bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery of Novel Ophthalmic Imaging Biomarkers for Neurodegenerative Disease
Authors: Cicalese Stephanie , Ping Xiaoli , Nunes Christopher , Luo Weiwei , Shen Xiaolan , Marcus Jacob , Smith Sean M , Uslaner Jason M. , Drolet Robert E
Published: December 2023

Background

The retina is increasingly investigated as a site of Alzheimer’s Disease (AD) manifestation, with amyloid β (Aβ) plaques being found in the retina of AD and mild cognitively impaired (MCI) patients, however functional changes in the retina are poorly understood. Retinal imaging techniques can be utilized for neurodegenerative biomarkers, since the retina is the only CNS organ available for noninvasive tracking.

Method

Retinal imaging techniques were using to compare the retina of wild‐type (WT) or AD transgenic mice containing the APP: Swedish and Indiana mutation expressed under the prion promoter (TgCRND8) at 20 and 30 weeks of age (n = 10 mice per genotype). Optical coherence tomography (OCT) for retinal thickness assessment, Fundus Autofluorescence Imaging (FAF) for aggregate visualization, and electroretinogram (ERG) for retinal neuronal electrical activity were performed. Aβ ELISA was also performed on retina and cortex to evaluate amyloid burden correlation.

Result

Mean retinal insoluble Aβ 1‐42 was significantly elevated in TgCRND8 mice relative to WT at 23 weeks (35 vs 4.2 pg/mL, P<0.05) and 42 weeks (77.9 vs 7.5 pg/mL, P<0.05), and correlated with insoluble cortical brain Aβ 1‐42 (Pearson’s r = 0.847, P = 0.001). Total retinal thickness was significantly higher in TgCRND8 mice relative to WT (233 µm vs 225 µm, P<0.01). Specifically, the retinal nerve fiber layer (RNFL) was thicker in TgCRND8 mice (28.5 vs 22.9 µm, P<0.01). FAF imaging revealed significant autofluorescent aggregate detection in TgCRND8 mice both in the RNFL (94.3 vs 59.8 spots, P<0.01) and outer plexiform layer (OPL) (87.8 vs 49.3 spots, P<0.01). Lastly ERG revealed reduced b wave amplitude in TgCRND8 mice relative to WT (197.45 vs 457.9 µV, P<0.001) and photopic negative response (PhNR) wave amplitude (8.2 µm vs 25.7 457.9 µV, P<0.001). These values are indicative of dysfunctional bipolar and retinal ganglion cell electrical activity.

Conclusion

TgCRND8 mice have functional changes in retina thickness, FAF lipofuscin deposition, and ERG, which may prove invaluable as biomarkers for pre‐clinical AD diagnosis, monitoring and drug efficacy trials.
Evaluation and modification of the 10‐item short form Communicative Participation Item Bank for persons with primary progressive aphasia
Authors: Fegter Ollie , Shaunfield Sara , Roberts Angela C , Rogalski Emily J
Published: December 2023

Background

Primary progressive aphasia (PPA) is a dementia syndrome characterized by language and communication impairments with relative sparing of other cognitive domains. Given the language difficulties associated with PPA, it is important to develop outcome measures relevant to the communication experiences of persons with PPA (PwPPA). The 10‐item Communicative Participation Item Bank (CPIB) has been used as a measure of communication participation in PPA. However, the CPIB was validated as a disorder‐agnostic measure of communication participation and the content validity has not been evaluated for PPA. The purpose of this study is to evaluate the face and content validity of the 10‐item CPIB for individuals with PPA and their communication partners (CP).

Method

Phase one of this project focused on conducting cognitive interviews with participants who had previously completed the CPIB during the Communication Bridge randomized controlled trial (NCT03371706). PwPPAs and CPs each completed the CPIB during a semi‐structured cognitive interview designed to evaluate the measure format, instructions, response options, item comprehension, and relevance of each item to PwPPA experiences. To evaluate content validity, participants were asked open‐ended questions to elicit relevant communication participation experiences missing from the questionnaire. Responses to closed‐ended questions (e.g., clarity, relevance) were tabulated and open‐ended responses (e.g., item comprehension, missing content) were analyzed via thematic analysis. Summaries of measure format, instructions, and response options were generated, as well as item‐level findings regarding comprehension, relevance, and missing content.

Result

Preliminary findings revealed both PwPPAs and CPs: a) considered the instructions to be clear (N = 12, 100%); b) recommended adding a fifth response option (e.g., “Somewhat) to better represent the range of communication situations; c) reported all items except one (“persuade…to see a different point of view”) were relevant (N≥10; ≥83%, for 9 items); and d) talking on the phone was the most reported missing communicative participation situation (N = 8; 66%). Further, 2 of 5 PwPPAs reported talking over videochat, and 2 of 5 CPs reported email/texting as missing.

Conclusion

Preliminary findings indicate that modifications to the 10‐item CPIB short form may be needed for use with PwPPA and their CPs to more fulsomely capture communication participation in PPA.
Identifying probable dementia in undiagnosed Black and White Americans using machine learning in Veterans Health Administration electronic health records
Authors: Tsuang Debby W , Shao Eugene , Todd Kaitlin , Shutes‐David Andrew , Millard Steve , Brown Karl , Wilson Katie , Thomas Amy , Zeng Qing
Published: December 2023

Background

The application of machine learning (ML) tools in electronic health records (EHRs) can help reduce the underdiagnosis of dementia, but models that are not designed to reflect minority population may perpetuate that underdiagnosis.

