bluuebunny/crossref_metadata_2025 huggingface dataset:
Speech markers of depression dimensions across the spectrum of cognitive functions
Authors: Soleimani Laili , Cho Sunghye , Kia Arash , Beeri Michal S , Liberman Mark Y , Grossman Murray , Nevler Naomi
Published: December 2023

Background

Depression is a common among patients with cognitive impairment and encompass different dimensions, which may vary in their association with cognitive outcomes and biological substrates. Previous studies have shown a shift toward the use of more negative words in written documents and social media posts of depressed patients with intact cognitive function. To objectively characterize depression dimensions across the spectrum of cognitive functions, we explored their association with the emotion‐based measures of speech in participants of memory clinic.

Methods

This study capitalized on semi‐structured digitized speech data collected at the hospital of University of Pennsylvania. Subjects (n = 302, 40% female, mean age = 67.13±9.59 years, education = 15.82±2.84 years, Mini‐Mental Status Exam (MMSE) = 24.36±5.04) were native English speakers with cognition ranging from normal cognition to mild dementia. Participants were instructed to describe the Cookie Theft scene using complete sentences and their descriptions were digitally recorded. Emotion‐based measures of the content words, including valence (i.e., the pleasantness), arousal (the intensity of emotions), and dominance (the word power), were rated based on published norms. Each emotional measure was averaged per speaker. Depression dimensions were defined based on itemized Geriatric Depression Scale – 15 item (GDS‐15) including Dysphoria, Withdrawal‐Apathy–Vigor (WAV), anxiety, hopelessness and Subjective Memory Complaint. Non‐parametric partial correlations examined associations between speech emotion‐based measures and depression scores adjusting for age, sex, education and MMSE.

Results

Overall depression score (total GDS) did not correlate with the speech measures. However, when examining specific depression dimensions, higher WAV and hopelessness correlated with reduced valence (WAV: r = ‐0.21, P = 0.00, hopelessness: r = ‐ 0.14, P = 0.01) and dominance (WAV: r = ‐ 0.18, P = 0.001, hopelessness: r = ‐ 0.16, P = 0.004). We did not find a significant association between emotional word scores and other depression dimensions.

Conclusion

Patients with high apathy and hopelessness select words that carry more negative and less powerful emotional valence. Our findings highlight the potential applicability of speech biomarkers in characterization of depression dimensions across spectrum of cognitive and are consistent with previous findings that reported more negative bias and more submissive speech in depressed patients.
Modelling Latent Environmental Modifiers of Polygenic Risk for Late‐Life Depression Using Structural Equation Modelling
Authors: Elsheikh Samar , Marshe Victoria , Kennedy James L. , Pare Guillaume , Fischer Corinne E. , Felsky Daniel , Mueller Daniel
Published: December 2023

Background

Our understanding of the interplay between genetic and environmental factors (Gene x Environment Interaction, or GxE) determining mental health disorders has improved through the proliferation of genome‐wide interaction association studies (GWIAS) and targeted GxE analyses. Moreover, multivariate modelling approaches, such as structural equation modelling (SEM) and polygenic risk scores (PRS), offer opportunities for the integration of clinical and genome‐wide genotype data in building improved biopsychosocial models of mental illness aetiology and their response to treatment.

Method

We propose to construct a SEM framework to uncover the inter‐correlation and directed structure of mental health phenotypes by leveraging the joint predictive capacity of PRS for comorbid traits that share underlying biological and environmental risk pathways. The proposed model will be capable of linking latent constructs to their observed measurements; these will include disease severity, comorbidities and clinical histories, and behaviours and lifestyle factors such as physical and social activity.

Result

Our gene‐by‐environment SEM (GESEM) will be initially developed and tested using four well‐characterized clinical cohorts for older adults diagnosed with late‐life depression and treated with antidepressants (CAN‐BIND, IRL‐GREY, STOP‐PD II and IMPACT; n = 1,238). The primary outcome will be antidepressant remission. Multiple PRS will be calculated to capture underlying genetic risk across vulnerable pathways which contribute to comorbidities. This selection will be made based on new, largely unpublished work from our group on the impact of PRS and targeted GxE studies on psychiatric outcomes across the lifespan. Each PRS will be calculated using both clumping and thresholding (PRSice‐2) and continuous shrinkage (PRS‐CS‐auto) methods across selected cohorts using well‐powered publicly available GWAS summary statistics. The multilevel GESEM model will include interactions between symptoms and comorbidities (i.e., observed measurements), which are caused by unobserved factors (i.e., latent constructs), and are subject to modification by background PRS. We will compare our GESEM model against existing SEM‐based approaches to GxE, including local SEM (LOSEM).

