bluuebunny/crossref_metadata_2025 huggingface dataset:
What causes relative difficulties with technology and non‐technology based activities of daily living in those with ADRD?
Authors: Benge Jared , Ali Arsh , Gonzalez David A. , Kiselica Andrew M , Scullin Michael K , Hilsabeck Robin C.
Published: December 2023

Background

Digital skills are critical to performing a host of instrumental activities of daily living (iADLs) in the 21st century. For example, financial management activities increasingly rely on managing accounts online, social interactions are frequently mediated by technologies like text messaging and social media, and critical health and commerce activities occur via tech enabled platforms. Despite the ever increasing importance of technology related iADLs to real world functioning, there are concerns that the digital divide may disproportionately impact those with ADRD making the modern technological environment more difficult to navigate. The current study explored two broad questions: 1) how do relative difficulties with tech iADLs relate to demographic factors and diagnostic staging?, and 2) what cognitive difficulties predict relative difficulties technology versus traditional iADL performance?

Method

Care‐partners of 135 older adults (mean age 75.3 years (sd = 7.9); 10.5% with no cognitive disorder diagnosis, 37.0% with mild cognitive impairment; 51.1% with dementia) referred to a comprehensive interprofessional memory clinic for neuropsychological evaluations completed both the Functional Activities Questionnaire (as a measure of traditional ADL performance) as well as a series of 11 technology based iADL items (i.e. remembering passwords, managing online accounts, etc). In addition, clinic patients completed a battery of neuropsychological measures.

Result

While decreasing performance in both traditional and technology iADLs were noted with the transition from MCI to dementia, diagnostic stage (Figure 1), age, and verbal memory performance did not predict disproportionately greater difficulties with tech iADLs relative to overall iADL performance. However, lower education (B = ‐1.77; p = .003; Figure 2), and more difficulties with cognitive set shifting (B = 1.03; p = .0116; Figure 3) predicted greater relative difficulties with tech iADLs.

Conclusion

In our current sample, relative difficulties with technology related iADLs was associated with greater executive dysfunction and less educational attainment. These factors may identify individuals with ADRD at particular risk for having difficulties navigating an ever more technologically enriched environment. Implications for helping those with ADRD cross the digital divide, clinical assessment, and technology based interventions for ADRD are discussed.
Sentiment Analysis on Household Audio Conversation with Automated Chatbot for Hospital Visits Prediction
Authors: Su Ting , Jouaiti Melanie , Vaidyanathan Ravi
Published: December 2023

Background

People living with dementia (PLwD) often experience difficulties describing their physical conditions and seeking medical attention timely, resulting in hospital visits that may cause frustration and exhaustion. Therefore, we aim to develop a machine learning model that helps identify potential hospital visit needs to provide early medical attention for PLwD.

Method

Portable smart chatbots are deployed to PLwD households. We collected audio clips between households and chatbots and the hospitalisation records of PLwD. We manually labelled the sentiment scores of each audio clip based on its content and tone to between ‐3 and 3, where ‐3 indicates very negative, 0 indicates neutral, and 3 indicates very positive. We use 10 days of sentiment scores on a minute basis (0 when there’s no interaction) to predict the need for hospital visits in the following days. The positive outputs indicate that hospital visits happened within the 5 following days, while the negative outputs indicate no hospital visits occurred. A gradient boosting model (GBM) is trained to predict if hospital visits will happen in the following 5 days. We evaluated the trained model using the cross‐validation (cv = 5) method and reported Accuracy, Sensitivity, Specificity and macro F1 score.

Result

Between May 13th, 2021, to June 5th 2022, we collected 14 PLwDs’ hospital visit records and 12,278 audio clips between their households and their chatbots. Among all the participating households, we constructed a total of 3065 days as training and testing data (albeit no activities some days), with 37 hospital visit occurrences. This results in 139 days where hospital visits occurred in the following 5 days. The GBM model classified the need for hospital visits in the following 5 days with 0.682 Accuracy while obtaining 0.890 in Sensitivity, 0.669 in Specificity, and 0.522 in F1 score.

Conclusion

Sentiment scores obtained by analysing audio clips between households of PLwD and their chatbots can be used to predict hospital visits in the following 5 days, with 0.890 in Sensitivity. This can help health professionals to provide more timely care to PLwD without frequent home visits. However, further research is needed to improve the Specificity and F1 of the predicting model.
Interaction between Hippo Pathway Elements and the E3‐ligase CHIP regulate a potential marker of Alzheimer`s disease
Authors: Suluova Melek , Nita Erisa , Ball Kathryn
Published: December 2023

Background

The transcriptional coactivator YAP‐1, a known CHIP substrate that has a role in the regulation of adaptation to cellular stress, cell size and metabolism, was investigated as a potential link between CHIP and VGF.

Method

Previously, CRISPR‐Cas9 method was used to create CHIP KO neuroblastoma cell line. Then, SWATH‐MS experiment was applied to get proteomic data of CHIP KO and WT neuroblastoma cells. Validation of data analysis done by immunoblot and IF. Following gene manipulations were applied by transfection of RNAi and following assessments done by immunoblot and IF.

Result

According to our proteomic analysis, CHIP KO neuroblastoma cells have 10X more VGF protein than isogenic WT cells. YAP1 was expressed at high levels in the nucleus of CHIP KO neuroblastoma cells and manipulation of YAP1 impacted on the expression of VGF.

