in a clinical setting.
Artificial intelligence reveals brain aging patterns in 27,402 individuals without diagnosed cognitive impairment that are linked to genetics, biomedical measures, and cognitive decline
Authors: Skampardoni Ioanna , Nasrallah Ilya M. , Wen Junhao , Cui Yuhan , Abdulkadir Ahmed , Yang Zhijian , Erus Guray , Mamourian Elizabeth , Singh Ashish , Shou Haochang , Shen Li , Nikita Konstantina , Davatzikos Christos ,   iSTAGING consortium
Published: December 2023

Background

Understanding heterogeneity of structural brain changes in aging may provide insights into susceptibility to neurodegenerative diseases. We characterize the genetics underlying brain structural heterogeneity within cognitively unimpaired (CU) individuals using data‐driven machine learning applied to a diverse dataset of 27,402 individuals from 11 neuroimaging studies from the iSTAGING consortium.

Method

Structural brain morphologic patterns of CU individuals were independently examined in four decade‐long intervals spanning ages 45 to 85. Within each interval, Smile‐GAN (Yang et al., 2021) was trained on baseline anatomic and white matter hyperintensity (WMH) volumes. Smile‐GAN probability scores were used as phenotypes in genome‐wide association studies (GWAS). Specifically, we performed multiple linear regressions controlling for confounders (e.g., age) via Plink (Purcell et al., 2007). We observed longitudinal clustering stability across decades, so individuals from adjacent age groups were combined into broader age groups ([45,65), [65,85)) due to the large sample requirement of GWAS. Genomic loci, represented by the top leading single nucleotide polymorphisms (SNPs), were defined considering linkage disequilibrium. We investigated associations of SNPs with clinical traits and mapped them to genes using the GWAS Catalog (Buniello et al., 2019).

Result

Three structural brain aging patterns, relative to resilient agers (A0), consistent across decades, emerged: A1, or ‘typical’ aging with low atrophy and WMHs, and two ‘advanced’ aging patterns, one showing elevated WMHs and modest atrophy (A2) and the other displaying severe, widespread atrophy and moderate WMH load (A3) (Figure 1). GWAS discovered eight and six genomic loci in [45,65) and [65,85) age groups, respectively (Table 1, Figure 2). The lead SNPs for A1 and A2 were previously associated with several cardiometabolic risk factors, WMHs, and regional brain volumes. Interestingly, rs4843552, previously associated with white matter microstructure and regional brain volumes, showed opposite effects for A1 (protection) and A2 (risk), consistent with the neuroimaging patterns. WDR41 in A3 group was previously associated with the age of Alzheimer’s disease onset (Herold et al., 2016).

Conclusion

Reproducible neuroimaging patterns defined by regional atrophy and WMH burden were identified across CU individuals and demonstrated unique genetics. Further research is needed to elucidate the neuropathological pathways that mediate these relationships.
Biofluid phospho‐tau with subthreshold tau‐PET predicts higher rates of tau accumulation: implications for secondary prevention trials
Authors: Groot Colin , Smith Ruben , Stomrud Erik , Binette Alexa Pichet , Leuzy Antoine , Wuestefeld Anika , Wisse Laura EM , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Janelidze Shorena , Strandberg Olof , Ossenkoppele Rik , Hansson Oskar
Published: December 2023

Background

An important end‐point for disease‐modifying treatments is to target the accumulation of tau. This highlights the need to determine which individuals are most likely to accumulate tau in the future. Different biomarkers of tau become abnormal at different stages of Alzheimer’s disease and capturing the evolution of tau pathology in its entirety will rely on multi‐modal assessments. Here, we examine longitudinal changes in tau accumulation associated with elevated CSF p‐tau and tau‐PET biomarkers.

Method

A total of 231 amyloid‐positive (A+) individuals from the BioFINDER‐2 study were categorised into groups based on cut‐offs for abnormal CSF p‐tau217 (P) and [18F]RO948 tau‐PET (T), yielding groups of tau‐concordant‐negative (A+P‐T‐;n = 30), tau‐discordant (A+P+T‐;n = 48) and tau‐concordant‐positive (A+P+T+;n = 18) individuals. In addition, 135 amyloid‐β‐negative, unimpaired individuals served as controls. Differences in regional tau‐PET between groups were assessed using general‐linear models, adjusted for age, sex, clinical‐diagnosis and (for cognitive measures) education. We additionally assessed the effects on cortical thickness and cognition. Mean follow‐up time was ∼2 years.