Method

To address the underdiagnosis of dementia in both Black Americans (BAs) and white Americans (WAs), we sought to develop and validate ML models that assign race‐specific risk scores. These scores were used to identify undiagnosed dementia in BA and WA Veterans in EHRs. More specifically, risk scores were generated separately for BAs (n = 10K) and WAs (n = 10K) in training samples of cases and controls by performing ML, equivalence mapping, topic modeling, and a support vector‐machine (SVM) in structured and unstructured EHR data. Scores were validated via blinded manual chart reviews (n = 1.2K) of controls from a separate sample (n = 20K). AUCs and negative and positive predictive values (NPVs and PPVs) were calculated to evaluate the models.

Result

Among Veterans with undiagnosed dementia who underwent chart review, those diagnosed by expert clinician reviewers with possible/probable dementia had higher ADRD ML risk scores compared to those diagnosed with no dementia (0.45 [0.38] vs. ‐0.02 [0.51] for BAs, and 0.38 [0.41] vs. ‐0.02 [0.47] for WAs; (see figure 1).

Of the 1,200 Veterans who underwent chart review, 15.3% (n = 92) of BAs and 9.5% (n = 57) of WAs were identified with possible/probable dementia. However, adjusting for oversampling of Veterans with higher scores, the adjusted estimated prevalence was 4.1% for BA Veterans and 3.6% for WA Veterans. There was a strong positive relationship between risk scores and the prevalence of undiagnosed dementia (Figure 2). As anticipated, for Veterans with scores below the 90th percentile, the percentages of undiagnosed dementia were low: 3.9% for BA and 2.9% for WA Veterans. Among Veterans with scores above the 90th percentile, we found that a higher percentage of BA Veterans had undiagnosed dementia than WA Veterans: 25.6% vs. 15.3%.

Conclusion

Our findings suggest that race‐specific ML models can assist in the identification of undiagnosed dementia, particularly in BAs. Future studies should investigate implementing EHR‐based risk scores in clinics that serve both BA and WA Veterans.
Cognitive reserve: the association between lifestyle enrichment and incident dementia
Authors: Wu Zimu , Pandigama Danushika , Wrigglesworth Jo , Owen Alice , Woods Robyn , Chong Trevor T.‐J. , Orchard Suzanne , Shah Raj C , Sheets Kerry M. , McNeil John J , Murray Anne , Ryan Joanne
Published: December 2023

Background

Whether socially and mentally stimulating activities in older age can contribute to cognitive reserve and influence dementia risk remains unclear. This study investigated the association between lifestyle enrichment and dementia risk in older individuals, after adjusting for education, socioeconomic status and a range of health‐related factors.

Method

Data came from a cohort of community‐dwelling adults aged 70+ recruited in Australia, who were generally healthy and without major cognitive impairment at baseline. Exploratory factor analysis was performed using 19 individual measures of leisure activities and social networks. The adjusted association between seven composite factors of lifestyle enrichment and incident dementia was examined using Cox proportional hazards regression.

Result

Among 10,318 participants, more frequent engagement in adult literacy (writing, computer usage and education classes) and active mental activities (games/cards/chess, crosswords/puzzles) was associated with an 11% (95% CI: 0.85‐0.93) and a 9% (95% CI: 0.87‐0.95) lower risk of dementia respectively. To a lesser extent, participation in creative artistic (craftwork/woodwork/metalwork, painting/drawing) (HR: 0.93, 95% CI: 0.88‐0.99) and passive mental activities (reading, watching television, music/radio listening) (HR: 0.93, 95% CI: 0.86‐0.99) were also associated with reduced dementia risk. In contrast, interpersonal networks, social activities and external outings were not associated with dementia risk in this sample.

Conclusion

These findings may guide policies for geriatric care and interventions targeting dementia prevention for older adults. Engagement in adult literacy, creative art, as well as active and passive mental activities, may help reduce dementia risk in late life.
Validity, Feasibility and Effectiveness of a Voice‐recognition Based Digital Cognitive Screener for Dementia and Mild Cognitive Impairment in Community‐dwelling Older Chinese Adults: A Large‐scale Implementation Study
Authors: Zhao Xuhao , Wen Haoxuan , Xu Guohai , Pang Ting , Zhang Yaping , He Xindi , Hu Ruofei , Yan Ming , Chen Christopher , Wu Xifeng , Xu Xin
Published: December 2023

Background

To investigate the psychometric properties, administration efficiency and implementational feasibility of a previously piloted voice recognition‐based digital cognitive screener for dementia detection in a large‐scale community of elderly participants.

Method

Eligible participants completed the demographic, lifestyle investigations and the DCS. Domain‐specific and global cognition was assessed by a comprehensive neuropsychological test battery. Diagnosis of mild cognitive impairment(MCI) and dementia was made based on the clinical dementia rating. Completion rate and administration time for the DCS were recorded. Correlation between the DCS and domain‐specific and global cognitive performance were assessed. Receiver operating characteristic (ROC) analyses examined the discriminate validity of the DCS in detecting MCI and dementia. A cost‐consequences analysis was conducted to compare the screening efficacy of DCS with two traditionally administered cognitive assessment tools, the Mini‐Mental State Examination(MMSE) and the Montreal Cognitive Assessment (MoCA), was conducted.