Conclusion

As VGF is an Alzheimer’s disease biomarker, discovering mechanisms of VGF regulation could support efforts to find new targets for the development of disease modifying drugs.
Family Caregiving in a Great Lakes Native American Community: A Mixed Methods Study of Service Utilization
Authors: Wyman Mary F. , Lambrou Nickolas H. , Lewis Jordan P. , Buerger‐Cole Haley M. , Hammock Colin , Klammer Kristianna , Lawrence Sacheen L. , Miller Debra A. , Petri Florence , Perzynski Joseph D. , Johnson Adrienne L. , Zuelsdorff Megan , Gleason Carey E.
Published: December 2023

Background

Native Americans are disproportionately impacted by ADRD, and family caregiving is uniquely significant within Indigenous communities. Caregiving services can improve outcomes but are underutilized, and increasing use of caregiver services is key to addressing the dementia care crisis. Indigenous populations are underrepresented in the ADRD caregiving literature, resulting in a significant gap in understanding of how to improve engagement with services. We examine perspectives on service utilization among caregivers in a large tribal nation in the US Great Lakes region.

Method

Within a community‐based research partnership between the Wisconsin ADRC and the Oneida Nation of Wisconsin, N = 481 completed a survey on use of seven common caregiver resources, including support groups, respite, caregiver training, household help, transportation for care recipient, nursing home, and financial assistance. Drawing on the Andersen model of utilization, multiple regression models examined correlates of positive attitudes toward use of services among caregivers (N = 207), defined as past, current, or intended future use of services. Follow‐up in‐depth interviews with 10 caregivers of elders with ADRD (Table 3) explored decision‐making regarding service utilization using qualitative content analysis.

Result

There were few demographic differences between caregivers and non‐caregivers in the sample (Mage = 52 and 54 yrs; 75% female; Table 1). Over half (54.6%) of caregivers were employed; most (64%) cared for someone with ADRD. In the final regression model in the caregiver subsample, only level of belief that traditional Oneida values and practices support caregivers in using caregiver services predicted positive attitudes toward service utilization (p<.001; Table 2). Interviews revealed barriers to service use include low awareness, complexities of service funding structures, and Elder preferences. Perceptions of alignment of traditional cultural values with service use were complex and nuanced.

Conclusion

Using mixed methods in a Native American community sample, we identified unique barriers to access resources to support elders with ADRD and their families, including perceived cultural support for service use. Our findings contribute to the scant literature on ADRD caregiving among Native Americans and provide support for tailored interventions (e.g., Savvy Caregiver in Indian Country). Results can inform public health initiatives to address ADRD disparities and improve outcomes for Indigenous persons with ADRD.
Utility of accessible neuroimaging markers of cerebrovascular disease in identifying cerebral amyloidosis across the Alzheimer’s disease spectrum
Authors: Howe Matthew D. , Emrani Sheina , Kunicki Zachary J. , Britton Karysa J. , Salloway Stephen , Oh Hwamee ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Alzheimer’s disease (AD) is defined by the presence of cognitive impairment and cerebral amyloidosis and is associated with several cerebrovascular disease (CVD) risk factors including age, apolipoprotein‐E ε4 (APOE‐ε4) genotype, hypertension, diabetes and hyperlipidemia. Despite this association, the clinical utility of individual CVD biomarkers in screening for AD pathology is understudied. Therefore, we sought to examine the relationship between cerebral amyloidosis and magnetic resonance imaging (MRI)‐based CVD measures, including cerebral microbleeds, ischemic infarction, and white matter hyperintensities (WMH). We hypothesized that CVD biomarker burden would be positively associated with amyloidosis. Given recent studies have shown plasma phospho‐tau181 (P‐tau181) is a promising early biomarker of amyloidosis, we further hypothesized that combining P‐tau181 with CVD biomarkers would predict amyloid status in cognitively unimpaired and impaired persons.

Method

Participant data were extracted from the Alzheimer’s Disease Neuroimaging Initiative database (N = 1,430). Volumetric data (WMH volume [WMHv], medial temporal lobe volume [MTLv]) were normalized and log‐transformed. Adjusted odds ratio (OR) was calculated using logistic regression with dichotomized amyloid‐PET status as the outcome. Area under the curve (AUC) was compared by the likelihood ratio test.

Result

After adjustment for age, sex, APOE‐ε4 status, MTLv, cognition (MoCA), and other CVD biomarkers of interest, we found that WMHv alone was significantly associated with amyloidosis in both cognitively impaired (OR = 1.21) and unimpaired (OR = 1.25) persons. We then developed an accessible diagnostic model incorporating WMHv, significant covariates and plasma P‐tau181. Addition of P‐tau181 to the model improved diagnostic accuracy in cognitively impaired persons (AUC = 0.85 to 0.87, p < 0.001), and did not attenuate the relationship between WMHv and amyloidosis.

Conclusion

We newly identify WMH, but not other CVD lesions, as predictive of amyloidosis in both preclinical and symptomatic AD. The current study adds to the literature regarding which CVD biomarkers are most predictive of AD pathology. Measurement of WMH alongside P‐tau181 and other biomarkers may produce an accessible screening algorithm for AD. Study generalizability is limited by ascertainment bias and lack of diversity. Future research will compare the performance of WMH to standard AD biomarkers in a more diverse, community‐based sample.
Comparison of longitudinal rates of atrophy and tau accumulation between posterior cortical atrophy and logopenic progressive aphasia
Authors: Sintini Irene , Radford Jonathan Graff , Machulda Mary M. , Singh Neha Atulkumar , Carlos Arenn Faye , Schwarz Christopher G. , Senjem Matthew L. , Jack Clifford R. , Lowe Val J. , Josephs Keith A , Whitwell Jennifer L
Published: December 2023

Background

Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are atypical variants of Alzheimer’s disease which typically show different cross‐sectional patterns of atrophy and tau deposition. Patterns of atrophy remain distinct longitudinally. A direct comparison of rates of atrophy and tau accumulation between these syndromes has not yet been reported.