Conclusion

An open‐source R package of the analytical code will be created and shared with the research community. This work has the potential to improve upon existing PRS‐based predictive models in a clinical setting.
Braak‐stage II atrophy links lower locus coeruleus – medial temporal lobe connectivity to cognitive decline in preclinical AD
Authors: Schneider Christoph , Prokopiou Prokopis C. , Papp Kathryn V. , Hsieh Stephanie , Schultz Aaron P. , Rentz Dorene M. , Sperling Reisa A. , Johnson Keith A. , Jacobs Heidi I.L.
Published: December 2023

Background

In preclinical human Alzheimer’s disease (AD), novelty‐related functional connectivity of the locus coeruleus (LC) with the medial temporal lobe (MTL) (ConnLC‐MTL) predicted beta‐amyloid (Aβ)‐related longitudinal cognitive decline. In animals, LC lesions in AD models led to dwindling LC projections to the hippocampus, hippocampal atrophy, and cognitive impairment. Following these observations, we investigated the contribution of cross‐sectional and longitudinal atrophy in early Braak stages as a potential mechanism underlying this relationship.

Method

We included 128 participants of the Harvard Aging Brain Study (HABS) with baseline Pittsburgh Compound‐B Positron Emission Tomography – Distribution Volume Ratio (PiB PET, DVR; 36 Aβ+), as well as baseline functional and longitudinal structural MRI (ntot = 372; ∼ every 3 years; follow‐up 5±3.4 years) and yearly cognitive assessments (PACC5 = Preclinical Alzheimer’s Cognitive Composite; ntot = 874; follow‐up 6.5±3.3 years) (Table 1). ConnLC‐MTL values were derived voxel‐wise and averaged across significant clusters. FreeSurfer‐estimated cortical thickness and hippocampus/amygdala volume (adjusted for intracranial volume) were z‐scored and averaged in two variables (THV2/THV3), encompassing regions associated with Braak stage II and III respectively (Table 1). Baseline associations were evaluated with linear models, longitudinal relationships between ConnLC‐MTL and THV2/THV3 with mixed‐effects models (random intercept and slope). Mediation of ConnLC‐MTL and PACC5 slopes (year 5‐13) by THV2/THV3 slopes (year 0‐5) was calculated (n = 79; bootstrapped n = 1000; Table 1). All models contained age, sex and education as covariates.

Result

At baseline, ConnLC‐MTL positively associated with THV2 (p = 0.005) and with PACC5 (p = 0.045), but not with THV3 (p = 0.26; Figure 1A‐C). Longitudinally, ConnLC‐MTL did not predict changes in THV2 nor THV3. However, we observed faster cortical atrophy with lower ConnLC‐MTL at higher levels of neocortical PiB (THV2: p = 0.02; THV3: p<0.001; Figure 1D‐E). Finally, THV2, but not THV3, mediated the relationship between ConnLC‐MTL and PACC5 decline (p = 0.024) and this effect was stronger in PiB+ individuals compared to PiB‐ (p = 0.026; Figure 2).

Conclusion

Worse LC‐MTL connectivity was associated with downstream atrophy in the target Braak‐stage II areas, which impacted cognitive performance in preclinical AD. Given that in similar previous animal findings activation of the norepinephrine LC system reversed memory deficits, maintaining optimal ConnLC‐MTL may be a promising intervention target to delay disease progression.
Domain‐specific cognitive decline associates with differential regional tau burden in the Alzheimer’s disease spectrum
Authors: St‐Onge Frederic , Binette Alexa Pichet , Chapleau Marianne , Breitner John C.S. , Villeneuve Sylvia
Published: December 2023

Background

Patients presenting with distinct clinical variants of Alzheimer’s disease (AD) present differential patterns of tau pathology measured with positron emission tomography (PET). Yet, a single set of brain regions like a temporal meta‐ROI is often chosen to study the association between cognition and tau. Instead, we aimed to map the associations between regional tau and multiple cognitive domains, and to test whether using whole brain information yields stronger associations with cognition compared to a singular composite region.

Method

We included 372 amyloid‐positive ADNI participants that had at least one tau‐PET scan (163 cognitively unimpaired [CU], 132 with mild cognitive impairment [MCI], 77 with AD dementia). Composite cognitive scores for memory, executive functioning, visuospatial and language were used for cross‐sectional (closest score to tau‐PET) and longitudinal analyses. Individual rate of cognitive decline was computed using linear mixed effect models, leveraging all visits available for each participant. We did region‐wise analyses, relating tau in the 64 regions of the Desikan‐Killiany atlas plus the amygdalae with cognitive performance and rate of cognitive decline. We also derived a “spatial extent index” where we computed the number of abnormal tau regions and compared the performance of this index to detect cognitive impairment to what would have been found with a classical temporal meta‐ROI SUVR value.