Result

Among a total of 11,186 participants, the completion rate of the DCS was 97·5% with a conduction time of 5·6–6·1 minutes, regardless of gender, age and education stratifications. DCS total score was significantly associated with domain‐specific and global cognitive z‐scores. Area under the curves (AUCs) of the DCS were 0·95 (0·92, 0·99) and 0·83 (0·79, 0·88) for dementia and MCI detection, respectively. There was no significant difference on the AUCs among different age‐ and education‐stratified subgroups. Comparing with the MoCA and MMSE, DCS resulted in time savings of 35·4%–36·0% and 30·7%–31·2% for identifying dementia cases, as well as 22·6%–22·8% and 16·2%–16·4% for identifying MCI cases.

Conclusion

Our findings demonstrated that the DCS was an effective and efficient tool for case‐finding of dementia and MCI in a Chinese community. The large‐scale implementation of the DCS among older Chinese adults could be an practical cognitive screening strategy to improve the management of healthcare resources.
Does FOXO3 longevity genotype explain the conflicting data on late‐life hypertension and risk of Alzheimer’s disease?
Authors: Chen Randi , Morris Brian J , Donlon Timothy A , Ross G. Webster , Kallianpur Kalpana J , Willcox Bradley J , Allsopp Richard C , Nakagawa Kazuma , Masaki Kamal H
Published: December 2023

Background

The association of late‐life hypertension (LHTN) with Alzheimer’s disease (AD) remains controversial. We hypothesize that FOXO3 longevity‐associated genotype modulates the association between LHTN and incident AD.

Method

Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0 ± 4.1 years, range 71‐93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, LHTN at baseline, and diagnosis of incident dementia over 21 years follow‐up. Association of FOXO3 genotype with LHTN and incident all‐cause dementia, vascular dementia (VD) and Alzheimer’s disease was assessed using Cox regression.

Result

During the follow‐up, 725 men were diagnosed with all‐cause dementia, 513 with AD and 104 with VD. A multivariable Cox model, adjusting for age, education, APOE‐ε4 and cardiovascular risk factors, showed LHTN increased VD risk (HR = 1.71, 95%CI = 1.08–2.71, p = 0.022), but not AD risk. We found no significant protective effect of FOXO3 longevity genotype, nor of LHTN, on all‐cause dementia and AD at the population level. However, in a full Cox model adjusting for age, education, APOE‐ε4 and other cardiovascular risk factors, there was a significant interaction effect of LHTN and FOXO3 longevity genotype on incident AD (ß = –0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), LHTN showed protection against AD (HR = 0.72; 95% CI = 0.55–0.95, p = 0.021). In men with FOXO3 rs2802292 non‐longevity genotype (TT), LHTN had no protective effect (HR = 1.16; 95% CI = 0.90‐1.51, p = 0.25).

Discussion

Since the effect of LHTN on AD incidence differed according to FOXO3 genotype, the overall effect, namely, a weighted average effect of LHTN on AD across different FOXO3 genotypes, would be moving towards the null (i.e., HR = 1). This would explain why most studies have found no significant association between LHTN and AD. One exception is the Ibadan study, in which all participants were African American. African Americans have the highest proportion (94%) of FOXO3 rs2802292 longevity genotype (TG/GG) in all races, and the strongest effect of LHTN in protecting against AD (RR = 0.33).

Conclusion

This longitudinal study found that FOXO3 genotype modulates the effect of late‐life hypertension on incident AD, thus explaining the conflicting data on late‐life hypertension and Alzheimer’s disease.
Combined DTI and NODDI Scalars Improves Understanding of At‐Risk Tissue in and Around White Matter Hyperintensities
Authors: Sudhakar Tejaswi D , Anderson Cole E , Peskind Elaine R , Li Ge , Iliff Jeffrey J , Levendovszky Swati Rane
Published: December 2023

Background

The novel diffusion‐based Neurite Orientation and Dispersion Imaging (NODDI) model may provide complementary information to Diffusion Tensor Imaging (DTI) to increase sensitivity in characterizing tissue microarchitecture. We examined if one or a combination of both approaches can improve our understanding of at‐risk tissue in and around white matter hyperintensities (WMH).

Method

From ADNI3, we identified individuals [n = 54, age = 78 ± 7, 46% F) with concurrent measures of multi‐shell DTI, 3D FLAIR, and 3D MPRAGE. We segmented WMH from structural data using Lesion Segmentation Toolbox. We derived DTI (FA, MD) and NODDI parameters (NDI, ODI, Fiso) using QSIprep. We dilated up to 5 mm outside the WMH, applied an FA threshold of ≥ 0.2 to exclude gray matter, calculated DTI and NODDI parameters at 1 mm intervals within this region. We performed Pearson correlations between all parameters. Assuming normal white matter at 5 mm, we normalized these parameters with their respective values at 5 mm and plotted the spatial variation of each parameter in and outside the WMH.

Result

Normalized DTI and NODDI parameters representing spatial variations within the 5 mm region are shown in Fig 1A. Table 1 shows p‐values comparing DTI and NODDI parameters between WMH the subsequent regions outside it. Compared to WMH, Fiso was significantly different at all distances. FA showed similar spatial characteristics with NDI and was negatively correlated with ODI. Fiso correlated very strongly with MD.