Method

We evaluated 20 PCA and 20 LPA patients; all were amyloid‐positive on [11C]PiB‐PET. Structural MRI and tau‐PET were performed at baseline and one‐year follow‐up. Annualized rates of change in grey matter volume (log Jacobians from tensor‐based morphometry) and flortaucipir‐PET SUVRs were calculated at the lobar level. A global tau SUVR was calculated using parietal, temporal, and occipital regions. Lobar rates were compared between PCA and LPA with linear models, accounting for education, sex, age, baseline global tau SUVR (for tau‐PET), with significance set at p = 0.05. SPM voxel‐level comparisons were performed, with the same covariates, with significance set at p = 0.001.

Result

Groups did not differ in age, Apoe status, baseline global tau SUVR or whole brain volume, or their annualized rates of change. LPA had shorter disease duration. In the lobar models, PCA had faster rates of atrophy in the occipital lobe and there were no significant differences on rates of tau accumulation, but a trend for LPA having faster rates of tau accumulation in all lobes. Baseline global tau SUVR was negatively associated with rate of tau accumulation in parietal and temporal lobes. Age was negatively associated with rates of tau accumulation in frontal, temporal and occipital lobes and with rates of atrophy in frontal and parietal lobes. Voxel‐level analysis confirmed these results, with PCA showing faster rates of occipital atrophy, and LPA showing subtle evidence for diffuse faster rates of tau accumulation (Figure 1).

Conclusion

Longitudinal patterns of neuroimaging abnormalities differ between PCA and LPA, although with divergent results for tau accumulation and atrophy that may reflect differences in disease stage. Rates of change are strongly influenced by age and severity of baseline tau, with faster rates of tau accumulation in patients with younger age and lower baseline tau deposition.
The Mobile Toolbox for monitoring cognitive change
Authors: Gershon Richard C.
Published: December 2023

Background

The NIH Mobile Toolbox (MTB) includes adapted self‐administered versions of the NIH Toolbox® measures in an expanding library of other brief, sensitive, and easy‐to‐use tasks. Investigators can use the MTB to design smartphone‐based test batteries, develop custom surveys, deploy and manage data collection, and aggregate results. Ease of deployment enables use of the measures in targeted studies, as well as for use in large‐scale surveillance of adults ages 18+ (e.g., to track cognitive functioning across many ages to better understand the life‐course development of Alzheimer’s Disease and ADRD). We describe MTB and demonstrate use of the platform.

Method

MTB was created through an NIA‐funded, multi‐institutional effort led by teams based at Northwestern University, Sage Bionetworks, UCSF, and Penn State. All MTB measures were developed for use on Apple and Android smartphones, and then fully validated and then normed in a large national sample.

Result

The MTB library includes eight core cognitive tests assessing language (Spelling; Word Meaning), executive functioning (Arrow Matching; Shape‐Color Sorting), associative memory (Faces and Names), episodic memory (Arranging Pictures), working memory (Sequences) and processing speed (Numbers and Symbols). The system can also passively collect contextual factors that might influence performance. Additional cognitive and non‐cognitive assessments from the International Cognitive Ability Resource (ICAR), Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS), Test My Brain, NIH Toolbox Emotion and the Patient‐Reported Outcomes Measurement Information System (PROMIS) will be available later this year

Conclusion

The MTB addresses many scientific, practical, and technical challenges to cognitive assessment by capitalizing on advances in technology, measurement, and cognitive research. Additional clinical validation is underway in clinical and healthy populations, including those at risk for or diagnosed with cognitive impairment or AD/ADRD. MTB is suitable for use in research incorporating point‐in‐time and burst designs as well as ecological momentary assessment (EMA). Guided by the principles of open science, the platform supports data sharing and many components are open source to allow researchers and developers to integrate externally‐developed measures. The MTB is available for use in clinical research and pharmaceutical studies.
Association between G‐Protein Coupled Receptor 55 (GPR55) Single Nucleotide Polymorphisms and Alzheimer’s Disease
Authors: Mori‐Fegan Daniel K , Noor Shiropa , Wong Yuen Yan , Wu Che‐Yuan , Black Sandra E. , Ross Ruth A , Swardfager Walter ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2023

Background

G‐protein‐coupled receptor 55 (GPR55) is a lysophosphatidylinositol and novel cannabinoid receptor. GPR55 signalling and single nucleotide polymorphisms (SNPs) have been implicated as a potential therapeutic target for neurodegenerative diseases such as Alzheimer’s Disease (AD); however, foundational knowledge on the role of GPR55 in AD progression remains lacking. We hypothesised GPR55 SNP minor allele carriers would have greater brain atrophy, cognitive decline, and AD‐related biomarker changes.

