bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying the metabolomics signatures of genetic variants identified for Alzheimer’s disease
Authors: Mustafa Rima , Pinto Rui , Elliott Paul , Tzoulaki Ioanna , Dehghan Abbas
Published: December 2023

Background

Integrating genomics and metabolomics data in humans has the potential to unravel mechanistic insights about and look for evidence of metabolite causality in complex disorders.

Method

We conducted metabolome‐wide association studies (MWAS) on Alzheimer’s disease (AD) associated loci using ultraperformance liquid chromatography–mass spectrometry (UPLC‐MS) in two cohorts of the Airwave Study (1). Expanding our previous study focusing on ABCA7 (2), current MWAS investigated genetic variants in all other loci based on the largest and most recent GWAS on AD (3) to identify metabolic features associated with AD. We performed genome‐wide association studies in the Airwave Study (N = 3,708) to obtain genetic instruments of those features to run Mendelian randomisation (MR) and colocalization analyses.

Result

Our MWAS identified 104 features associated with AD loci at metabolome‐wide significance level. MR analysis was conducted on 29 out of 104 features with at least three genetic instruments, showing the potentially causal effects of four metabolic features associated with rs1800978 (ABCA1) and rs587709 (LILRB2). Our in‐house annotation pipeline mapped those features as sphingomyelin (SM)(18:1/20:1), putative sphingolipid, and N‐Acylphosphatidylethanolamines (NAPE). We conducted pairwise colocalisation and HyPrColoc analysis, supporting evidence of common causal variants between SM(18:1/20:1), putative sphingolipid, and NAPE with AD (posterior probability of shared causal variant >0.8).

Conclusion

This analysis has broadened our insight into the metabolic signatures of AD, with further study needed to dissect the underlying molecular mechanisms.
Mechanisms of sepsis‐induced inflammation in the aging brain
Authors: Bastarache Julie A , Lee Han Noo Ri , Harrison Fiona E.
Published: December 2023

Background

Sepsis affects millions worldwide with adults over the age of 65 at particularly high risk. Up to 70% of sepsis patients develop delirium and the severity and length of delirium are strong predictors of acquisition of Alzheimer’s Disease and Related Dementias (AD, ADRD). We hypothesize that older adults and those at risk for AD have augmented neuroinflammation during sepsis that correlates development of delirium and persistence of long‐term cognitive impairment.

Method

Male and female wild‐type (young‐3 months and aged‐18 months) and 4 month old Tau P301S transgenic AD mice were used to test the effects of polymicrobial sepsis on markers of neuroimflammation and behavior. Sepsis was induced by intraperitoneal injection of a slurry of cecal contents. Plasma and brain were collected from 8 hours to 7 days post infection for measurement of pro‐inflammatory cytokines (IL‐6, CXCL‐1, TNF‐a) and markers of neuroinflammation (GFAP, IBA1 and s100B) using a combination of protein quantification, multiplex and immunohistochemical approaches. Behavior, including measures of locomotor activity, motor learning (rotarod) and cognition (Y‐maze, nest building) were tested up to 7 days post infection.

Result

Sepsis increases plasma markers of acute neuroinflammation between 8 and 48 hours that resolves by 7 days. Despite this, mice who have recovered from sepsis have persistent microglial activation in the hippocampus at least 7 days later suggesting prolonged damage. Some recovered mice also have persistent deficits in behavioral tasks including activity and nest building despite appearing healthy and fully recovered. Older WT mice are more susceptible to sepsis as measured by severity of illness (Figure) and mortality and mice genetically predisposed to AD have greater deficits in behavioral measures compared to their WT counterparts following infection.

Conclusion

Sepsis is accompanied acutely by marked neuroinflammation and chronically by microglial activation and behavior deficits. Older age and presence of even early stages of AD‐relevant pathology augment these deficits. Persistent microglial activation may underlie this pathology and prime the aged brain to develop an ADRD‐like syndrome.
Experimental Validation of Bioinformatically Prioritized Therapeutic Hypotheses and Targets for Alzheimer’s Disease
Authors: Cary Gregory A. , Wiley Jesse C , Li Qianjin , Nwakamma Richard , Du Yuhong , Zoeller Elizabeth , Duong Duc M. , Fu Haian , Seyfried Nicholas T , Levey Allan I. , Betarbet Ranjita , Carter Gregory W , Center The Emory‐Sage‐SGC TREAT‐AD
Published: December 2023

Background

The complex etiology of Alzheimer’s disease (AD) challenges therapeutic development efforts by obscuring which altered biological processes are optimal candidates for intervention. We have created a workflow to prioritize molecular targets based on signatures of AD risk from patient data and assemble candidate targets into functional groupings from which we can articulate sets of hypotheses. Prioritized data‐derived hypotheses to date include mitochondrial dysfunction and chronic neuroinflammation. We present an approach to rapidly assess whether the hypothesized driver genes affect the predicted biological outcomes in the appropriate cellular contexts.

Method

Immortalized mouse BV2 cells were used as a microglial surrogate. To test the candidate hypotheses in an AD‐relevant context, we examined both wild‐type BV2 cells and cells where Psen2 expression has been stably knocked down. To perturb the nominated target genes, each cell line was transfected with one of a panel of 29 siRNAs targeting the genes or a control siRNA prior to phenotypic assessment. We tested mitochondrial function using both MitoTracker TMRM staining and the AlamarBlue assay. For immune function, we tested phagocytic activity using pHrodo Green Zymosan Bioparticles and the transcriptional output from NF‐kappaB using a luminescent reporter. Finally we measured proteomic differences between the siRNA treated cells and control cells to assess the impact of each perturbation on the expression of protein sets targeted by the hypotheses.