Conclusion

In the WMHs and its immediate vicinity, low FA, NDI, ODI suggest lower cell density, while low Fiso and MD suggest low extracellular fluid volume. Together these observations may reflect cytotoxic edema, cell loss, and injury. Normal appearing white matter (3‐5 mm) showed high FA, NDI, ODI, and low MD consistent with high cell density and normal extracellular water. In the transition between WMH vicinity and normal white matter, low FA, NDI, ODI, high MD and Fiso suggest cell loss only. This transition region could be at risk of converting to WMH. Future work will include longitudinal evaluation of WMH growth in the at‐risk tissue. However, final validation of WMH pathology will need histological confirmation.
Spontaneous‐ and Perturbation‐Based Cortical Excitability Markers of Plasma pTau181 Concentrations in Healthy Middle‐aged Adults
Authors: Perellón‐Alfonso Ruben , Abellaneda‐Pérez Kilian , Cabello‐Toscano María , Mulet‐Pons Lídia , Vaqué‐Alcázar Lídia , Cattaneo Gabriele , Redondo‐Camós María , España‐Irla Goretti , Delgado‐Gallén Selma , Pileckyte Indre , Sánchez Javier Solana , Zetterberg Henrik , Franzmeier Nicolai , Tormos‐Muñoz Josep Mª , Pascual‐Leone Alvaro , Bartrés‐Faz David
Published: December 2023

Background

Alzheimer’s disease is characterized by cortical hyperexcitability in the early stages, which may be attributed to the intricate interplay between tau and amyloid β pathologies. To combat the propagation of tau pathology and cognitive decline, it may be beneficial to maintain a high degree of functional brain network segregation. Additionally, the use of non‐invasive brain stimulation techniques to alter cortical excitability could help alleviate cognitive deficits. However, it is unclear how these interventions are related to tau or amyloid biomarkers.

Method

In this study, 530 participants aged 40 to 65 from the Barcelona Brain Health Initiative cohort were analyzed to investigate the connection between plasma concentration of tau phosphorylated at amino acid 181 (pTau181), cortical excitability, and segregation of functional brain networks. Participants had functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and pTau181 available. A subset of 47 participants also underwent transcranial magnetic stimulation with concurrent EEG (TMS‐EEG). Cortical excitability was assessed using the one‐over‐f slope of the EEG power spectrum (1/f‐slope) and evoked response to a TMS perturbation (TEP) of the left prefrontal cortex (L‐PFC) between 160‐240ms post single‐pulse TMS. The degree of segregation between major functional networks was measured from fMRI data using the system segregation statistic.

Result

A generalized linear model with a gamma distribution (Table 1) revealed that steeper 1/f‐slope correlated with higher pTau181 concentration, particularly in participants older than 53 years of age (Figure 1.A), or system segregation below 0.28 (Figure 1.B). A multiple linear regression within the TMS‐EEG subsample (Table 2) revealed that the TEP response correlated positively with pTau181 as age increased, and that this model, despite including a smaller sample size, better explained pTau181 concentrations.

Conclusion

The study shows that cortical excitability is related to pTau181 based on age and system segregation. The TEP response is a more sensitive marker than unperturbed EEG metrics in explaining the relation between excitability and pTau181 concentrations. Combined TMS with EEG could potentially be an inexpensive and scalable approach for early identification and longitudinal tracking of middle‐aged adults at risk for cognitive decline and dementia.
Preliminary results investigating synaptic density across the Alzheimer’s Disease continuum
Authors: Giorgio Joseph , Soleimani‐Meigooni David N. , Chen Xi , Toueg Tyler N , Weimer Robby , Zinnhardt Bastian , Baker Suzanne L. , Janabi Mustafa , Rabinovici Gil D. , Jagust William J.
Published: December 2023

Background

Progressive loss of synapses occurs throughout the Alzheimer’s Disease (AD) continuum and is closely associated with cognitive impairment. Here, we present pilot data investigating variation in synaptic density across aging and AD using 18F‐SynVesT‐1 molecular imaging, a ligand for the SV2A site.

Method

26 participants underwent 18F‐SynVesT‐1 imaging to estimate synaptic density in‐vivo. Participants were young adults (Y) (n = 7; Age = 26.1+‐3.8; Sex(F) = 4), cognitively unimpaired older adults (O) (n = 13; Age = 79.7+‐4.27; Sex(F) = 7) or patients (P) (n = 6; Age = 66.3 +‐8.2; Sex (F) = 1; Diagnoses EOAD = 3, MCI = 1, PCA(AD) = 1; lvPPA(AD)). We collected a 90 min dynamic sequence after injection of 5 mCi of tracer. Participant whole brain Distribution Volume Ratio (DVR) images were generated using a cerebellar grey matter reference region. O and P groups also underwent tau and β‐amyloid (Aβ) PET imaging (O: 18F‐flortaucipir,11C‐PiB; P: 18F‐PI‐2620, 18F‐Florbetaben) and a visual assessment of tau and Aβ positivity for AD was determined by an expert reviewer (DSM).

Result

We contrasted 18F‐SynVesT‐1 uptake in four cortical regions for Y, O and P. In each region, we observed a significant effect of group (Hippocampus F(1,23) = 4.35, p = 0.025 (uncorrected); Meta‐Temporal ROI F(1,23) = 4.36, p = 0.025 (uncorrected); Temporal F(1,23) = 9, p<0.01(FWE corrected); F(1,23) = 14.4, p<0.001 (FWE corrected)) Figure 1. Further, we observe non‐significant numerical differences suggesting lower synaptic density in participants with biomarker evidence of Aβ and tau Figure 1. Finally, we observe a positive partial correlation between temporal cortical thickness and temporal 18F‐SynVesT‐1 uptake controlling for age (r(23) = 0.54,p = 0.006) Figure 2. We observe no relationship between age and tracer uptake in the cerebral white matter (r(24) = ‐0.01,p = 0.95), suggesting the reference region selected does not introduce systematic biases in the DVR image.