Method

This retrospective, longitudinal, observational study used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We selected participants with clinically normal cognition, mild cognitive impairment (MCI) or mild AD from ADNI2 and ADNIGO phases as a discovery sample. Exploratory screening of GPR55 SNPs identified rs2969126G/C associated with brain volume. Cerebrospinal fluid amyloid beta‐42 (CSF‐Aβ42), total and phosphorylated‐tau (t/p‐tau) were considered. Mini‐Mental State Exam and the Logical Memory Delayed Recall Test were also selected to evaluate overall cognitive status, executive function, and memory. ANCOVA models evaluated baseline differences between SNP carriers and major allele homozygotes (dominant model), controlling for sex, age, baseline cognitive status and APOE e4 across AD biomarkers, brain volumetrics and cognitive measures. Longitudinal associations were assessed as interactions between SNP and visit (baseline, 12 and 24 months) in mixed models.

Result

In ADNI2/GO (n = 755), minor allele carriers represented 15% of the sample. Significantly greater decline in CSF‐Aβ42 levels was observed in Aβ42‐positive clinically normal minor allele carriers (F(1,45.2) = 6.35, p = 0.015). Carriers with MCI had significantly higher t‐tau (F(1,126) = 4.303, p = 0.04) and p‐tau concentrations (F(1,129) = 6.98, p = 0.009) longitudinally. Significantly smaller hippocampal volumes over time were seen in minor allele carriers in the whole group (F(1,444) = 5.74, p = 0.017), with a trend in the AD/MCI subgroup (F(1,325) = 3.364, p = 0.06). Clinically normal minor allele carriers had significantly poorer baseline logical memory scores (F(1,285) = 6.92, p = 0.009). These results did not replicate in the ADNI3 cohort.

Conclusion

Carriers of the GPR55 SNP rs2969126G/C minor allele had greater Aβ42 and tau biomarker abnormalities, smaller brain volumes and poorer memory scores over time in different stages of AD. This preliminary study prompts replication studies in different stages of AD progression to implicate GPR55 as a potential therapeutic target for AD.
Dopamine‐enriched functional connectivity alterations associated with neuropsychiatric symptoms in people with mild cognitive impairment and mild Alzheimer’s disease
Authors: Manca Riccardo , Venneri Annalena
Published: December 2023

Background

Alterations in neurotransmission and brain functioning are likely to be among the first neuropathological changes occurring in Alzheimer’ disease (AD). However, how such alterations are associated with neuropsychiatric symptoms still remain elusive. The aim of this study is to investigate resting‐state functional connectivity based on a priori knowledge of dopamine receptor distribution in the brain as a potential marker of AD‐related behavioural problems.

Method

Clinical, Neuropsychiatric Inventory (NPI) and structural and resting‐state functional MRI data were collected for people with either mild cognitive impairment or mild dementia due to AD. Functional MRI data were pre‐processed by using the Receptor‐Enriched Analysis of functional connectivity by targets (REACT) procedure to obtain functional connectivity (FC) maps informed by dopamine D1 (D1r) and D2 receptor (D2r) PET atlases. The association between NPI total scores and dopamine‐enriched FC was tested with multiple regression models in SPM12 by including age, education, sex, MMSE scores and total intracranial volume as covariates. An exploratory analysis was carried out to compare dopamine‐enriched FC maps between 10 patients with and 10 without psychotic symptoms.

Result

The total NPI score was negatively correlated with D1r‐enriched FC in the brainstem, thalamus, medial and inferior temporal cortices and in the precuneus and with D2r‐enriched FC in fronto‐parietal and superior temporal areas. Psychotic patients showed primarily lower D1r‐enriched FC than non‐psychotic patients in occipito‐ and medio‐temporal areas and lateral fronto‐parietal areas and lower D2r‐enriched FC in occipito‐parietal areas. However, psychotic patients also had higher D1r‐enriched FC in dorsolateral prefrontal cortices and D2r‐enriched FC in the basal ganglia, thalamus and hypothalamus than non‐psychotic patients.

Conclusion

A widespread decrease in FC influenced by the distribution density of different dopamine receptors, especially in fronto‐parietal, occipito‐temporal and brainstem areas, may represent the neural process driving behavioural alterations in people with mild AD. Such alterations may be particularly predisposing to psychotic symptoms, although a combination of both downregulation and upregulations in specific dopamine‐informed FC pathways may play a pivotal role.
Sleep Patterns and Prospective Diffusion Weighted Imaging Biomarkers: the Sleep and Dementia Consortium (SDC)
Authors: Baril Andree‐Ann , Misialek Jeffrey , Cavuoto Marina G. , Yiallourou Stephanie , Himali Dibya , Sanchez Erlan , Kline Christopher , Redline Susan , Purcell Shaun , Beiser Alexa S. , Seshadri Sudha , Gottesman Rebecca F , Lutsey Pamela L. , Pase Matthew P. , Himali Jayandra Jung ,   Sleep and Dementia Consortium
Published: December 2023

Background

Adequate sleep is necessary to maintain brain health, with sleep disturbances associated with higher Alzheimer’s disease (AD) risk. Diffusion‐weighted imaging (DWI) metrics are increasingly recognized as useful neuroimaging biomarkers to detect AD‐related white matter degeneration. We assessed the relationship between sleep patterns and prospective DWI metrics in the Sleep and Dementia Consortium (SDC). The SDC studies associations between polysomnography (PSG)‐derived sleep with dementia risk and cognitive and MRI endophenotypes.