Result

In the A+P+T‐ group, even though below the threshold for positivity, tau‐PET was higher at baseline than in the control and A+P‐T‐ groups, while cortical thickness and cognition were not different between these groups. For the A+P+T+ group, tau‐PET was higher, and cortical thickness, and cognition were lower at baseline than for controls, A+P‐T‐ and A+P+T‐. Longitudinal increase in tau‐PET was faster in the A+P+T‐ group than in controls and A+P‐T‐, primarily in the medial‐temporal lobe. The A+P+T+ group showed a faster rate of tau‐PET compared to controls and A+P‐T‐ (across the entire brain), and compared to A+P+T‐ (primarily neocortex). There were no differences in cortical thinning or cognitive decline between controls, A+P+T‐ and A+P‐T‐. The A+P+T+ group showed faster cortical thinning and cognitive decline compared to controls, A+P‐T‐ and A+P+T‐.

Conclusion

The A+P+T‐ group only shows tau accumulation and no cortical thinning or cognitive decline, and therefore represents an interesting population for early intervention in the AD pathological process, preventing downstream effects. The A+P+T+ group shows fast and widespread tau accumulation and will, therefore, show the greatest beneficial effect of tau‐targeted treatment but already shows cortical thinning and cognitive decline at baseline.
The role of Neuroimaging in Patient Selection and Safety Monitoring during Lecanemab Treatment
Authors: Apostolova Liana G.
Published: December 2023

Background

Lecanemab (Leqembi) is a monoclonal antibody therapy approved in the United States for the treatment of Alzheimer’s disease (AD). Administration of lecanemab in community settings will be guided by the appropriate use recommendations (AURs) that are soon to be published.

Method

The lecanemab AUR’s use clinical trial data as well as evidence from research and clinical practice regarding AD to inform clinicians how to administer lecanemab with optimal safety and opportunity for efficacy. Neuroimaging will play a significant role in selecting the appropriate patients for administration of lecanemab as well as in safety monitoring for adverse events such as amyloid related imaging abnormalities (ARIA). In this presentation we will review the selection and monitoring guidelines for lecanemab as detailed in the AURs.

Result

Most ARIA are asymptomatic, but a few cases are serious or fatal. While micro‐ and macrohemorrhages are rare, they can occur in patients receiving lecanemab. Patients who are apolipoprotein E4 (APOE4) gene carriers, and especially those that are APOE4 homozygotes, are at higher risk for ARIA than APOE4 non‐carriers. The AURs recommends genotyping to better inform risk discussions with patients who are candidates for lecanemab therapy. The AURs recommends a screening MRI and periodic along with symptom‐triggered MRI surveillance to detect asymptomatic and symptomatic ARIA and address it appropriately.

Conclusion

Clinician and institutional preparedness are mandatory for the use of lecanemab. This includes training of neurologists, geriatric psychiatrists, radiologists, primary care, emergency room and intensive care physicians, and stroke neurologists in safety monitoring and treatment of symptomatic ARIA.
Cognitive Aspects of Prymary Sjögren’s Syndrome
Authors: Macedo Lorena Barbosa , Foss Maria Paula
Published: December 2023

Background

Sjögren’s primary syndrome (PSS) is an autoimmune disease that affects the tear line exocrine glands and saliva and may also interfere with the central (CNS) and peripheral nervous systems. PSS patients presenting with the disease can be divided into a profile characterized by the greater intensity of symptoms such as pain, fatigue, and dryness and another with fewer symptoms but a more severe prognosis. Therefore, it was verified the involvement of the CNS through neuropsychological evaluation in the different profiles of PSS.

Method

24 women, 11 with profile 1 (more intense symptoms, PSS1), and 13 with profile 2 (worse prognosis, PSS2), performed neuropsychological assessment composed by: MoCa, Boston reduced version, FAS. Mann Withney’s nonparametric test compared the groups, and the variables were correlated by Spearman coefficient of SPSS 23.

Result

There was a predominance of women (100%) with a mean age of 49.91 ±10.56 years and schooling of 7,83 ± 2.79 years. The comparison between PSS1 and PSS2 showed no significant difference between age (PSS1 = 52,72±8.83; Pss2 = 47.53±11.64; p = 0.257), schooling (PSS1 = 528.18± 2.67;; Pss2 = 7.53±2.96, p = 0.451) and between the tests for profiles, Moca (p = .636), Boston (p = .194), FAS (p = 1.00). Between the tests, we can verify significant positive correlations between Moca x Boston; Moca x FAS_F; Moca x FAS_A; Moca x FAS_S; Moca x FAS, and the FAS variables among themselves. The correlation between age and schooling was not significant.