Conclusion

This demonstrates 18F‐SynVesT‐1 PET can capture age and AD related decreases in synaptic density across the cortex. Further, we show an association between cortical thickness and synaptic density in the temporal cortex controlling for biases due to age. Future work will incorporate additional participants and investigate participant level associations between regional 18F‐SynVesT‐1 uptake, cognition, and in‐vivo AD pathologies.
Cholinergic white matter hyperintensity volume, cognitive decline, and incident dementia in older adults
Authors: Lu Heyang , Wang Yingzhe , Jiang Yanfeng , Chen Xingdong , Cui Mei
Published: December 2023

Background

White matter hyperintensities (WMHs) are frequently observed in the elderly and their severity tends to increase with age. Previous studies have revealed that WMHs are closely related to cognitive dysfunction. However, as inter‐individual variations and a clinicoradiological discrepancy exist, not all individuals with severe WMH burden experience worse cognitive performance. Furthermore, the location of WMHs appears to be a critical factor in the relationship between WMHs and cognitive function. Few studies take both volume and location of white matter hyperintensities (WMHs) into account to explore the association between WMH burden and cognitive impairment. We therefore investigated associations of cholinergic WMH volume (WMHV) with global cognitive function, cognitive decline, and incident dementia in older adults.

Method

A total of 752 older adults (mean age 60 years, 50% female) from the Taizhou Imaging Study were involved. Brain magnetic resonance imaging data at baseline and repeated measures of cognition over 5 years were collected and analyzed. WMHV in whole brain, the cholinergic pathways, and different tract classes in the Montreal Neurologic Institute standard space was obtained using the Lesion Segmentation Toolbox and tools from FMRIB Software Library. Multivariable linear regression, Cox regression, and partial correlation tests were performed.

Result

Over a median 5.67 (IQR: 2.88‐6.84) years of follow‐up, cholinergic WMHV was associated with annual decline of Mini‐Mental State Examination (MMSE) (β = ‐0.206; P = 0.006), and incident dementia (HR = 3.45; 95%CI: 2.08‐5.74). Within the cholinergic pathways, WMHs in commissural fibers were related to incident dementia. However, greater global WMHV only slightly increased the risk of incident dementia (HR = 1.03; 95%CI: 1.01‐1.06). Neither global nor cholinergic WMHV was associated with MMSE in cross‐sectional analysis.

Conclusion

Cholinergic WMHV is associated with longitudinal cognitive decline and incident dementia in older adults. Within the cholinergic pathways, commissural fiber tracts were strategic locations correlated to incident dementia. Our findings suggest cholinergic WMHV might be a potential indicator of cognitive deterioration.
Neuropathological changes of a patient with AD treated with verubecestat
Authors: Lleo Alberto
Published: December 2023

Background

Clinical trials with BACE‐1 inhibitors in patients with Alzheimer’s disease (AD) have been discontinued due to safety concerns. The adverse effects included reversible early cognitive worsening and brain atrophy. Some data suggest that these effects could be due to an off‐target effect of the inhibitor on other BACE‐1 substrates that could impact synaptic function and structure. However, the precise underlying mechanisms of these effects in humans remain controversial.

Method

We describe the neuropathological examination of a patient with AD treated for 38 months with low doses of the BACE‐1 inhibitor verubecestat.

Result

Brain examination showed small plaque size, reduced dystrophic neurites around plaques, and reduced synaptic‐associated Aβ compared with a group of age‐matched untreated sporadic AD (SAD) cases. We also describe a detailed analysis of synaptic morphology in this case.

Conclusion

Our findings suggest that BACE‐1 inhibition has an impact on synaptic soluble Aβ accumulation and neuritic derangement in AD. Neuropathological data could help to understand the effect of BACE inhibition in humans.
Impact of Empathy on Oxytocin and Cortisol Responsivity in Caregivers to Older Adults with Chronic Conditions
Authors: Beadle Janelle , Warren David E
Published: December 2023

Background

Individuals who provide care for older adults with chronic conditions, such as dementia, experience poorer mental health when care recipients have low empathy. Empathy is thought to have two components: cognitive empathy (i.e., understanding others’ mental perspectives) and emotional empathy (i.e., feeling empathic concern/sympathy). Due to chronic stress, many caregivers experience burnout and compassion fatigue (i.e., emotional exhaustion and secondary traumatic stress). However, the impact of the caregiving role on empathy has not been well‐characterized in caregivers to older adults. Evidence from other populations show that stress hormones (e.g., cortisol) decrease when individuals engage in social bonding which in turn can increase levels of oxytocin. The present research study is highly novel because no previous studies have specifically investigated how empathy affects cortisol and oxytocin hormone levels in caregivers to older adults with chronic conditions.

Methods

Participants included 21 women caregivers to older adults with chronic conditions (Mage = 54.1; Medu = 16.1). Participants watched one video to induce empathy (empathy condition) and a separate video to induce an unemotional state (control condition) and completed self‐report ratings of empathy and distress before and after the videos. Saliva was collected using the passive drool method at baseline and after each video. Salivary hormone assays were conducted for cortisol and oxytocin. Participants completed standard measures of empathy (Interpersonal Reactivity Index) as well as compassion fatigue and burnout (Professional Quality of Life Scale).