Result

Of the targets screened, 28% are found to exhibit mitochondrial phenotypes in both assays and 38% are found to exhibit immune phenotypes in both assays. Hits from the immune assays are generally more specific to the immune hypothesis targets (70%) whereas the hits from the mitochondrial assays are more evenly divided between both hypothesis areas (50%). Examining the proteomic results highlights the pathways that are altered by each perturbation and we align these with patient data to identify perturbations that affect the targeted pathways.

Conclusion

We have established a platform to rapidly assess biologically‐informed and interpretable hypotheses and targets derived from large‐scale data resources for disease relevance. The targets validated by these experiments will be prioritized for further resource development within the TREAT‐AD consortium.
Dual PET imaging of microtubules and synaptic density in a mouse model of Alzheimer’s Disease
Authors: Damuka Naresh , Bansode Avinash , Krizan Ivan , Gollepalli Krishna Kumar , Miller Mack , Bhoopal Bhuvanachandra , Whitlow Christopher T. , Lockhart Samuel N. , Craft Suzanne , Sai Kiran K Solingapuram
Published: December 2023

Background

While microtubule (MT)‐destabilization and synaptic loss hallmark AD pathological events, no study has systematically quantified their in vivo levels in the same brain. Any therapeutic intervention relying on MT destabilization and synaptic vesicle protein (SV2A) levels will benefit from a dual PET imaging strategy, providing target engagement, dosing, and occupancy studies for new drugs. Here, we report MT destabilization and synaptic density imaging results using [11C]MPC‐6827 and [18F]UCB‐H respectively in the same transgenic (TG) and wild‐type (WT) APP/PS1 mice.

Method

Male APP/PS1 TG and WT mice (12‐14 mo, 20± 2g, n = 8/group) underwent 30‐min dynamic brain microPET/CT imaging with [11C]MPC‐6827 (0.2±0.02 mCi, iv tail). Four hours later, the same animals underwent another 30‐min brain PET/CT with [18F]UCB‐H (0.2±0.01 mCi, iv tail). A sub‐set of TG and WT mice (n = 4/group) were used to measure ex vivo destabilized MTs and SV2A levels using western blot to confirm MT destabilization and synaptic loss. Whole‐brain standard uptake values (SUVs) were calculated from co‐registered PET‐CT using PMOD. Ex vivo post‐PET biodistribution studies were performed, with percent injected dose‐pe‐ gram (%ID/g) calculated. 48h post‐biodistribution, in vitro autoradiography studies were performed on frozen brain samples from the same animals with [11C]MPC‐6827 and [18F]UCBH; regional uptake was quantified using phosphor‐stimulated luminescence.

Result

[11C]MPC‐6827 and [18F]UCBH were produced in high (>97±2%) radiochemical purities (n = 20 productions) and specific activities (∼3980±100 mCi/µmol), decay‐corrected to end‐of‐synthesis. Western blot analysis confirmed high destabilized MTs, and low SV2A levels in TG vs. WT. SUV analysis (Fig. 1) showed 56% higher [11C]MPC‐6827 and 66% lower [18F]UCB‐H in vivo brain uptake in TG compared to WT (**p = 0.0032). %ID/g analysis showed 58% higher [11C]MPC‐6827 and 61% lower [18F]UCB‐H ex vivo brain radioactive uptake in TG vs WT (*p = 0.04). Importantly, autoradiography demonstrated 44% higher [11C]MPC‐6827 and 34% lower [18F]UCB‐H in vitro uptake in cortical and hippocampal regions of TG vs. WT (*p = 0.05).

Conclusion

TG APP/PS1 mice demonstrated higher [11C]MPC‐6827 and lower [18F]UCB‐H brain uptake compared to WT littermates. In vivo PET, ex vivo biodistribution, and in vitro autoradiography data corroborated each other. Preliminary [11C]MPC‐6827 and [18F]UCB‐H PET evaluations showed negative correlations (*r = ‐0.778), suggesting MT destabilization and synaptic loss happen concurrently.
The RESIST Study: Do TNF Inhibitors Protect Against Cognitive Decline in Rheumatoid Arthritis Patients With Mild Cognitive Impairment?
Authors: Marr Calum , McDowell Bethany , Holmes Clive , Edwards Christopher J , Cardwell Christopher , McHenry Michelle , Meenagh Gary , McGuinness Bernadette
Published: December 2023

Background

Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation in the joint synovium. Considering growing research interest into the role that systemic inflammation might play in the pathogenesis of Alzheimer’s disease (AD), studying cognitive decline in RA patients can provide important insights into the potential effects of inflammation on cognitive health. Furthermore, evidence suggests that biological drugs used to treat RA, specifically TNF inhibitors (TNFi), may protect against AD progression by reducing systemic inflammation. The rheumatoid arthritis medication and memory study (RESIST) is a multicentre longitudinal observational study which aims to compare rates of cognitive decline in adults with both RA and mild cognitive impairment who are on either a conventional synthetic disease modifying anti‐rheumatic drug (csDMARD) or a TNFi.

Method

251 participants were recruited (160 on csDMARDs, 91 on TNFis). Participants completed assessments at six‐month intervals for eighteen months. The primary outcome was performance on the Free and Cued Selective Reminding Test (FCSRT). It was hypothesised that the rate of decline in FCSRT score would be lower among participants taking TNFis.