Conclusion

There was no difference between age and schooling or neuropsychological assessment, considering the techniques used. Then, cognition may be preserved in this sample, reflecting a non‐involvement of the CNS in this disease. However, future studies that are being conducted need to complement these results by expanding the sample or using other instruments.
Validation of A Novel MAO‐B PET tracer [18F]SMBT‐1 on postmortem human brain samples
Authors: Harada Ryuichi , Yiqing Du , Yokoyama Yuka , Ishiki Aiko , Kudo Yukitsuka , Tashiro Manabu , Furumoto Shozo , Okamura Nobuyuki
Published: December 2023

Background

Neuroinflammation in various neurodegenerative conditions involves reactive astrogliosis that overexpresses glial fibrillar acid protein (GFAP) as well as monoamine oxidase‐B (MAO‐B). Recently, we developed a reversible MAO‐B PET tracer, [18F]SMBT‐1. Initial clinical PET studies demonstrated that [18F]SMBT‐1 showed higher regional binding not only amyloid (Aβ)‐positive Alzheimer’s disease (AD) but also Aβ‐negative elderly cognitively normal (CN). To validate initial clinical finding, we investigate the binding of [18F]SMBT‐1 in postmortem human brain samples.

Methods

In vitro autoradiography of [18F]SMBT‐1 (MAO‐B), [18F]Florbetaben (Aβ), and [3H]MK‐6240 (Tau) was performed using postmortem brain sections from CN and AD. In vitro binding assay of [18F]SMBT‐1 was performed against brain homogenates from CN, argyrophilic grain disease (AGD), Lewy body disease (LBD), and frontotemporal lobar degeneration with TDP‐43 (FTLD‐TDP). GFAP levels were measured to investigate the association with tracer binding. Double immunohistochemistry of MAO‐B and A1/A2 reactive astrocyte markers were performed to understand the relationship of astrocytic phenotype in MAO‐B expressing astrocytes.

Results

Higher specific binding of [18F]SMBT‐1 was observed in Aβ‐positive/Tau‐positive AD brain sections. Interestingly, intense patchy signal of [18F]SMBT‐1 was observed in Aβ‐positive/Tau‐negative CN brain section, which was partially co‐localized with that of Aβ detected by [18F]Florbetaben. These observations were consistent with the findings of clinical [18F]SMBT‐1 PET study. In the brain samples of AGD, LBD and FTLD‐TDP, the amount of [18F]SMBT‐1 binding was correlated with GFAP levels. Double immunostaining demonstrated that MAO‐B was expressed in both A1 and A2 reactive astrocytes.

Conclusions

Significant [18F]SMBT‐1 binding was detected in the postmortem brains of both AD and Aβ‐positive/Tau‐negative CN, reflecting reactive astrogliosis induced by early Aβ accumulation. [18F]SMBT‐1 would be a promising marker for reactive astrogliosis in neurodegenerative diseases.
Dynamic imaging and targeted degradation of the RNA‐binding protein hnRNP A2B1 using nanobodies
Authors: Cho Yongku P , Pirhanov Azady
Published: December 2023

Background

RNA‐binding proteins (RBP) are a primary component of stress granules, a key indicator of various cell stress responses. Recently, the heterogeneous nuclear ribonucleoprotein hnRNP A2B1 emerged as a primary protein that preferentially interacts with tau oligomers than tau monomers. Here we studied the dynamics of hnRNP A2B1 in cultured cells and primary neurons using a novel nanobody reagent that enables live‐cell imaging.

Method

We screened a recombinant nanobody library to identify nanobodies (Nbs) that bind to hnRNP A2B1. The Nbs were designed to bind to all isoforms of hnRNP A2B1. We applied protein engineering approaches to improve the binding affinity of the identified Nbs. Live cell imaging was conducted in cultured cell lines and primary mouse hippocampal neurons. We also generated Nb‐E3 ligase fusions for targeted degradation of hnRNP A2B1.

Result

The Nbs revealed an unexpected localization of hnRNP A2B1 previously not observed using GFP fusions. We observed bright puncta throughout the cytoplasm in addition to typical nucleoplasmic distribution of hnRNP A2B1. The hnRNP A2B1 puncta were co‐localized with exosomal markers. In cell lines, the nucleoplasmic hnRNP A2B1 was dramatically reduced during mitosis, while the cytoplasmic puncta did not change, suggesting cell cycle‐dependent nucleocytoplasmic translocation. The Nb‐E3 ligase fusion constructs caused a significant reduction in hnRNP A2B1, lowering the level by 60%.