Result

No regional association between tau and cognition survived FDR correction in CU participants. Cross‐sectionally and longitudinally, participants with MCI and with AD dementia, associations between tau and memory were predominant in the temporal lobe, associations with language were restricted mostly to the left hemisphere and associations with executive functioning spanned the entire cortex. (Fig 1) Comparing the sum of tau positive regions (spatial extent index) to tau SUVR in the temporal meta‐ROI, both measures were similarly associated with cognition, except for executive functioning at baseline where the spatial extent index was more strongly associated with cognition than the meta‐ROI. (Fig 2)

Conclusion

While temporal meta‐ROI tau SUVR may be sufficient to track non‐executive cognitive performance in individual with cognitive impairments, a whole brain measure may provide additional information regarding executive impairment occurring in AD.
Investigating the Role of Estrogen Receptor Alpha in Alzheimer’s Disease Pathogenesis in Down Syndrome
Authors: Andrews Elizabeth J. , Phelan Michael J. , Ngo Phong , Pascual Jesse R , Gonzalez Freddy , Wright Sierra , Kofler Julia , Ikonomovic Milos D , Lai Florence , Ances Beau , Handen Benjamin L. , Christian Bradley T. , Mapstone Mark , Head Elizabeth ,   Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS)
Published: December 2023

Background

People with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are at a higher risk for AD, while others find the opposite. Sex differences may be mediated by estrogen, which is critically involved in neuronal survival and modulation. We hypothesized that lower levels of ERα protein would correlate with increasing AD pathology in DS.

Method

We examined 34 brains (frontal and occipital cortices) of people with DS and DS with AD. Serial sections were immunostained for phosphorylated tau (pTau ‐AT8) and Aβ (6E10) along with ERα and quantified using QuPath. Spearman rank correlations using log transformed % load data were calculated, Kruskal‐Wallis was used to compare men (n = 19) and women(n = 15).

Result

No significant differences in protein levels of ERα, Aβ, or tau were observed when comparing men and women with DS. However, we found higher levels of ERα protein were associated with higher levels of Aβ in the gray matter of the occipital cortex (r = 0.7078; p = 0.0005) in all cases. This positive correlation was driven primarily by women. Females with DS showed a significant positive association with Aβ and ERα (r = 0.93; p = 0.00012) whereas men showed a weaker trend (r = 0.62; p = 0.057). In contrast, no significant associations between ERα, Aβ or pTau were observed in the frontal cortex. PTau measures in the occipital cortex in women with DS were positively associated with ERα (r = 0.61; p = 0.055), whereas men with DS showed a slight negative, though not significant association (r = ‐0.29; p = 0.41). There was no such trend in the frontal cortex.

Conclusion

These results suggest ERα, in contrast to our original hypothesis, may be increasing in response to AD pathology to preserve neuronal health in the occipital cortex. Lack of similar positive associations in the frontal cortex may be related to AD progression, with the occipital cortex being affected later in disease, giving us the opportunity to observe increased ERα.
MCI in Caribbean Hispanics shows increased impairment in attention and working memory domains relative to non‐Hispanic White individuals
Authors: McInerney Katalina , Zaman Andrew , Mena Pedro R. , Adams Larry D. , Tejada Sergio J. , Sanchez Jose Javier , Celis Katrina , Hamilton‐Nelson Kara L. , Feliciano‐Astacio Briseida E. , Rajabli Farid , Beecham Gary W. , Vance Jeffery M. , Cuccaro Michael L. , Pericak‐Vance Margaret A.
Published: December 2023

Background

Patterns of cognitive performance associated with different stages of dementia have been primarily studied in Non‐Hispanic White (NHW) populations. This study compares patterns of cognitive performance, on a brief neuropsychological battery, in Caribbean Hispanic (CH) and NHW individuals with mild cognitive impairment, based on Clinical Dementia Rating (CDR) staging scores.

Method

Our data included 427 individuals including 299 self‐identified CH (mean age = 76.0; 69.6% female; mean education = 11.9) and 128 NHW (mean age = 72.9; 61.7% female; mean education = 13.8) who completed the CDR and a brief neuropsychological battery. Participants with other medical conditions known to impact cognition were excluded. Sex‐, age‐, and education‐adjusted Z‐scores were calculated for all cognitive tests (Logical Memory (Immediate and Delayed recall), Digit Span (Forward and Backward), and Verbal Fluency (Animals and Vegetables)). ANOVAs were used to examine the effects of ethnicity (NHW, CH) and CDR Global Score (0.5, 1.0) on the adjusted Z‐scores for all cognitive tests. CDR score distribution was adjusted through factorial ANOVA (ethnicity x CDR). Descriptive analyses included independent t‐tests to examine differences between ethnicity groups on age, sex, education, percent AD, percent Unclear, and CDR Global Score.