Result

Between‐groups ANCOVA was conducted to compare mean FCSRT scores at 12/18 months, adjusting for baseline score, age, disease activity, pain, wellbeing, depressive symptoms and physical function. Results showed that neither group declined in FCSRT free recall score on average over the 18 month follow‐up period, and that there was no significant difference between groups at 12 (mean difference = 0.59, 95% CI = ‐1.54, 2.72) or 18 months (mean difference = 1.24, 95% CI = ‐0.99, 3.47).

Conclusion

The absence of decline in FCSRT performance in either group was unexpected. These findings raise the possibility that both csDMARDs and TNFis may protect against cognitive decline However, a major limitation of the study was attrition due to the COVID‐19 pandemic, which may have influenced results – those who experienced a greater degree of cognitive decline may have been more likely to withdraw from the study. Additional planned analyses will examine the potential moderating effect of APOE genotype, and the relationship between peripheral serum C reactive protein, cytokine levels and cognitive outcomes.
Effects of cerebrovascular disease on tau progression and cognitive decline in Alzheimer’s disease
Authors: Dewenter Anna , Steward Anna , Dehsarvi Amir , Biel Davina , Roemer Sebastian Niclas , Wanger Fabian , Franzmeier Nicolai
Published: December 2023

Background

Recent post‐mortem studies suggest that cerebrovascular disease contributes to Alzheimer’s disease (AD) pathophysiology and clinical progression. In particular, cerebral amyloid angiopathy is highly common in AD and has been linked to faster cognitive decline. Yet, in‐vivo evidence on the contribution of cerebrovascular disease to pathobiological and/or clinical AD progression is rare. Thus, we assessed in‐vivo, whether i) higher cerebrovascular burden is associated with accelerated progression of primary AD pathology and ii) whether cerebrovascular burden synergistically accelerates AD‐related cognitive decline.

Method

We included n = 256 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) across the AD spectrum with longitudinal 18F‐flortaucipir tau‐PET (follow‐up∼2.30±1.32 years), 18F‐florbetapir or 18F‐florbetaben Aβ‐PET transformed to centiloid (Aβ–: n = 85 Cognitively normal (CN); Aβ+: n = 83 CN, n = 57 Mild Cognitive Impairment, n = 31 Dementia). We focused on global white matter hyperintensity (WMH) volume adjusted to intracranial volume and microhemorrhage (MCH) count as well‐established cerebrovascular disease markers. Cognition was probed through the AD Assessment Scale Cognition 13‐item scale (ADAS‐13). Subject‐specific annual changes in tau‐PET and cognition were calculated via linear mixed models, including random slope and intercept. To enhance reproducibility of our findings, statistical analyses were pre‐specified at AsPredicted.org. All statistical models were controlled for age, sex and APOE.

Result

Using linear regression, we found no main effect of cerebrovascular disease markers on baseline amyloid‐PET or tau‐PET (ps>0.05). Further, higher cerebrovascular burden was not associated with faster Aβ‐related tau‐PET SUVR increase (Fig. 1A+B). In contrast, higher cerebrovascular burden was associated with accelerated cognitive decline. Specifically, interaction models revealed that a higher MCH count was associated with faster cognitive decline at higher tau levels (Fig. 1C), while higher white matter hyperintensity burden was associated with faster cognitive decline at lower tau levels (Fig. 1D).

Conclusion

We found no effect of cerebrovascular disease on primary AD pathology. In contrast, cerebrovascular disease was linked to accelerated tau‐associated cognitive decline. This suggests that cerebrovascular disease may not modulate pathobiological AD trajectories but rather add synergistically to AD symptom severity. This has important therapeutic implications, as treating cerebrovascular disease in addition to primary AD pathology (e.g. amyloid) may yield largest clinical efficacy.
ASSOCIATION BETWEEN ALZHEIMER DISEASE AND CANCER: A POSTMORTEM CROSS‐SECTIONAL STUDY IN BRAZIL
Authors: Veitzman Fernanda , Leite Renata Elaine Paraizo , Grinberg Lea T. , Paes Vitor Ribeiro , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Nitrini Ricardo , Suemoto Claudia Kimie
Published: December 2023

Background

A biological mechanism in cancer promotion may have a protective role against AD1. Although disparities between the clinical and the anatomopathological postmortem diagnoses related to the etiology of dementia and cancer were described2, most previous studies were based only on the clinical diagnoses for both diseases. Therefore, we aimed to investigate the association between AD and cancer in a large autopsy study from a racially diverse sample.

Method

This cross‐sectional study analyzed data with postmortem brain tissue from participants over 55 years of age from the Biobank for Aging Studies. Data from the full‐body autopsy reports and a Functional Clinical Questionnaire (FCQ) applied to an informant were used to determine the presence of cancer. The association between AD and cancer was investigated using logistic and linear models adjusted for sociodemographic and clinical variables and APOE allele 4.

Result

689 subjects were included (mean age 74.2 ± 10.8 years old, 47.5% women, 68% White) (Table 1). 18% of the sample had cancer. The frequencies of cancer types and neuropathological post‐mortem diagnoses are shown in Figure 1. Cancer was not associated with AD (OR = 0.56, 95% CI = 0.21;1.39), or CERAD neuritic plaque score [ b = 0.057, 95% CI = ‐0.31; 0.41], but was associated with lower Braak neurofibrillary tangle staging (b = ‐0.49, 95% CI = ‐0.98; ‐0.03] (Table 2).

Conclusion

In a large autopsy study, we found an association between cancer and Braak neurofibrillary tangle staging, which is in accordance with previous research suggesting a protective role of cancer in AD risk3.