Conclusion

These novel tools will greatly aid the study of endogenous hnRNP A2B1 dynamics and function. Isoform‐dependent localization of hnRNP A2B1 and whether it is involved in protein loading to exosomes remains to be studied.
The NC Registry for Brain Health: Increasing Access to Brain Health Information and Research in Underserved & Under‐represented Communities
Authors: Chanti‐Ketterl Marianne , Dewees Rachel A , Bozoki Andrea , Price Stephen Russ , Martin Patrick McPhail , Edmonds Henry , Adams Latorius S , Williams Kelvin , Gaven Julie , Matchar Bobbi , Herron Susan , Ries Michelle G , Plassman Brenda L , Byrd Goldie S. , Welsh‐Bohmer Kathleen A. ,   the NC Registry for Brain Health
Published: December 2023

Background

Diverse racial/ethnic representation in scientific studies is crucial for generalizability of results and development of potentially effective treatments. Racially diverse registries with research ready individuals have the potential to fill this gap. However, despite having signed up as part of a research registry and being invited to participate in clinical trials, many do not participate. To better understand research participation, the NC Registry for Brain Health surveyed its members to identify the characteristics of those likely to participate in research studies, their views on research, expectations when joining the group, and impediments to participation.

Method

The NC Registry for Brain Health has been state‐funded since 2018 with goals of increasing access for all to information and research opportunities in brain health. Focused recruitment to under‐served and under‐represented groups across the State occurs through community outreach events sponsored by a five member university network. An email survey was sent to the 5,946 Registry members enrolled as of October 15, 2021.

Result

Approximately 10% (n = 576) responded to this anonymized survey. Most were older women with high levels of formal education (Table 1). Despite the Registry’s demographics of 28% African American enrollees, only 8% of the survey respondents self‐identified as African Americans. Most individuals joined the Registry for the joint purpose of getting involved in research and receiving information about brain health (75%). When asked to describe what “brain health research” means, most reported studies involving dementia risk factors and memory testing. All participants had been approached to get involved in studies, but only 60% recalled getting an email invitation. The biggest impediment noted for participating in studies was inconvenient appointment times. The participants also wanted more available studies and more information about the opportunities.

Conclusion

This study suggests that most participants in the Registry are seeking to be informed about brain health and have access to research opportunities at times convenient with their schedules. There was an observed gap between African Americans enrolled in the research registry and those who participated in the survey. Addressing gaps in research involvement of under‐represented groups in research is necessary to achieve inclusive representative science.
Convergent and clinical validity of a remote smartphone‐based self‐assessment of cognition, function, and behavior in early Alzheimer’s disease
Authors: Perumal Thanneer M , Wolfer Arnaud M , Veloso Miguel , Kurniawan Irma T , Aponte Eduardo A , Keita Goullou , Hagenbuch Niels , Shi Beijue , Orfaniotou Foteini , Colell Macarena Garcia Valdecases , Chatham Christopher H , Rey‐Riek Simone , Sink Kaycee M. , Watson David , Boada Mercè , Taylor Kirsten I
Published: December 2023

Background

Trials in early Alzheimer’s disease (eAD) require the quantification of cognitive and functional progression. Compared with traditional in‐clinic assessments, remote assessments via digital health technologies (DHT) enable the collection of a broader palette of cognitive and functional measures at higher frequency and in patients' home environments. However, these must demonstrate validity against standard clinical outcome measures and relevant biomarkers. To this end, the present study aims to determine the reliability, convergent clinical, and functional neuroanatomic validity of a novel DHT, the Alzheimer’s Disease Digital Assessment Suite (AD‐DAS), for individuals on the AD continuum.

Methods

In total, 123 participants from 2 countries across 5 sites (3 USA, 2 Spain) participated (https://www.isrctn.com/ISRCTN17035495): 32 healthy controls (HC), 31 amyloid‐PET negative and 30 amyloid‐PET positive subjective cognitive decline (SCDn, SCDP, respectively), and 30 eAD. All participants completed standard in‐clinic neuropsychological assessments and remotely performed the AD‐DAS tasks daily for 28 days without supervision. AD‐DAS comprised 9 active tasks of cognitive/motor functioning and 4 survey questionnaires. Convergent and clinical validity analysis were performed using linear and proportional odds logistic regression modeling with age, sex, education, and site as covariates, respectively. Functional neuroanatomic validity was tested with voxel‐based morphometry (VBM) analyses with anatomic MRIs.

Results

Outcome metrics from all AD‐DAS cognitive/motor tasks correlated with their corresponding clinical comparators (ρpartial (range) = 0.16 ‐ 0.52), supporting their convergent validity. Similarly, outcome metrics from all tasks significantly differentiated the eAD from all the other groups in the expected directions (odds ratio (range) = 0.01 ‐ 61), supporting their clinical validity. The reliability of the outcome metrics ranged from good to excellent (interclass correlation coefficient (range) = 0.71 ‐ 0.91). VBM analyses provided independent and largely confirmatory results, further validating the AD‐DAS.