Method

The SDC includes five community‐based cohorts, two of which have DWI acquisitions: The Framingham Heart Study (FHS) and the Atherosclerosis Risk in Communities study (ARIC). Dementia‐free participants who underwent both PSG and DWI‐MRI were selected, including 354 FHS participants (56.6±7.1y, 57%W), and 184 ARIC participants (61.6±5.0y, 52%W). The MRI session was approximately 15 years after the PSG on average (FHS:17.0±1.3y; ARIC:15.8±0.8y). Fractional anisotropy (FA) and mean diffusivity (MD) were considered for both cohorts, in addition to free‐water (FW) in the FHS. Sleep metrics were harmonized centrally, distributed for cohort‐specific linear regressions, and study‐level estimates were pooled in random effects meta‐analyses. Analyses were adjusted for demographics, obesity, time between PSG and MRI, antidepressants and sedative medication usage. An interaction term by APOE4 allele carrier status in regression models was used to test its moderating effect.

Result

In the FHS, sleep fragmentation was associated with DWI measures in the expected direction: Higher Wake After Sleep Onset and lower Sleep Maintenance Efficiency were associated with lower FA (β±SE = ‐0.17±0.09,p = 0.04; β±SE = 0.23±0.10,p = 0.03), higher MD (β±SE = 0.15±0.07,p = 0.04; β±SE = ‐0.20±0.09,p = 0.03), and higher FW (β±SE = 0.17±0.07,p = 0.02; β±SE = ‐0.22±0.08,p = 0.008). Meta‐analysis of FHS and ARIC revealed significant pooled effects between lower Sleep Maintenance Efficiency and lower FA (β±SE = 0.17±0.08,p = 0.04). In the FHS, APOE4 allele significantly moderated the association between REM sleep proportion with FA and MD, where lower REM sleep percentage was associated with higher MD (β±SE = ‐4.89±1.95,p = 0.02) and lower FA (β±SE = 4.93±2.26,p = 0.03) in APOE4 carriers only.

Conclusion

In the SDC, sleep fragmentation was associated with MRI markers of poorer white matter integrity 15 years later. Less REM sleep was associated with poorer white matter integrity in APOE4 allele carriers only, suggesting that disrupted sleep architecture may contribute and interact with neurodegenerative processes to affect brain integrity.
ConnectShareCare builds connections among care partners of people with serious illness
Authors: O'Donnell Elizabeth A. , Buccelleto Andrea C. , Van Citters Aricca D. , Nelson Eugene C. , King Joel , Holthoff Megan , Kirkland Kathryn B.
Published: December 2023

People living with chronic illnesses naturally turn to peers and community members to address the need for emotional support, practical advice, and quick help with emergent problems. Health systems have been slower to incorporate the expertise that comes from patients and caregivers/ care partners’ lived experience into the design and delivery of care.

A coproduction learning health system model aims to draw on the expertise of all to deliver optimal “whole person” care and to capture learning for improvement in the process of care delivery. This model harnesses naturally occurring peer‐to‐peer connections outside the traditional healthcare system into facilitated support networks, which extend the scope of services offered by the health system to support lay care partners, thereby improving their resiliency and inviting them to share their expertise with others.

With patients and care partners, we co‐designed and piloted an online facilitated support network, connectsharecare.org, to help persons providing care or support to an adult with a serious illness better prepare to cope with surprises that arise post diagnosis and/or during bereavement. The team prioritized two network functions (1) connecting care partners to information and (2) facilitating emotional support.

Between its launch in April 2021 and January 2023 the network has grown to more than 200 members with more than 3,500 posts over 21‐months. Most members report satisfaction with the support and information received, and say that the network helps them find meaning and purpose by supporting others. The most frequently used discussion threads focus on well‐being, emotions, and sources of joy and hope. The network is being adapted and improved as we learn from the data generated.

It is feasible to engage a multi‐stakeholder team to co‐design an online peer‐to‐peer facilitated support network for care partners of people with serious illness. ConnectShareCare is valued by care partners. This work has the potential to contribute to a coproduction learning health system for people living with Alzheimer’s disease and other dementias by (1) prioritizing and addressing potentially unique needs of their care partners, (2) generating data for continuous quality improvement, and (3) contributing to scientific knowledge.
Depression: A risk factor for Dementia?
Authors: Chummar Sydney , Parmar Mayur
Published: December 2023

Background

Dementia refers to impaired cognition, including the ability to remember, think, or make decisions that interfere with everyday activities. The most common types of dementia include Alzheimer’s disease, vascular dementia, and Lewy body dementia. There are various risk factors for dementia, but one factor that needs a more profound understanding is depression. This review study outlines the relationship between depression and the onset, as well as the prognosis of dementia.

Method

A literature review (2000‐2022) regarding the impact of depression on the development and progression of dementia was conducted. Eligibility criteria included papers published in peer‐reviewed journals, and studies involving human subjects. Exclusion criteria for this study included systematic reviews and articles published prior to 2000. A computerized search of databases (Google Scholar, PubMed) was performed using keyword search terms such as “depression” AND “dementia.”

Result

The risk of dementia varies with the presence and resolution of depression at different ages. The resolution of depression earlier in life is not associated with an increased risk of dementia, but persistent depression from adulthood to late‐life leads to a greater risk of cognitive decline. Distinct phenotypes of cognitive impairment have been noted in patients with early‐onset vs. late‐onset depression. Late‐life onset depression (LLD) may be an early sign of Alzheimer’s disease, while recurrent depression may contribute to the etiology of vascular dementia. For depression to be a modifiable risk factor, the two treatment modalities studied are: pharmacological and non‐pharmacological. Long‐term treatment of depression with antidepressants like TCAs are associated with a reduced rate in dementia, while treatment with antidepressants like selective serotonin reuptake inhibitors or nonselective serotonin reuptake inhibitors did not reduce the rate of dementia. On the other hand, treatment with exercise training has been shown to improve depressive symptoms.