1. Ospina‐Romero M, Glymour MM, Hayes‐Larson E, Mayeda ER, Graff RE, Brenowitz WD, Ackley SF, Witte JS, Kobayashi LC. Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Metaanalysis. JAMA Netw Open. 2020 Nov 2;3(11):e2025515.

2. Landefeld CS, Chren MM, Myers A, et al. Diagnostic yield of the autopsy in a university hospital and a community hospital. The New England Journal of Medicine. 1988 May;318(19):1249‐1254.

3. Nakamura M, Kaneko S, Dickson DW, Kusaka H. Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies. J Neuropathol Exp Neurol. 2020 Jan 1;79(1):22‐33.
Amyloid deposition and neuroinflammation in middle‐aged to older individuals with Down syndrome: a PET evaluation
Authors: de Oliveira Laura Cavalcanti , Coutinho Artur Martins , Forlenza Orestes Vicente , Buchpiguel Carlos A , Faria Daniele P de Paula
Published: December 2023

Background

Down syndrome (DS) is characterized by trisomy for chromosome 21 and presents a high incidence and early development of Alzheimer’s disease (AD) (Ram G et al. 2011). The current study aims to evaluate the presence of amyloid in people with DS in different age spans and its correlation with neuroinflammation.

Method

Individuals with DS aged 20‐34 (n = 8), 35‐49 (n = 8), ≥ 50 (n = 4), and cognitively normal individuals without DS (controls n = 11) were evaluated with [11C]PK11195 PET imaging (neuroinflammation) and [11C]PIB PET (β‐amyloid) in a hybrid PET/MRI equipment. The radiopharmaceuticals were administered intravenously (∼370 MBq), and the images were acquired dynamically during 60 min ([11C]PK11195) and 70 min ([11C]PIB). PET images were quantified in the PMOD™ v4.1 software and the results were presented in SUV (Standardized Uptake Value) for [11C]PK11195 and SUVratio with the cerebellum crus as a reference region for [11C]PIB. [11C]PIB images were also visually classified as amyloid positive or negative by an experienced nuclear physician. Statistical analysis was performed by one‐way ANOVA and Bonferroni posthoc, and the differences were considered significant when P≤0.05.

Result

All individuals with DS ≥50 years were amyloid positive and showed increased [11C]PK11195 uptake when compared to younger DS subjects and the control group. Differences were seen particularly in the ≥50 group in the following areas: a) posterior cingulate (1.32±0.05, vs. control = 0.71±0.13, p<0.0001; vs. 20‐34 group = 0.67±0.16, p<0.0001; and 35‐49 group = 0.75±0.14; p = 0.0003); b) amygdala (0.86±0.14, vs. control = 0.62±0.10, p = 0.0450; vs. 20‐34 group = 0.57±0.09, p = 0.0114); c) caudate (0.70±0.12, vs. 20‐34 group = 0.47±0.10, p = 0.0195); d) and thalamus (0.90±0.11, vs. the 20‐34 group = 0.62±0.11, p = 0.0171). [11C]PIB uptake in the posterior cingulate correlated with [11C]PK11195 uptake (r = 0.6201; p = 0.006) in individuals with DS across all age spans.

Conclusion

The increased uptake of [11C]PK11195 in subjects with DS≥ 50 years indicates the presence of a neuroinflammatory process in different brain areas that may be associated with β‐amyloid plaque deposition early in the aging process.
Innovative recruitment strategies for a multi‐domain lifestyle intervention trial (FINGER‐NL) via the Dutch Brain Research Registry
Authors: Waterink Lisa , Soons Lion M. , Keun Jikke T. Boelens , van Harten Argonde C. , Sikkes Sietske A.M. , Scherder Erik J.A. , Deckers Kay , Köhler Sebastian , Flier Wiesje M. , Zwan Marissa D.
Published: December 2023

Background

Finding eligible participants for dementia prevention trials is challenging, resulting in prolonged recruitment periods, underpowered studies, and excessive costs. The Dutch Brain Research Registry (DBRR) is an online platform to facilitate recruitment of research participants. We evaluated different recruitment strategies with the ambition to optimize recruitment for the multi‐domain lifestyle intervention trial FINGER‐NL.

Method

DBRR registrants were prescreened for FINGER‐NL based on available profile information. Potentially eligible registrants received an automatic study invitation. Those interested were contacted for additional telephonic screening and, if eligible, included in the trial. Five recruitment strategies within 2022 were executed with the goal to increase the number of DBRR registrants: 1) a paid Facebook‐campaign, 2) referral via (patient)‐organizations, 3) newspaper articles, 4) live‐events, and 5) national television appearance (W.F&E.S.). Recruitment source was traced (online; UTM tags) and/or reported by the participant. For most recruitment strategies, we involved a nationally well‐known ambassador (E.S.) who advocates a healthy lifestyle to improve brain‐health (Figure 1). For each strategy, we described the number of individuals registered, eligible and included in FINGER‐NL. We calculated efficiency (%eligible/prescreened) as a reflection of the proportion of eligible participants reached, and effectiveness (%included/registered) as a reflection of the proportion of participants included in FINGER‐NL

Result

In 2022, the DBRR recruited 11234 new registrants. The highest numbers of registrants and highest number of inclusions were reached with national television appearance and the Facebook‐campaign (Table 1). In particular, the Facebook advertisement with a lifestyle theme and well‐known ambassador outperformed all other advertisements in number of registrations (Figure 1). After initial prescreening, between 18‐35% of registrants were eligible. Most efficient were national television and the Facebook‐campaign. Between 4‐12% of new registrants were included in the trial. Most effective strategies were national television appearance and referrals via patient‐organizations