Conclusions

The AD‐DAS remote, smartphone‐based assessments of cognition show good to excellent test‐retest reliability, and preliminary analyses indicate that they may show convergent, clinical and exploratory functional neuroanatomic validity. Thus, these results provide a foundation for building towards the overarching goals of remote screening, prediction of progression, and monitoring of cognitive decline for future clinical trials and clinical care for preclinical and eAD.
The impact of the Alzheimer Society of Canada’s First Link program: Results of a caregiver client survey
Authors: Whate Alexandra , Sivananthan Saskia , Apostolides Haridos , Elliott Jacobi , Stolee Paul , Armstrong Joshua J.
Published: December 2023

Background

In Canada, the Alzheimer Society’s First Link program connects people living with dementia and their caregivers to the information, supports and services they need as early as possible and throughout the progression of their condition. As part of an ongoing national evaluation, the Alzheimer Society of Canada has conducted a survey to provide evidence of the impact of the program across Canada.

Method

Electronic surveys were distributed to caregiver clients of the First Link program by six Provincial Alzheimer Societies (AB, MB, NB, NS, PEI, and SK) and one regional Alzheimer Society (Toronto, ON). The survey included questions about client demographics, healthcare service usage, caregiver confidence and caregiver experience, the latter of which was asked using a retrospective pre‐test post‐test design whereby clients were asked to report their current response or status, and also retrospectively recall their perceived response prior to their interaction with The Alzheimer Society. This approach will allow us to determine whether clients report having experienced change over time.

Result

A total of 732 surveys were completed by caregivers across Canada. Results varied by province. Caregivers reported that since their connection to the Alzheimer Society they were ‘much’ or ‘a little’ more confident in their ability to: care for the person with dementia (59%), avoid crises (44.5%), and access services (55.2%). They also reported improvements in their knowledge (74.6%) and preparedness (56.8%). Less than 10% of clients reported lower levels of confidence in any of the areas. Of those accessing healthcare services, the Alzheimer Society was credited with connecting people to a variety of services, including counselling (48.2%), adult day programs (43.5%), and home care (22.2%). Of those accessing Long‐Term Care (LTC), similar proportions of participants reported that they accessed LTC later (13.7%) or sooner (11%) than they would have without involvement of the Alzheimer Society. Overall, 69.7% of participants felt that their journey with dementia was improved by their connection with the Alzheimer Society.

Conclusion

The results of this survey help to demonstrate the significant role that the Alzheimer Society plays in the lives of caregivers and people living with dementia across the country.
Prospective Randomized Placebo‐Controlled Trial of Long‐Term Durability of Effect of One Year of Grape Consumption on Preventing Decline of Cerebral Function
Authors: Liu Stephen S. , Lu Josephine L. , Alcantara April R. , Varughese Deepu V. , Silverman Daniel H.
Published: December 2023

Background

Long‐term impact of one year of grape consumption on regional brain metabolism and associated neuropsychologic status was examined across multiple years of follow‐up.

Method

Twenty subjects (74.6±5.4 years) were randomized to consume an active grape formulation (36g reconstituted freeze‐dried grape powder) or placebo (matched for sweetness and appearance but free of polyphenols) twice daily for one year. Changes in brain metabolism were assessed by PET with radiotracer [F‐18]fluorodeoxyglucose and cognitive performance was measured through neuropsychological testing, at baseline, 1 year after initiating consumption of grape or placebo formulation, and again 2 to 3 years after completing the randomized regimen in half of the subjects on each arm, with all subjects remaining blinded to which regimen they had been assigned until after final assessments. Activity in 47 standardized volumes of interest (sVOI’s) were measured, voxel‐based analyses using statistical parametric mapping were conducted, and associations were examined between interval changes in metabolism and neuropsychologic status.

Result

During the year while consuming formulations, subjects randomized to placebo underwent metabolic decline in 27 sVOI’s, including particularly inferior posterior temporal (p = 0.006) and inferior frontal (p = 0.004) areas, correlating with neuropsychologic decline, while significant (p<0.05) decline was seen in none of the 47 sVOI’s in the active formulation group. Voxel‐based analyses corroborated differential metabolic decline in placebo and active formulation groups, and direct difference‐of‐differences analyses further documented significantly more decline in the placebo group. Moreover, a significant difference in regional metabolism persisted at the end of follow‐up, after having discontinued randomized formulations for 28.1±5.7 months (40.0±5.4 after baseline), with mean medial temporal sVOI’s demonstrating significant decline in the group that had been randomized to placebo (‐4.6%, p = 0.009), but not in the group that had been in the active arm (‐1.5%, N.S.). Difference of magnitudes of long‐term metabolic decline between arms was significant in direct difference‐of‐differences analysis, and correlated with neuropsychologic decline (p<0.001) in both inferior posterior temporal and inferior frontal regions.