Conclusion

Literature findings suggest that depression has an impact on the development and progression of dementia. Future studies can delve further into whether depression serves as an etiological factor in the development and progression of dementia. The study of such a relationship is important for preventing and treating dementia in the elderly population affected with depression.
Cumulative Frailty in Late‐Middle Aged Men is Associated with Later Regional Abnormal White Matter and Decreased Processing Speed
Authors: Hunt Jack F.V. , Fennema‐Notestine Christine , Buchholz Erik , Lyons Michael J. , Kremen William S. , Franz Carol E
Published: December 2023

Background

Frailty refers to a person’s physical and functional capabilities and increases during aging. Abnormal white matter (AWM; e.g., hyperintensities on T2‐weighted MRI) is a neuroimaging marker of small‐vessel vascular disease associated with increased risk of Alzheimer’s Disease and related dementias. While some studies have found associations between frailty indices (FIs) and global AWM, their association with accumulation of regional AWM and any related cognitive correlates is understudied.

Method

342 men from the Vietnam Era Twin Study of Aging with frailty measured at study baseline (mean age = 56.4) and structural MRI scans at follow‐up (mean 5.5 years later) were included (Table 1). The FI measure was based on a cumulative deficit model[1] using an index of 37 health‐ and function‐related items. Global AWM was defined using morphological operators on multi‐channel, three‐class tissue segmentation[2]. A novel watershed routine, applied to our AWM frequency atlas, generated 5 distinct AWM parcellations: frontal, posterior, anterior periventricular, deep, and temporal stem (Figure 1A). Cognitive factor scores (memory, processing speed, executive function, fluency) were derived from normative neuropsychological test performance.

Result

Mixed‐effects linear regression models controlling for age, years of education and twin‐pair demonstrated that higher baseline FI was associated with greater future AWM volume in temporal stem (p = 0.03) and anterior periventricular (p = 0.02) regions, but not for global or other parcellations (Figure 1B). Baseline FI was not cross‐sectionally associated with any cognitive factor score but was associated longitudinally with decreased processing speed (p = 0.002) (Table 2).

Conclusion

Higher cumulative frailty in late‐middle aged men was associated with greater future AWM burden and greater decline in processing speed. These findings suggest that cumulative frailty during the 6th decade is a relevant indicator and possible predictor of future pathological structural and functional processes in the brain. Longitudinal studies may elucidate whether frailty affects AWM progression and cognitive decline along a common causal pathway.

References:

[1] Rockwood K. A global clinical measure of fitness and frailty in elderly people. Canadian Medical Association Journal 2005;173:489‐95.

[2] Fennema‐Notestine C, et al. White matter disease in midlife is heritable, related to hypertension, and shares some genetic influence with systolic blood pressure. NeuroImage: Clinical 2016;12:737‐45.
Long‐term D‐galactose Administration Mimics Natural Aging in Rat’s Hippocampus
Authors: Pantiya Patcharapong , Thonusin Chanisa , Ongnok Benjamin , Chunchai Titikorn , Kongkaew Aphisek , Nawara Wichwara , Arunsak Busarin , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

D‐galactose has been widely used for an induction of premature aging in laboratory animals (1). However, it was observed that short‐term administration of D‐galactose failed to induce some aging phenomena (2). Therefore, we aimed to determine whether long‐term administration of D‐galactose could mimic natural aging of the rat’s hippocampus, based on the primary, antagonistic, and integrative hallmarks of aging.

Method

Seven‐week‐old male Wistar rats (n = 12) were randomly injected with either normal saline as vehicle (n = 6) or 150 mg/kg/day of D‐galactose subcutaneously for 28 weeks. Seventeen‐month‐old male Wistar rats (n = 6) were also included as the naturally aged controls. At the end of week 28 of the experiment (when the rats were 35 weeks old for D‐galactose‐induced aging and 24 months old for natural aging), all rats were sacrificed for brain collection. The, the hippocampus was examined for molecular studies.

Result

Long‐term D‐galactose administration demonstrated the features of natural aging in the hippocampus of young rats. These include loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication (Figure A). In the context of cognitive function, natural aging and long‐term D‐galactose administration similarly impaired hippocampal learning and memory, as indicated by reducing the novel object location and recognition tests (Figure B, C).

Conclusion

Long‐term administration of D‐galactose‐induced aging potentially mimic natural aging process of the hippocampus. These findings suggest that long‐term administration of D‐galactose is suitable for an establishment of the aging model in young animals.

Reference

1. Shwe T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. Role of D‐galactose‐induced brain aging and its potential used for therapeutic interventions. Exp Gerontol. 2018;101:13‐36.