Results

Caregivers with higher compassion fatigue reported higher levels of burnout (p<.05) and burden (p<.05). In addition, caregivers with higher compassion fatigue reported a reduced tendency to help others in daily life (p<.05). In response to an empathy‐evoking video, momentary feelings of distress were positively associated with greater oxytocin (p<.01), and there was a non‐significant trend towards lower cortisol (p = .1). Caregivers who reported higher levels of momentary empathic concern in response to the empathic video had lower oxytocin (p<.05), whereas participants reporting higher cognitive empathy had greater oxytocin (p<.05).

Conclusions

These results help to lay the groundwork for the possibility of developing hormonal interventions that may help to increase empathy and reduce stress in caregivers to older adults with chronic conditions.
A brief questionnaire of self‐reported cognitive decline predicts MMSE and study partner QDRS: findings from the Davis Memory and Aging Cohort at Mass General Brigham
Authors: Anzai Juliana A. U. , Christiano Caitlyn , Moreno Stephanie , Viera Andrea M Román , Kirn Dylan , Papp Kathryn V. , Chhatwal Jasmeer P. , Johnson Keith A. , Rentz Dorene M. , Selkoe Dennis J , Sperling Reisa A. , Amariglio Rebecca E. , Yang Hyun‐Sik
Published: December 2023

Background

A brief self‐reported questionnaire to efficiently capture subjective cognitive decline, a stage considered to be between cognitively unimpaired and mild cognitive impairment, could enhance clinical research and practice. We hypothesized that a 3‐question measure of self‐reported cognitive decline is associated with worse cognitive performance and increased functional changes reported by a study partner (SP).

Method

The Davis Memory and Aging Cohort (MAC) at Mass General Brigham recruits individuals 45 years or older with a broad range of cognitive symptoms. Participants answered the following three questions adapted from the NIA‐AA research framework: Q1. “Have you experienced a change in your memory in the last 1‐3 years?” Q2. “Has this been a persistent change over the last 6 months?” Q3. “Are you concerned about this change?” scored on a Likert scale (0‐4), with high scores representing greater decline. Responses to Q2 and Q3 were set to 0 if Q1 = 0. Participants completed the Mini‐Mental State Examination (MMSE; cognitive performance), and SPs completed the Quick Dementia Rating System (QDRS; functional changes). We tested the association between the total BCSS score (Q1+Q2+Q3; predictor) and MMSE or QDRS total scores (outcome) using linear regression controlling for age, sex, and years of education. We then tested these associations in a subgroup without significant SP concern (QDRS<1.5).

Result

There were 399 MAC participants with complete data (mean age = 67.2±8.3, 64% female, Table 1). Based on QDRS cut‐offs, there were 248 cognitively unimpaired participants, 118 with mild cognitive impairment, and 33 with dementia. The total score was associated with lower MMSE (beta = ‐0.30, p<0.001) and higher QDRS (beta = 0.51, p<0.001). Q1 score by itself was associated with lower MMSE (beta = 0.98, p<0.001) and higher QDRS (beta = 1.2, p<0.001) (Figure 1). In a subset with QDRS<1.5 (n = 248), both the total score (beta = ‐0.22, p = 0.002) and Q1 score (beta = ‐0.62, p<0.001) were associated with lower MMSE.

Conclusion

Self‐reported cognitive decline was associated with worse global cognition, even among those whose SPs reported no significant functional concerns. Our results suggest that the brief self‐reported questionnaire could be a useful screening tool in research and clinic that efficiently probes cognitive functioning.
Mediating effect of depressive symptoms on the relationship between digital literacy and cognitive function in older adults
Authors: Hong Jaewoo , Roh Hyun Woong
Published: December 2023

Background

Although several studies have examined the individual relationships between digital literacy, cognitive function, and depressive symptoms, few have integrated all three factors into a single model. In this study, we aim to address this gap in the literature by investigating the mediating effect of depressive symptoms on the relationship between digital literacy and cognition. By doing so, we hope to contribute to a more comprehensive understanding of the complex interplay among these variables and their implications for mental health and well‐being.

Method

Participants were 7988 adults, 65 or older, who participated in Living Profiles of Older People Survey (LPOPS) 2020. The main exposure was digital literacy (communication literacy, information literacy, online transactions literacy, media literacy). The main outcome was depressive symptoms measured by Korean version of the 15‐item Geriatric Depression Scale (SGDS‐K), and cognitive function measured by a Mini‐Mental State Examination (MMSE) score. Multiple linear regression analyses and mediation analysis were performed.

Result

After adjusting for covariates, our analysis found a significant association between digital literacy and both depressive symptoms and cognitive function (β of four types of digital literacy and depressive symptoms = ‐0.73, ‐0.152, ‐0.942, and ‐1.041 respectively, β of four types of digital literacy and cognitive function = 2.102, 2.217, 1.620, and 2.276 respectively). Moreover, our study suggests that depressive symptoms play a mediating role in the relationship between both online transactions and media literacy with cognitive function (95% CI of indirect effects = 0.1051 to 0.1928 and 0.1104 to 0.1864 respectively), implying an indirect pathway (digital literacy → depression → cognitive function).