Conclusion

Subjects randomized to consume reconstituted grapes twice daily enjoyed long‐term protection from loss of cerebral function, as assessed more than two years beyond the last consumed dose.
Information Seeking and Technology Use Among Dementia Caregivers: Findings from a Statewide Survey of Diverse Caregivers in the U.S. South
Authors: Ruggiano Nicole , Winton Tish , Daquin Jane , Herzog Monica Anderson , Jiang Zhe , Gray Jeff
Published: December 2023

Background

Family caregivers are often tasked with decision making about their loved one’s health care treatment and daily care and have reported that such decision making can be challenging, overwhelming, and stressful (Gaugler et al., 2022; Miller et al., 2016; Ruggiano et al., 2019). For this reason, caregivers often report being highly active in seeking out information to improve their health literacy regarding dementia and caregiving, frequently turning to various information technologies (IT) to gather information (Bangerter et al., 2019; Soong et al., 2020). However, more research is needed on how IT can support health literacy and information seeking for vulnerable caregiver populations, such as caregivers who are rural‐dwelling, low‐income, and those from underserved racial/ethnic groups (Soong et al., 2020).

Method

This project involved a statewide survey of caregivers living in Alabama, a U.S. state that has large populations of rural, African American, and underserved residents. To recruit participants, community‐based organizations distributed flyers and two public radio campaigns made announcements about the project between June 2022 and December 2022. The survey included questions about: the sources participants used to learn more about dementia and caregiving; ease of gathering information from these sources; their level of trust in these sources; their experience with different types of IT; their current information needs; and participant demographics. Univariate and bivariate analyses were performed.

Result

Seventy‐eight caregivers completed the survey: 50% identified as African American, 37.2% lived in rural communities, and 30.8% had household incomes of less than $30K per year. The survey revealed several findings regarding information seeking and technology use. Participants reported using an average of 4.8 sources to gather information. Level of trust in some information sources and interest in using certain types of IT for information seeking varied based on some demographics, including race, age, and income.

Conclusion

The findings suggest that public education about dementia should not be a one‐size‐fits all approach and that strategizing public health education campaigns by source and technology platform may better facilitate health literacy of sub‐populations of caregivers, especially those who may be underserved or have challenges in navigating health and long‐term care systems.
Curriculum‐based CME Programming Results in Comprehensive Improvements in Knowledge, Competence, and Confidence in Diagnosing Early Forms of Alzheimer’s Disease Among a Global Audience of PCPs and Neurologists
Authors: Finnegan Thomas , Stan Adriana , McFarland Frances , Chatterjee‐Shin Piyali , Guedj Philippe , Cohen Sharon , Petersen Ronald C.
Published: December 2023

Background

Early diagnosis of Alzheimer’s disease (AD) is crucial for ensuring patients have timely access to essential care. Given the symptoms of early AD are often subtle, it is important that both primary care physicians (PCPs) and neurologists are able to diagnose their patients. Several sources of evidence have indicated that most PCPs and neurologists lack knowledge, competence, and confidence regarding recognition of early forms of AD. To address the clinical practice gaps, a series of CME‐certified programs covering the symptoms, assessment, and diagnosis of early forms of AD were developed.

Method

The data presented here are based on outcomes from four online CME‐certified multimedia programs housed on a single destination page. Each CME‐certified program utilized expert physicians to educate learners on recognizing early forms of AD. Each CME program asked a series of pre‐post questions designed to assess immediate changes in knowledge, competence, or confidence. The questions were grouped into clinically relevant themes. The educational effect for all of the programs was determined by using a paired‐samples t‐test to identify significant differences between pre‐ and post‐assessment responses for each question. Data across all four programs were collected from February 2022 through December 2022. All four programs were promoted to an audience of US‐ and ex‐US physicians.

Result

Participation across the four programs ranged from 543 to 2,510 PCPs and 256 to 1,025 neurologists. PCPs and neurologists demonstrated significant (P<0.05) pre‐vs post education improvements on the following themes: biomarkers in AD, clinical trial outcomes, cognitive assessment scales, diagnosis of AD, diagnosis of mild cognitive impairment (MCI), and symptoms differentiating AD from MCI. Participation in the education also significantly (P<0.001) improved confidence in the identification of early forms of AD among PCPs and neurologists. No substantial differences in knowledge, competence, or confidence were seen for either clinician group based on geographic location of the learner.