Conclusion

Our results show that mass‐media, i.e. tailor‐made Facebook‐campaigns, national television appearance and events, are efficient ways to reach large numbers of eligible participants, especially when well‐known ambassador(s) were included. Recruitment strategies with detailed information about in‐ and exclusion of the trial are most effective. The DBRR provides an efficient and effective recruitment and prescreening process for the FINGER‐NL trial.
Challenges and Opportunities in a Resource Desert: Las Vegas Boot Camp Translation
Authors: John Samantha E , Moeller Stacey , Tanner Denise Lafont
Published: December 2023

Background

The state of Nevada has the 3rd fastest growing rate of Alzheimer’s disease and related dementias (ADRD) in the country with a 30.6% projected increase between 2020 and 2025. Growth in ADRD is complemented by growth in the diversity of residents, particularly in Las Vegas, where the growth of minoritized populations outpaces national rates. Nevada is 30% Hispanic/Latino (H/L) and Las Vegas is 33% H/L. Among the challenges presented by this growth, Nevada is characterized as a ‘neurology desert’, lacking the necessary specialists to meet the state’s care demands and lacking the traditional infrastructure for care and research referral. In order to better understand local experiences seeking care and address communication barriers, we applied the Boot Camp Translation model for the Las Vegas H/L community.

Method

We identified 14 community members to participate in our ADRD BCT through community connections, targeted email blasts, and social media. BCT members ranged in age from 23 to 62 (M = 43, SD = 13.74), were majority female (10/14) and H/L (11/14), and most (10/14) were connected to local non‐profit organizations serving H/Ls, those with ADRD, and/or older adults.

Result

BCT members identified messages to increase AD awareness that reflected love, “respeto” (respect), resilience, and connection; messages targeted younger and middle‐age adults and community organizations: 1) “Amar es saber” (“To love is to know”), which encourages discussions among family members; 2) “The community cares. Let’s talk.”; and 3) “Podemos afrontar el Alzheimer juntos.” (”We can face Alzheimer’s disease together.”). BCT members identified our resource desert as a key challenge to message‐based calls to action. As reflected by their messages, they also highlighted opportunities for community members to engage and support message dissemination.

Conclusion

The Las Vegas BCT effectively identified messages, challenges, and opportunities to increasing AD knowledge and research engagement. Many BCT members joined our community advisory board; they emphasize the need for ongoing advocacy in the state, Spanish‐language resources, and an online presence that simplifies and supports navigation of services and information.
Differential dementia diagnosis using event‐based modelling: Alzheimer’s disease versus Dementia with Lewy Bodies
Authors: Leal Gonzalo Castro , Whitfield Tim , Walker Zuzana , Oxtoby Neil P
Published: December 2023

Background

Differential diagnosis of dementias in the clinic is challenging, especially in the prodromal phase where early symptoms overlap. Here we prototype a differential diagnosis system based on event‐based modeling of MRI atrophy in two dementias.

Method

Public data from ADNI, NACC, PPMI, PDBP (N = 1978). Inclusion criteria: baseline T1w‐MRI successfully processed by FreeSurfer 7.1.1, CN/AD/DLB/MCI diagnosis. A nearest‐neighbour approach matched disease‐specific control groups to AD and DLB by Age/Sex/scanner (field strength), and Desikan‐Killiany volumes were adjusted for normal trends in Age/Sex/field‐strength/intracranial volume. The final analysis dataset consisted of 91 DLB, 298 AD, and 786 MCI (N = 1175), with matched control groups for each.

One event‐based model (EBM) of regional brain atrophy was fit per disease, using Kernel Density Estimation mixture models to quantify biomarker abnormality. Input features were brain volumes having disease signal in both AD and DLB.

The EBM patient‐staging tool was adapted to perform differential diagnosis. The tool converts individual data into a probability distribution over stages — stage likelihood — for each model. We define EBM diagnosis as the model having the maximum stage likelihood.

Result

Figure 1 shows the event‐based model posterior (positional variance diagram) for AD (left) and DLB (right). AD atrophy starts in a subset of limbic regions before progressing to the temporal cortex and beyond. The DLB atrophy pattern diverges considerably (off‐diagonal density in Figure 1), including involvement of additional limbic regions early on. Figure 2 shows patient staging results for each model, with MCI individuals earlier than patients as expected. Differential diagnosis accuracy was 63%, which is comparable to previous studies.

Conclusion

We successfully adapted event‐based modeling of MRI atrophy for differential diagnosis of AD vs DLB. More data for other dementias, especially in the prodromal phase, is needed to test and deploy such a tool in memory clinics.
Unraveling the relationship between heart rate and agitation in people with dementia
Authors: Davidoff Hannah , Van Helleputte Nick , Vandenbulcke Mathieu , De Vos Maarten , Hoof Chris Van , Bossche Maarten Van Den
Published: December 2023

Background

Agitation is a critical behavioral and psychological symptom of dementia, leading alone to increased caregiver burden, more frequent hospitalization, and earlier institutionalization. The results presented here provide preliminary insights into one facet of multimodal agitation detection, specifically analyzing the relationship between heart rate and agitation.