2. Cardoso A, Magano S, Marrana F, Andrade JP. D‐Galactose High‐Dose Administration Failed to Induce Accelerated Aging Changes in Neurogenesis, Anxiety, and Spatial Memory on Young Male Wistar Rats. Rejuvenation research. 2015;18(6):497‐507.
Combinations of blood biomarkers in a real‐life memory clinic in Thailand
Authors: Haethaisong Thanaporn , Thanapornsangsuth Poosanu , Booncharoen Kittithatch , Luechaipanit Watayuth , Sarutikriangkri Yuthachai , Tangnimitchoke Suchart , Likitjaroen Yuttachai , Hemachudha Thiravat
Published: December 2023

Background

Different Alzheimer’s disease (AD) blood‐based biomarkers (BBM) exhibit unique patterns and trajectories throughout the natural history of AD, and thus, their combination may result in a higher diagnostic accuracy. While the usefulness of BBM combinations had been demonstrated in research cohorts, their performance in real‐life memory clinics is unclear. Additionally, previous BBM studies have been largely confined to high‐income countries and have often excluded non‐white populations. We aimed to evaluate the performance of BBM combinations in a real‐world clinical setting, specifically in a memory clinic in Thailand

Method

The study enrolled 64 memory clinic patients who had undergone amyloid‐positron emission tomography (PET) or cerebrospinal fluid (CSF) assessment for AD biomarkers. Plasma amyloid‐β42 (Aβ42), Aβ40, p‐tau181 were quantified for each participant using single molecule array as well as APOE genotype determined. The accuracy of individual biomarkers in discriminating amyloid status (as confirmed by PET or CSF) were assessed using receiver operating characteristic (ROC) analysis. Logistic regression models were then created for different BBM combinations, and their performance was determined using ROC analysis. To ensure robustness and generalizability of the results, two‐fold cross‐validation was repeated 10 times on the best‐performing model

Result

The study consisted of 47 (73.4%) female participants with a median age of 70.0 years (interquartile range: 63.75‐75.25). Amyloid status was positive in 43 (67.2%) of the participants. Plasma Aβ42/Aβ40 ratio, Aβ42/p‐tau181 ratio and p‐tau181 had areas under the curve (AUC) of 0.68 (95% confidence interval (CI) 0.52‐0.84), 0.88 (95%CI 0.79‐0.98) and 0.87 (95%CI 0.79‐0.96) for detecting amyloid status, respectively. Logistic regression models that included APOE genotype, Aβ, and p‐tau181 had the highest AUC of 0.90‐0.91. Two‐fold cross‐validation performed on the model that included APOE genotype and the Aβ42/p‐tau181 ratio revealed an average AUC of 0.90 (standard deviation: 0.029) over 10 repeats

Conclusion

The combination of APOE genotype, plasma Aβ, and p‐tau181 displayed an exceptionally high diagnostic accuracy in discriminating amyloid status in a memory clinic setting. However, further studies are needed to evaluate the cost‐effectiveness of various ways to implement BBMs into real‐world clinical practice, particularly in low‐ and middle‐income countries
Speech processing in the brain at risk for dementia
Authors: Bolt Elena , Giroud Nathalie
Published: December 2023

Background

Given the close relationship between hearing and cognitive function in older age, characterization of speech processing deficits along the auditory pathway is of great importance for the brain at risk of dementia. In the ascending, primary auditory pathway, signals pass through subcortical relay stations in the brainstem and midbrain before being integrated into cortical areas. A recent study suggests that the pathophysiology of MCI extends to speech encoding in the brainstem and that both cortical and subcortical markers of speech processing have predictive potential for putative Mild Cognitive Impairment (MCI). In this project, we are testing these neural speech processing markers to see if they can distinguish healthy older adults with age‐related hearing loss from those at risk for dementia.

Methods

Electroencephalography (EEG, 32 channels, sampling rate = 16 384 Hz) will be recorded from N = 40 older participants (age ≥ 60 years, retired) while listening to excerpts from an audiobook. We use a novel EEG paradigm that allows us to simultaneously measure cortical and subcortical responses to natural running speech. Based on their Montreal Cognitive Assessment (MoCA) score, participants are divided into an experimental group with “putative MCI” (MoCA < 26) and a control group (MoCA ≥ 26). In addition, we perform audiometric testing with pure tones (PTA) and speech‐in‐noise (SiN) tests to assess participants' hearing function.

Results

We are currently in the middle of data collection and will be able to present preliminary results at AAIC. We expect to see altered speech processing in the experimental group, particularly driven by slower and weaker encoding at the subcortical level. In a next step, we aim to use the neural markers of speech processing that emerge from this framework as features for a diagnostic model that predicts MCI using a binary classifier, considering the hearing status of the participants.

Conclusion

The main goal of this study is to investigate neural markers of speech processing for their differential diagnostic potential for the brain at risk for dementia. Depending on the results, such neurophysiological markers could prove useful for early diagnosis in the clinic in the longer term.
Cognitive profile of idiopathic normal pressure hydrocephalus (INPH)
Authors: Belessiotis‐Richards Clara , Abrol Esha , Toma Ahmed , Joyce Eileen , Livingston Gill
Published: December 2023

Background

Cognitive deficits in people with idiopathic normal pressure hydrocephalus (INPH) are thought to differ from Alzheimer’s dementia (AD) but this has not been systematically explored.

Method

We undertook a systematic review and meta‐analysis. Peer‐reviewed studies publishing new data, with defined diagnostic criteria for INPH, and using formal cognitive tools were included. Quality was assessed using the Newcastle‐Ottawa Scale. Weighted mean difference (WMD) in score was calculated using random‐effects meta‐analysis for cognitive tests used in at least 2 studies. We assessed heterogeneity using I2. Sensitivity analyses explored results according to global cognition.