Conclusion

The results indicated that clinicians who participated in CME‐certified curriculum‐based education in multiple formats were better prepared to recognize early forms of AD. Future education should continue to discuss the use of clinical strategies to recognize early forms of AD.
Perimenopause: A critical window to intervene to reduce the risk of cognitive impairment in females
Authors: Cirone Victoria , Hsu Chun Liang , Barha Cindy K , Liu‐Ambrose Teresa
Published: December 2023

Background

Two‐thirds of all persons with late‐onset Alzheimer’s disease (AD) are female. The transition to menopause, or perimenopause, negatively impacts the female brain and is proposed to contribute to a female’s greater lifetime risk for dementia. Declining 17‐β estradiol levels during perimenopause is associated with markers of AD pathology, such as reduced cerebral glucose metabolism. Preliminary evidence suggests APOE4‐positive perimenopausal females have greater amyloid In cognitively normal individuals, the T1‐weighted and T2‐weighted (T1w/T2w) ratio from magnetic resonance imaging can be used as a non‐invasive proxy measure of amyloid‐β deposition. Specifically, higher T1w/T2w ratios are associated with higher amyloid‐β accumulation in cognitively normal individuals. Thus, to better understand the impact of perimenopause on the female brain and cognitive health, we compared the T1w/T2w ratio, hippocampal volume, and cognitive performance in perimenopausal females vs. aged‐matched males.

Methods

Data was acquired from the Human Connectome Project. We included 44 perimenopausal females, defined by the Stages of Reproductive Aging Workshop + 10 Staging System, and 44 age‐matched males. Executive function was measured by the Flanker Task in the NIH Toolbox Cognition Battery and data were available for all 88 individuals. Hippocampal volume data were available for 23/44 perimenopausal females and 27/44 age‐matched males. T1w/T2w neuroimaging data were available for 19/44 perimenopausal females and 27/44 age‐matched males. Between‐group differences in these measures of interest were determined by analysis of covariance (ANCOVA). For the Flanker Task ANCOVA model, the Montreal Cognitive Assessment score and free estrogen levels were included as covariates. For hippocampal volume model, intracranial volume was included as a covariate. For the T1w/T2w ratio model, the Pittsburgh Sleep Quality Inventory score was included as a covariate.

Results

Perimenopausal females performed significantly worse vs. their male counterparts on the Flanker Test (mean difference: ‐28.194; p = .000). Compared with age‐matched males, perimenopausal females had a significantly smaller hippocampal volume (mean difference: ‐544.829; p = .033) and higher T1w/T2w (mean difference: 0.290; p = .042).

Conclusion

Our results support the hypothesis that the menopause transition is a critical window to intervene to reduce the risk of cognitive impairment in females.
An Integrative Multi‐Omics Approach Reveals Molecular Signatures Associated with Age and High‐Fat Diet in Mouse Models of Alzheimer’s Disease
Authors: Pandey Ravi S , Kotredes Kevin P , Garceau Dylan , Haber Annat , MahmoudianDehkordi Siamak , Shantaraman Anantharaman , Duong Duc M. , Seyfried Nicholas T , Kaddurah‐Daouk Rima F. , Sasner Michael , Howell Gareth R , Oblak Adrian L , Lamb Bruce T , Carter Gregory W
Published: December 2023

Background

Alzheimer’s disease (AD) is a complex, multifactorial pathology with high heterogeneity in biological alterations. Our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. Therefore, it is required to integrate the information from multiple data modalities for thorough exploration of endophenotype networks, biological interactions related to disease and thus accelerate our understanding of heterogeneity in Alzheimer’s disease.

Method

In this study, we performed multi‐level omics in a cohort of mouse models expressing humanized Abeta and two genetic risk factors (APOE4 and Trem2*R47H) at multiple ages for both sexes. Data from multiple omics platforms (transcriptomics, proteomics, and metabolomics) were analyzed at single‐omic level as well as integrated in an unbiased fashion, considering interaction between modalities using multi‐omics factor analysis (MOFA). We also systematically aligned multimodal mouse data to relevant human studies cohort.

Result

Multi‐omics integration identified major components of heterogeneity explaining the variance within the cohort and differentially associated with age, sex, and high fat diet. Enrichment analysis of genes and protein associated with these components were significantly enriched for multiple AD‐related processes. Specifically, components associated with age and diet related heterogeneity exhibited overrepresentation of immune response and metabolic processes as well as increased levels of long‐chain acylcarnitine’s and reduced levels of spermidine in aged and high‐fat diet fed AD mouse models, similar to human AD. In addition, we observed weak correspondence between change in protein and RNA expression in mouse models compared to controls, similar to recent results from the ROSMAP cohort, which reported weak correlation between protein and RNA expression. We also identified a negative correlation for the change in RNA expression between male and female mice.

Conclusion

We identified axes of variation within a cohort of LOAD mouse models using integrative multi‐omics approach. Our analysis revealed multiple interaction between distinct multi‐omics molecular signatures associated with Alzheimer’s disease. We determined that mRNA profiling alone provides an incomplete picture of molecular mechanism of AD. In this study, we highlighted that assembling multi‐omics measurements reveal interrelated pathway alterations in AD and the ability to identify biomarkers combinations that may inform clinical practice.
Examining the relationships between cognitive function and physical and mental health: interim findings from HKMMSOP
Authors: Chan Wai‐Chi , Lam Linda Chiu Wa C.W. , Lee Allen TC , Fung Ada WT , Ma Suk Ling , Cheng Calvin Pak Wing , Wong Samuel YS , Lai Frank HY
Published: December 2023

Background

Population ageing is associated with an increase in the number of persons with dementia, which constitutes a significant public health issue. The Hong Kong Mental Morbidity Survey for Older People (HKMMSOP) was carried out to evaluate the local prevalence of dementia and the factors that modulated the disease development.