Conclusion

This study sheds light on the relationship between digital literacy, depressive symptoms, and cognitive function in older adults. We found that depressive symptoms mediate the association between specific aspects of digital literacy (online transactions and media literacy) and cognitive function. Our results indicate that community‐based digital literacy programs could be effective interventions for reducing depression and preserving or improving cognitive function in older adults.
Topological Network Analysis of Beta‐Amyloid and Tau in Alzheimer’s Disease Using PET Imaging Data
Authors: Wu Yuexuan , Ormsby Kyle , Shibata Dean , Chen Yen‐Chi , Biber Sarah , Kukull Walter A. , Chan Kwun Chuen Gary
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by the presence of beta‐amyloid (Aβ) and tau in the brain. Understanding the interplay between these proteins and their spatial distribution may provide insights into disease progression. This study aims to investigate the topological features of Aβ and tau networks in AD, mild cognitive impairment (MCI), and normal cognition (NC) groups using PET images from the ADNI dataset.

Method

Partial correlation matrices between the standardized uptake value ratio of 68 regions of interest (ROI’s) were used to generate networks for the AD, MCI, and NC groups, with nodes representing ROI’s and edges representing correlation coefficients. Topological features, including H0 features (connected components), H1 features (loops), and landscape functions of H1 features, were calculated for each sample’s persistent homology. For each group, 100 bootstrapping samples were used to generate the 95% confidence intervals for landscape functions. The connected components were further studied by representing the samples as hierarchical tree structures. In the tree space, the first few generated connections, representing the most consistent pairs of regions positive for Aβ and tau, were compared across groups. Clustering performances were compared using Wasserstein distance of H0 features, Wasserstein distance of H1 features, landscape function distance, and geodesic distance in tree space respectively.

Result

The geodesic distance in tree space showed the best clustering accuracy in both Aβ and tau analyses. Compared with Aβ, H1 features and the corresponding landscape functions performed better for tau. Unique connections in AD and MCI groups were identified, with AD showing more unique connections than MCI compared to NC samples. Dominant unique connections in the AD group included left‐right isthmus cingulate and left fusiform‐left inferior temporal for Aβ, and left‐right paracentral and left cuneus‐left pericalcarine for tau. These connections indicate region pairs with related concentrations of Aβ and tau in AD.

Conclusion

Topological network analysis can reveal complex underlying structures in PET images and identify consistent patterns in ROI’s associated with Aβ and tau localization. Tau aggregation exhibits more complex behavior than Aβ and is more strongly associated with AD. The identified unique connections in the AD group may serve as potential biomarkers for disease progression.
Disruptions in cell‐cell communication in the entorhinal cortex of patients with Alzheimer’s disease and the 5xFAD mouse model
Authors: Bartas Katrina , Macchia Desiree , Zhao Wei , Nie Qing , Beier Kevin T
Published: December 2023

Background

Single‐cell sequencing has been instrumental in understanding cell‐type specific changes in Alzheimer’s disease (AD). While sequencing provides information about changes in individual cells, how these changes impact the interaction between cells is not as well‐defined. Understanding how the transcriptional and epigenetic changes that emerge during disease impact cellular communication will be critical in understanding key pathological changes that contribute to AD.

Method

We performed single‐nucleus RNA and ATAC‐seq (10x Multiome) to investigate gene expression and epigenetic regulation of cells in the entorhinal cortex (ENT) of 2‐month and 8‐month‐old 5xFAD and WT mice (n = 2 for each age, condition), and used publicly available single‐nucleus RNA‐seq data from the ENT of patients with and without AD. We used CellChat and the new package NeuronChat to explore how intercellular communication networks change between healthy and AD humans and mice. Based on these results, we then explored relationships between chromatin accessibility and gene expression for genes of interest.

Result

We observed changes in cell‐cell communication between AD and healthy samples in both mice and humans, particularly in the later stages of disease. The most prominent change was increased signaling from astrocytes to glutamatergic neurons in AD (Figure 1). This relationship included upregulation of neuroligin and ephrin‐A‐mediated signaling in AD, both previously implicated in synaptic regulation. In inter‐neuronal communications, the pathways most significantly disrupted in both human and mouse neurons were related to glutamatergic signaling. Multiple types of glutamate receptors were upregulated in both AD patients and 5xFAD mice in glutamatergic neurons, while GABAergic signaling did not appear to change. This finding is consistent with the hypothesis that glutamatergic neurons are hyperactive in AD and extends these observations by providing a potential mechanistic explanation of this phenomenon.

Conclusion

Our results indicate that in patients with AD and 5xFAD mice, dysfunction of the glutamatergic system is a prominent feature of pathogenesis and includes both inter‐neuronal signaling and communication with astrocytes. These results provide a series of testable hypotheses to explore the consequences of the transcriptional and epigenetic changes on the circuit dysfunction observed in AD.
Older Adults’ Awareness and Perceptions of Blood Biomarker Testing for Alzheimer’s Disease: Results from the US National Poll on Healthy Aging (NPHA)
Authors: Roberts J. Scott , Cox Chelsea G. , Kirch Matthias , Malani Preeti N. , Singer Dianne C. , Solway Erica , Kullgren Jeffrey T.
Published: December 2023

Background

Blood‐based biomarker testing (BBT) to detect amyloid‐beta and tau is becoming part of dementia care, with likely future use in asymptomatic populations. Little is known about older adults’ awareness of and experiences with BBT, or their perceptions of its potential benefits, risks, and limitations.