Result

13 studies met inclusion criteria. Participants with INPH had a pooled weighted MMSE score of 22.6 (95% confidence interval (CI) 21.3‐23.9). Studies were divided into those that matched AD participants to INPH participants for global cognition or selected mild AD (n = 6) and those that did not (n = 7). Participants with INPH performed better on the Boston Naming Task across all studies (n = 2; WMD: 1.41; 95% CI: 0.50, 2.31; I2 47%). There were no significant differences in semantic or phonemic fluency, delayed verbal recall, digit span backwards or forwards, or constructional praxis between AD and INPH across all studies. However, sensitivity analyses examining INPH participants compared to mild or matched AD showed significantly worse performance in INPH for semantic (n = 3; WMD: ‐1.37; 95% CI: ‐2.19, ‐0.55; I2 0%) and phonemic fluency (n = 3; WMD: ‐5.18; 95% CI: ‐6.95, ‐3.41; I2 0%), and in the Frontal Assessment Battery (n = 3; WMD: ‐2.33 points; 95% CI: ‐3.30, ‐1.36; I2 0%). Worse performance was also seen on sensitivity analysis in digit span backward (MD: ‐0.70; 95% CI: ‐1.20, ‐0.20) and constructional praxis (MD: ‐0.50; 95% CI: ‐0.90, ‐0.10) but only 1 study was available for each test.

Conclusion

In this meta‐analysis, people with INPH tended to score within the mild dementia range on global cognitive testing. There were observable differences in cognitive profile between INPH and AD. People with INPH may have less aphasia but score significantly lower on tests of executive function than people with mild AD. These results could inform identification of INPH in memory services.
Investigating how CSTB affects the activity of cysteine cathepsin in the AD‐DS, EOAD, and human cellular models of trisomy Hsa21
Authors: Wu Yixing , Cleverley Karen , van Dalen Floris , Verdoes Martijn , Crawford Samuel , Wray Selina , Wiseman Frances K
Published: December 2023

Background

People with Down syndrome (DS) have a high genetic risk of developing Alzheimer’s disease (AD) ‐related dementia and pathology. Triplication of a human chromosome 21 (Hsa21)‐located gene APP play an important role in AD pathology. Wiseman et al. demonstrated that triplication of a gene or genes on Hsa21, other than APP exacerbates amyloid‐β pathology in an APP transgenic mouse model. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and Aβ accumulation. Cystine cathepsins are predominantly expressed in microglia in the brain and are involved in key neuroinflammation pathways. Hsa21‐located gene CYSTATIN B (CSTB) is an endogenous inhibitor of cathepsin proteases. We hypothesise that three copies of CSTB inhibit cathepsin activity and that this could contribute to altered neuroinflammation in people with DS.

Method

Human fibroblasts from individuals with DS and euploid controls, temporal cortex samples from individuals who had AD‐DS and Braak‐stage matched euploid cases of early‐onset AD (EOAD) or healthy aging and human iPSC‐derived microglia‐like cells (iMLCs: T21 and an isogenic control) were used. Western blot and immunocytochemistry were conducted to determine the abundance and subcellular localisation of CSTB. Cathepsin B (CatB) activity in human fibroblasts and temporal cortex samples was measured using an enzymatic assay (Abcam) and/or a pan‐cysteine cathepsin quenched activity‐based probe (BMV109).

Result

Western blotting confirmed that trisomy of Hsa21 resulted in an increase in the protein level of CSTB, that endogenous CSTB is predominantly localised in the cytoplasm and that its subcellular localisation is not altered by trisomy of Hsa21. Significantly lower CatB activity occurs in the temporal cortex of people who had AD‐DS compared with individuals who had EOAD. However, CatB enzymatic activity was not significantly altered in Hsa21 trisomic fibroblasts.

Conclusion

Next, we will determine in iMLCs, whether trisomy of chromosome 21 alters CatB activity and which genes have altered expression at baseline and after neuroinflammatory challenge.
The clinical, neuropsychological and neuroimaging characters of GRN mutations carriers in a Chinese PUMCH dementia cohort
Authors: Liu Caiyan , Dong Liling , Wang Jie , Li Jie , Huang Xinying , Lei Dan , Chu Shanshan , Mao Chenhui , Sha Longze , Xu Qi , Peng Bin , Cui Liying , Gao Jing
Published: December 2023

Background

Mutations in the progranulin gene on chromosome 17(GRN) is considered as one of most common causes of frontotemporal lobe degeneration. However, the phenotype and genotype correlation of GRN varies among different cohorts and ethnicities. In Chinese people, the genotype of GRN has not been fully elucidated.

Method

1945 patients with dementia at Peking Union Medical College Hospital underwent next‐generation sequencing (NGS) analysis. GRN variations classified as likely pathogenic and of uncertain significance were identified. Demographic information, clinical presentations, and neuroimaging were collected. The clinical, neuropsychological and neuroimaging characters were investigated.

Result

Three patients with four likely pathogenic mutation: p.P50fs & p.W49_P50delinsX, p.P439fs, p.R110X, and thirteen patients with uncertain significance mutations were enrolled. Cognitive dysfunction, behavior, and personality changes as well as aphasia were the most common presentations. Asymmetrical atrophy of the frontal lobe and temporal lobe appeared in 64% GRN mutation carriers. Parietal lobe dysfunction or parietal lobe atrophy existed in all patients. White matter lesions existed in 79% patients. The majority of clinical phenotype was frontotemporal lobe degeneration, though cerebral vascular lesions were obvious in some of them especially among old onset patients. The proportion of ApoE e4 carriers were higher in old onset patients than those in young onset ones.

Conclusion

GRN mutation is rare in Chinese dementia patients. The phenotype and genotype correlation is specific and overlaps.