Method

To date, 26 people with dementia have been included in our study to detect agitation using a multimodal approach1. In this analysis, heart rate is derived from the wristwatch wearable measuring photoplethysmography (PPG). Data points were included in subsequent analysis if the signal quality index of the original PPG signal was > = 0.8 (on a scale from 0‐1). For each complete survey, the mean heart rate (HR) was extracted from 1‐minute intervals in a 6‐minute window centered on the survey timestamp (± 3 minutes). For each mean HR per minute, the presence or absence of agitation was derived from the Pittsburgh Agitation Scale integrated into the survey. The data was centered within‐patient. Due to the nested structure of the data, hierarchical mixed models were used to predict presence of agitation as a binary response variable.

Result

The resulting dataset of high‐quality HR data consists of 1286 data points, from 21 patients (Age mean: 81 (8.3), nfemale: 8) The 3‐parameter model built included mean heart rate as an explanatory fixed effect, and two random intercepts: day and patient. In the model, increased HR compared to a participant’s average HR over a week, was significantly associated with an increase in odds of agitation (p< 0.001). Every 1 beat increase in mean HR over a minute, from the participants’ mean heart rate, increased the odds of that 1‐minute interval indicating agitation by 7.68% (CI: 5.43‐10.1).

Conclusion

These results provide insight into the relationship between heart rate and agitation, possibly indicating activation of the autonomic nervous system, due to the association of increased HR with increased odds of agitation. Analyses like these provide the basis for future agitation detection algorithms that account for a multi‐faceted patient response.

1. Davidoff, et al, 2022, Innovation in Aging, Volume 6, Issue 7, 2022, igac064, https://doi.org/10.1093/geroni/igac064
To evaluate the prevalence, subtypes and risk associations of mild cognitive impairment in elderly Indian individuals with type 2 diabetes
Authors: Gupta Anu , Goyal Alpesh , Rajan Roopa , Vishnu Venugopalan Y , Kalaivani Mani , Tandon Nikhil , Srivastava MV Padma , Gupta Yashdeep
Published: December 2023

Background

Diabetes is an important modifiable risk factor for dementia. The prevalence of mild cognitive impairment (MCI) in type 2 diabetes (T2D) is high (You et al, 2021). This data is largely derived using screening tools (MMSE or MoCA), with little information on MCI subtypes. Evidence from the South Asian region is particularly scarce, where prevalence of diabetes is high, and is seen a decade earlier compared to Caucasians.

Method

We have established a cohort of elders (³ 60 years of age), with and without diabetes, visiting a tertiary care hospital in North India (from 2019, ongoing). The participants underwent an interview to collect information on their demographic profile, risk associations, vascular health, and other comorbidities. Culturally validated neuropsychological battery was used for cognitive evaluation. MoCA was done in a subset of patients.

Result

We recruited 840 participants in the cohort, 683 with T2DM and 157 without T2DM (controls). The mean age of the cohort was 65.3±4.5 years, 65.2% were males. Risk profile is described in Table 1. The cognitive z scores of participants with T2DM ranged from ‐0.25 to +0.44. The worst affected domain was attention, working memory and executive functions (Table 2). Using an actuarial definition of MCI (Bondi MW et al, 2014), the prevalence in participants with T2D was 29.7%. 17.3% had amnestic impairment, 14.8% dysexecutive, 14.2% language, 2.4% visuo‐perceptual and 9.1% multidomain impairment. The cognitive raw scores (by dementia risk stratification) are provided in Table 3. On logistic regression, lower education 3.45(2.09,5.68), depression 2.04(1.26,3.29), poor sleep quality 1.77(1.15,2.71), family income 1.70(1.22,2.38), followed by age 1.05(1.00,1.10) had a significant association with global low cognition.

Conclusion

Roughly one‐third of elders with T2D visiting tertiary care services in North India have mild cognitive impairment. Amnestic subtype is the most frequent. Attention, working memory and executive functions are worst affected. Enhancing the cognitive reserve, mood and sleep quality may be important targets in prevention of cognitive decline in the elderly population with T2D.
Identification of genes and blood co‐expression networks associated with cerebrovascular neuroimaging phenotypes
Authors: Chen Xuan , Quicksall Zachary , Wang Xue , Reyes Denise A. , Graff‐Radford Jonathan , Nguyen Thuy , Lincoln Sarah J. , Malphrus Kimberly G. , Crook Julia E. , Reddy Joseph S. , Allen Mariet , Jack Clifford R. , Lowe Val J. , Knopman David S. , Petersen Ronald C. , Kantarci Kejal , Bu Guojun , Carrasquillo Minerva M. , Ertekin‐Taner Nilufer
Published: December 2023

Background

A hallmark of Alzheimer’s disease is amyloid‐β (Aβ) deposition in the brain parenchyma as senile plaques which Aß frequently accompanies in the cerebral vasculature as cerebral amyloid angiopathy (CAA). Previous studies demonstrated that the cerebrovascular system is essential for Aβ clearance and interactions exist between cerebrovascular disease and AD. Neuroimaging data, including measures on small vessel disease, amyloid deposits, and microhemorrhages (MCH), can reflect both cerebrovascular disease and AD pathology, thereby serving as intermediate phenotypes of both conditions. We aim to identify genes and co‐expression networks in blood associated with these neuroimaging endophenotypes and the biological pathways enriched in these perturbed transcriptional networks.

Method

We conducted differential gene expression and Weighted Gene Co‐Expression Network analyses (WGCNA) on blood RNA sequencing data of 407 participants from the longitudinally followed Mayo Clinic Study of Aging cohort. The neuroimaging phenotypes include MCH, infarction, and amyloid deposits measured by Pittsburgh compound B positron emission tomography (PiB PET).