Method

We analyzed data from the March 2023 NPHA, a recurring nationally representative web and telephone survey of community‐dwelling US adults aged 50‐80. For this substudy, respondents aged 65‐80 were provided a brief definition of BBT for AD and asked about: 1) their familiarity and experiences with BBT, 2) perceptions of its pros and cons, and 3) their likely responses if they tested positive. For comparative purposes, a parallel set of questions was posed about cognitive screening. Chi‐square analyses assessed differences in responses to the two types of testing (BBT vs. cognitive screening), as well as demographic differences in responses to items regarding BBT (significance level p < .05).

Result

Of 1,296 respondents, 19% said they were at least somewhat familiar with BBT, with 0.6% reporting having undergone BBT. Overall, respondents were more likely to endorse test pros than cons (e.g., 76% said BBT could be useful to inform medical care or advance planning). Women were more likely than men to say they’d respond to a positive BBT result with significant distress (21% vs. 10%) and engagement in brain health behaviors (67% vs. 56%), with men more likely to endorse concerns regarding privacy of test results (38% vs. 27%). Overall, BBT beliefs were similar to those about cognitive screening, although respondents were less likely to agree that BBT should be offered annually to all older adults (51% vs. 60%) and more likely to believe a positive test result would mean they’d be likely to develop AD (74% vs. 65%).

Conclusion

Most US older adults are not currently familiar with blood biomarker testing for AD but view it as potentially useful for informing medical care and health behaviors to reduce AD risk. Women may respond differently to BBT results than men, with future studies needed to examine the process and impact of disclosing test results.
Facebook interaction as a potential marker of cognitive decline
Authors: Qansuwa Esraa M
Published: December 2023

Background

The growth of social media and the continuous improvement of machine‐learning algorithms suggest that social media‐based screening methods for mental diseases will become increasingly feasible with high accuracy in the next few years. Additionally, artificial intelligence, particularly predictive machine learning (ML) Models, has been established as one of the more powerful approaches to building reliable models that might be useful as an early predictor for Mental disorders. Specifically, one of the current challenges in brain disorders is identifying patients with mild cognitive impairment (MCI) that might be converted to Alzheimer’s (AD) or other types of dementia. Cognitive decline in older adults is associated with decreased social interaction and changes in other features. We aim to use vast quantities of historical Facebook data from participants who conducted the MoCA test as a cognitive assessment test to examine if there are changes in their language mistakes and in a range of psychological features derived from natural language processing use and social engagement over time as a sign of MCI.

Method

To develop a Machine learning model to predict MCI using (n = 225), we should first consider how we can formulate Language mistakes and social interactions. Then, we aim to perform a longitudinal and cross‐sectional examination of the data to examine the changes in a range of features extracted from Facebook subjects’ data over time, using NLP algorithms, LIWC 2022, Go‐emotion dataset, and supervised Classification ML tools, such as support vector machine model (SVM).

Result

We are collecting identified Facebook data, de‐identifying it, translating the Arabic text into English, processing text augmentation and text preprocessing, defining language mistakes, social engagement over time features, and sentiments impeded in each syntax. Our classification model SVM shows significant prediction results, differentiating between patients (MCI& dementia) and normal subjects, using a sample of 225 subjects, resulting that the SVM prediction test score is 70%.

Conclusion

Using our suggested pipeline, Our classification model SVM shows promising primary results in building a predictive model that has the ability for early detection of MCI.
Impact of the COVID‐19 Pandemic on Dementia Research Participants
Authors: Zhao Chen , Harvey Danielle J. , Whitmer Rachel A. , Meyer Oanh L. , Farias Sarah Tomaszewski , Decarli Charles
Published: December 2023

Background

The impact of COVID‐19 on Alzheimer’s disease and related dementias (ADRD) research participation is not fully known. Individual differences in stress and coping may impact research findings (Goldfarb, 2020). It is possible that participants with questionable cognitive impairment (QCI) may be more vulnerable to stress and loss to follow up. The objective of this study is to examine the differential impact of the COVID‐19 pandemic on dementia research participants among individuals with varying degrees of cognitive impairment.

Method

The COVID‐19 impact survey was mailed to participants of the UC Davis Alzheimer’s Disease Research Center (ADRC) in August 2020. The survey asked questions related to feelings about the pandemic and how it impacted willingness to participate in research. Fisher’s exact test was used to compare responses across diagnostic groups. All analyses were conducted using SAS software, version 9.4.

Result

Of 115 participants (69.6% female, 52.2% non‐White), 38 had normal cognition, 38 had questionable cognitive impairment (QCI; defined as having one or more neuropsychological tests that was slightly low but did not rise to the threshold of impairment), 16 had mild cognitive impairment (MCI), and 22 had dementia (Table 1). Overall, 9% of the participants were very or extremely worried about getting COVID‐19, 19% felt very or extremely isolated, 36% felt the pandemic had been very or extremely disruptive. The pandemic changed willingness to participate in research at least a little for 50% and very much or extremely for 13%. Impaired participants (either MCI or dementia) were less concerned about getting COVID‐19 and felt less isolated than those with normal cognition or QCI (Table 2). A higher percentage of those with QCI (vs. normal cognition or impaired groups) felt that the pandemic was very or extremely disruptive. Although not statistically significant, a higher percentage of those with QCI also reported that the pandemic changed their willingness to participate in in‐person research very much or extremely.

Conclusion

The COVID‐19 pandemic was more disruptive to participants with QCI than participants with normal or impaired cognition. More research is needed to evaluate the impact of the pandemic on dementia research participants.