Method

Participants aged 60 or over, stratified with age groups, were recruited through random sampling of residential addresses in Hong Kong. They underwent an assessment of their cognitive function (Montreal Cognitive Assessment, MoCA; Clinical Dementia Rating, CDR), physical health (Cumulative Illness Rating Scale, CIRS) and mental health (Clinical Interview Schedule‐Revised, CIS‐R; Short Warwick‐Edinburgh Mental Wellbeing Scale, SWEMWBS). Associative factors of neurocognitive disorders were determined by multinomial regression, with neurocognitive disorders as dependent variables.

Result

In this interim analysis, 4369 participants of HKMMSOP were included. Their mean age was 69.6, and there was a slight female preponderance (56.3%). On average, they received 8.8 years of education, and their mean MoCA score was 23.8 (SD 4.9). Using CDR, 71.8% were evaluated as having normal cognition, 23.1% with a mild neurocognitive disorder (ND), and 5.2% with a major ND. Older or less educated participants had a higher risk of developing mild and major ND (p<0.001). But the relationships between cognition and physical and mental health differed in the mild and major ND groups. Among those with mild ND, a higher CIRS total score (p<0.001), a higher CIS‐R total score (p<0.001) and a lower SWEMWBS score (p = 0.002) were significantly associated with CDR. However, only CIRS total score (p = 0.004) and SWEMWBS score (p<0.001) remained significant in the major ND group.

Conclusion

Poorer physical and mental health and lower mental well‐being and life satisfaction were associated with an increased risk of mild ND. But as the disease progressed, lower mental well‐being and life satisfaction and poorer physical health remained significant factors. On the contrary, a higher level of mental symptoms, as exemplified by CIS‐R, was not significantly associated with major ND. It sheds some light on the factors that may modulate the course of the disease and appropriate preventive measures.
Development of a patient‐reported outcome measure for Alzheimer’s disease: the Alzheimer’s Disease‐Health Index (AD‐HI), a fully validated tool to bolster clinical trial and research infrastructure
Authors: Rosero Spencer , Varma Anika , Seabury Jamison , Weinstein Jennifer , Engebrecht Charlotte , Dilek Nuran , Arky Abigail , Santos Elizabeth , Heatwole Chad
Published: December 2023

Background

As therapeutic advancements are made in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI), it is important to have a fully validated, sensitive, and reliable disease‐specific patient‐reported outcome measure (PRO) to accurately measure changes in AD and MCI symptomatic disease burden. The U.S. Food and Drug Administration has encouraged the use of PROs to measure therapeutic benefit of potential new treatments. This research describes the development, testing, and validation of a novel, multifactorial PRO: The Alzheimer’s Disease‐Health Index (AD‐HI).

Methods

We conducted interviews and a large cross‐sectional study involving individuals with AD and MCI and their caregivers to determine what symptoms and issues are most important to patients (Figure 1). Questions were selected for the AD‐HI based on their importance to patients with MCI and AD, potential to respond to therapeutic intervention, and generalizability to the broader MCI and AD patient population as determined through qualitative interviews and a cross‐sectional study. We beta tested the initial version of the AD‐HI with individuals with MCI and AD to determine its clarity, ease of use, and relevance to those with MCI and AD. We performed test‐retest reliability, known groups validity, internal consistency, and area under the curve analyses of the AD‐HI to assess the statistical characteristics, performance, and clinical meaningfulness of the outcome measure.

Results

The content of the AD‐HI was validated using a cross‐sectional study of 104 patients. The final version of the AD‐HI contains 9 subscales that measure disease burden in the following areas: 1) Memory, 2) Cognitive health, 3) Fatigue, 4) Sleep, 5) Social health, 6) Communication, 7) Emotional health, 8) Physical health, and 9) Pain. The AD‐HI was identified as easy to use, relevant to the patient population, responsive, and clear during beta testing. The ADCR‐HI was shown to be reliable during test‐retest reliability testing with 22 individuals and able to distinguish between patient cohorts with different disease severities.

Conclusion

The AD‐HI is a is a valid, sensitive, and reliable marker of disease burden in AD This disease‐specific outcome measure is available for use by researchers, clinicians, patient organizations, and companies to measure changes in disease burden during therapeutic trials.