Result

WGCNA analysis showed a nominally significant association (p<0.05) between several module eigengenes (MEs) and MCH and PiB PET. One module, M42, remained significantly associated with PiB PET after Bonferroni correction for all 43 modules tested. Pathway enrichment analysis of M42 identified two significant pathways (FDR‐adjusted p<0.05) including phosphodiesterase I activity and IgE binding. These pathways contain genes such as MS4A2 encoding the high‐affinity IgE receptor involved in the immune response. Similarly, ENPP2 in the phosphodiesterase I activity pathway represents an additional candidate gene previously implicated in Alzheimer’s disease.

Conclusion

We generated co‐expression networks and identified one network module with a statistically significant association between brain amyloid deposits and blood transcriptome data. Further investigations of this network and its enriched pathways are necessary to understand their roles in amyloidosis, CAA, and neurodegeneration. Future studies will include seeking replication of these results in other datasets. Such studies can help elucidate the biological mechanisms of pathogenesis of cerebrovascular damage and amyloid deposits. In addition, in a clinical setting, blood levels of transcripts discovered in this study may serve as predictive or diagnostic biomarkers with mechanistic implications.
Risk‐taking behavior in older adults is related to cognitive outcomes in a domain‐specific manner
Authors: Waltrip Leah H. , Joyce Jillian L. , Chapman Silvia , Cosentino Stephanie , Sunderaraman Preeti
Published: December 2023

Background

Risk tolerance, a crucial component of decision‐making, has been shown to be highly domain‐specific (Blais, 2006). Nevertheless, when risk‐taking behavior is studied in the context of aging, it is almost exclusively examined using behavioral economics tasks which focus on financial risk‐taking behavior, neglecting other important domains such as health, recreational, ethical, and social risk‐taking. Such studies have associated risk‐aversion with cognitive impairment (James, 2015; Dohmen, 2010), however no studies have evaluated domain‐specific risk‐taking behavior and cognition in older adults. Evaluating the association of risk tolerance and cognition in a domain‐specific manner can help inform whether individuals are at an increased risk of poor decision‐making, and which domains of their everyday functioning may be impacted.

Method

Cognitively normal participants (n = 56) completed the Domain‐Specific Risk‐Taking Scale (DOSPERT) a 30‐item self‐reported survey consisting of financial, health, ethical, recreational, and social risk‐taking domains. Participants rated their likelihood of participating in risky activities on a 7‐point Likert scale with higher scores indicating higher likelihood of risk‐taking. Sum scores for each domain were calculated. Cognitive data was collected on tasks assessing associative, verbal, and working memory, as well as semantic and category fluency. Spearman’s two‐tailed correlations adjusted for age (69.55 ± 7.35), gender (59% female), and level of education (16.69 ± 2.19) were run to evaluate the relationship between specific risk‐taking domains and cognitive function.

Result

Financial risk‐aversion was associated with better long‐term verbal memory retrieval (p = 0.009, r = ‐0.359). Ethical risk‐seeking was associated with higher semantic fluency (p = 0.036, r = 0.292). Health risk‐aversion was associated with slower processing speed (p = 0.011, r = ‐0.348).

Conclusion

Our findings indicate that domain‐specific risk‐taking behaviors are uniquely related to different aspects of cognition. These findings suggest that measuring risk‐taking behavior in a single domain is not sufficient. Understanding the association between cognition and risk‐taking can provide insight on whether older individuals with impaired cognitive function are more likely to engage in risk‐taking with potential negative impacts on wellbeing. Future work can be conducted longitudinally in older populations to understand whether specific domains of risk‐taking consistently map on to the same aspects of cognition.
Association between sleep difficulties, bodily symptoms, and subjective cognitive decline in urban Black men
Authors: Esiaka Darlingtina K , Nwakasi Candidus
Published: December 2023

Background

Sleep has been linked to subjective cognitive decline (SCD) in older adults, which may indicate an onset of cognitive decline to Alzheimer’s disease and related dementia. There is a dearth of studies on the role of sleep difficulties and bodily symptoms in influencing cognitive status of middle‐age and older Black men. This limits our understanding of the potential role of sleep and bodily symptoms on Black men’s brain health.

Method

This cross‐sectional study examined factors predicting subjective cognitive decline in Black men living in urban settings. Participants (N = 117, Mage
= 48.45) responded to a survey assessing sleep difficulties, sleep comorbidities, bodily symptoms, self‐rated health, sociodemographic characteristics, and subjective cognitive decline. SCD was operationalized as a self‐reported experience with increasing confusion or memory loss in the last 12 months.

Result

Hierarchical regression revealed that in Model 1 with sociodemographic characteristics, only education was a significant predictor of SCD (F (4,112) = 6.33, p<.05), accounting for 18% of the variation in SCD. In Model 2 with self‐rated health and bodily symptoms added, socioeconomic status, education, and bodily symptoms were significant predictors of SCD (F (6,110) = 11.82, p<.001) and explained an additional 39% of the variation in SCD. When sleep difficulties and sleep comorbidities were added to Model 3, sleep difficulties, sleep comorbidities, bodily symptoms, socioeconomic status, and education were significant predictors of SCD (F (8,108) = 13.79, p<.001), accounting for 50% of the variation in SCD.

Conclusion

Our findings may be used as a groundwork for future research examining the causal link between cognitive decline, sleep, and bodily functions. It can also inform health intervention programs for middle‐aged and older Black American men.
Tau and Amyloid Plasma Biomarker Analysis in Alzheimer’s Disease Cohorts from Diverse Genetic Ancestries
Authors: Griswold Anthony J. , Rajabli Farid , Gu Tianjie , Garcia‐Serje Catherine , Arvizu Jamie , Golightly Charles G. , Whitehead Patrice , Hamilton‐Nelson Kara L. , Adams Larry D. , Celis Katrina , Sanchez Jose Javier , Tejada Sergio J. , Mena Pedro R. , Starks Takiyah D. , Cornejo‐Olivas Mario , Illanes‐Manrique Maryenela Z , Silva‐Vergara Concepcion , Cuccaro Michael L. , Vance Jeffery M. , Feliciano‐Astacio Briseida E. , Byrd Goldie S. , Beecham Gary W. , Haines Jonathan L. , Pericak‐Vance Margaret A.
Published: December 2023

Background

Plasma concentrations of phosphorylated threonine‐181 of Tau (pTau181) and the ratio of amyloid beta isoforms Ab42/Ab40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, measurement of these biomarkers is mostly from individuals of non‐Hispanic, European ancestry. Given differences in AD risk, generalizability of these findings is not assured in individuals of diverse ancestry. This study evaluates the utility of plasma pTau181 and Ab42/Ab40 in discriminating clinically diagnosed AD from cognitively intact, age‐matched controls in ancestrally diverse, admixed cohorts.

Method

We measured plasma pTau181 and Aβ42/Aβ40 with Simoa chemistry using the pTau181 AdvantageV2 and NEUROLOGY 3‐PLEX A assays, respectively. Our cohorts consisted of: 642 African Americans (162 AD and 480 cognitively intact (CI)), 906 Puerto Ricans (385 AD and 521 CI), 149 Peruvians (49 AD and 100 CI), 60 Cubans (26 AD and 34 CI), and 246 non‐Hispanic, European ancestry (22 AD and 224 CI). Linear mixed‐effect regression models adjusted for age, sex, population substructure and relatedness followed by Bonferroni correction was applied to identify differences across AD status. Diagnostic performance and construct receiver operator characteristic (ROC) curves were created from logistic regression models.

Result

Plasma pTau181 concentrations were increased in individuals with AD compared to CI (p < 2×10−16) taking into account all individuals and in each cohort separately (African Americans, p = 1.2×10−9; Puerto Ricans, p = 7.6×10−9; Peruvians, p = 0.02), and European ancestry, p = 2.2×10−8) except for the Cubans where there was a trend. There was no significant difference in the plasma Aβ42/Aβ40 ratio, however there was a trend towards a decreasing concentration in AD. Using the area under the ROC, pTau181 was more accurate at predicting status than the Aβ42/Aβ40 ratio, but the classification improved when both biomarkers were combined. The accuracy varied widely over the individual cohorts with AUC from 0.845 for African Americans to 0.683 for Peruvians.

Conclusion

These results suggest AD biomarkers are generalizable across ancestries, though the predictive value may differ depending on specific ancestral backgrounds. Ultimately, combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses in individuals of diverse ancestries.
The contribution of Oculomotor and Motor Deficits in The Assessment of Executive Function in Progressive Supranuclear Palsy Patients
Authors: Khoja Abeer , Monteiro Marta , Morales‐Rivero Alonso , Cordero Indira Ruth Garcia , Gold David , Antwi Jeffrey , Sasitharan Johnathan , Bhakta Puja , Couto Blas , Tsang Michelle , Kovacs Gabor , Fox Susan , Tang‐Wai David F. , Lang Anthony E , Tartaglia Carmela
Published: December 2023

Background

Progressive supranuclear palsy (PSP) was first described in 1964 and is associated with motor, oculomotor, and cognitive deficits. Cognitive assessments often assume intact physical function. Some tests like The Trail Making Test (TMT), a measure of executive function may be impacted by oculomotor and motor impairments. Our aim was to investigate the impact of oculomotor impairments and arm dysfunction on the TMT.

Method

71 patients from the Rossy PSP Center that met criteria for probable PSP and underwent a neuropsychological test battery, the Toronto Cognitive Assessment (TorCA), were included. Data from the following tests and assessments were used for this study: TMT A and B time, digit forwards and backwards, verbal and animal fluency, Benson copy, and Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) delayed recall, PSP Rating Scale (PSPRS) total score and its oculomotor subscore, MDS‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS part III) subscore of the dominant hand was used to rate the motor impairment. We performed spearman correlations and used false discovery rate test correction for multiple comparisons.

Result

The PSP patients (60.6% male, mean age 71.3+/‐6.61) had mean PSPRS score of 41.5+/‐15, PSPRS‐oculomotor subscore 8.0+/‐3, and MDS‐UPDRS III subscore dominant hand 6.5+/‐3.3. We found a positive correlation between PSPRS‐oculomotor subscore and TMT A (r = 0.43 p = 0.005) and TMT B (r = 0.35 p = 0.008). We also found negative correlations between PSPRS‐oculomotor subscore and digits backward (r = ‐0.39 p = 0.005), Benson copy (r = ‐0.39 p = 0.005), CERAD delayed recall (r = ‐0.29 p = 0.034), and animal fluency (r = ‐0.44 p = 0.004). No tests were related to MDS‐UPDRS part III subscore of the dominant hand.

Conclusion

Oculomotor but not motor function affect TMT A and B. However, oculomotor function also relates to other executive and non‐executive tests that do not require visual scanning. Although important to factor in physical deficits when doing cognitive assessments, the TMT appears to be a reliable test for assessing cognitive function in patients with PSP who can perform the test.