Result

There was a main effect of ethnicity on Digit Span Forward (p < 0.001), Digit Span Backward (p < 0.001), and Verbal Fluency – Vegetables (p < 0.01), where CH individuals showed greater impairment regardless of Global CDR score. We found a main effect of Global CDR score on all cognitive tests, where individuals with Global CDR score of 1.0 demonstrated more impairment than individuals with a Global CDR score of 0.5. No ethnicity x CDR interactions were significant.

Conclusion

Our sample of older CH and NHW individuals, presumed to have mild cognitive impairments based on CDR staging, did not differ in memory abilities. However, the CH group scored significantly lower on measures of attention and working memory. Finally, semantic fluency performance was variable and possibly influenced by cultural familiarity with different semantic categories. Among older CH individuals with mild dementia, cognitive difficulties may extend beyond memory problems and include attentional and executive function difficulties. These findings have clinical implications for diagnosis and management of CH patients.
Association of contemporary dementia diagnosis rate with clinician characteristics: Evidence from Medicare claims
Authors: Liu Ying , Becker Andrew , Jun Hankyung , Wallick Christopher , Mattke Soeren
Published: December 2023

Background

Population‐level gap and disparities are documented for the dementia diagnosis. Little is known, however, the extent to which clinician’s characteristics, including the characteristics of the patient population they serve, are associated with their likelihood of adequately diagnosing dementia, after accounting for patient characteristics.

Method

We used the 100% Medicare fee‐for‐service and Advantage Plan data from 2017 to 2019. Patients were attributed to primary care clinicians based on plurality of office visits. We determined each clinician’s observed number of patients with a diagnosis of dementia of any etiology and estimated the expected number of cases with a predictive model using patient characteristics (age, sex, race/ethnicity, whether dually eligible for Medicare and Medicaid). The ratio between the clinician’s observed and expected diagnosis rates (O/E ratio) serves as performance measure for diagnostic accuracy. We calculated 95% confidence intervals (CI) around those O/E ratios and categorized those whose 95% CI included 1 as diagnosing dementia at an adequate rate and those whose 95% CI did not reach 1 as underdiagnosing dementia. We then used logistic regression to predict a clinician’s likelihood of having adequate diagnosing compared to under‐diagnosing using clinician characteristics: their attributed patient panel’s composition on race/ethnicity, dually eligible, and having had annual wellness visit, urban‐rural location of the practice, the clinician’s specialty, and state fixed effects.

Result

Among 194,699 included clinicians, those serving more White (Odds Ratio [OR] = 1.50 for 10 percentage points [pp] increase, p<0.001), fewer Black (OR = 0.94 for 10 pp increase, p<0.001) or Hispanic patients (OR = 0.98 for 10 pp increase, p = 0.003), and fewer duals (OR = 0.82 for 10 pp increase, p<.001) were more likely to have an adequate diagnosis rate than under‐diagnosing. Clinicians who practiced outside of metropolitan areas were less likely to have an adequate diagnosis rate (compared to metropolitan, OR = 0.91, p = 0.025 for micropolitan; OR = 0.75, p<0.001 for small town; OR = 0.63, p<0.001 for rural areas). No association is seen with percent of patients having annual wellness visit (OR = 1.00 for 10 pp increase, p = 0.913).

Conclusion

Primary care clinicians who serve racial/ethnic minority or dually eligible patients and practice outside of big cities may under‐detect dementia cases.
Posterior cingulate cortex microRNA alterations in cognitive resilience, mild cognitive impairment, and Alzheimer’s disease
Authors: Counts Scott E. , Beck John S. , Maloney Bryan , Malek‐Ahmadi Michael H. , Kockmanski Joseph J. , Ginsberg Stephen D. , Mufson Elliott J. , Lahiri Debomoy K.
Published: December 2023

Background

MicroRNA (miRNA) dysregulation is linked to Alzheimer’s disease (AD) pathophysiology. We recently reported a role for miR‐298 and miR‐20b in AD risk and amyloid and tau metabolism. To examine the extent to which miRNAs are dysregulated during the earliest stages of AD, we quantified miRNA transcript levels in postmortem samples of posterior cingulate cortex (PCC), a default mode network (DMN) hub that underlies autobiographical memory, in normal subjects and those who died within the AD continuum.

Method

PCC samples were obtained from Rush ROS/MAP participants who came to autopsy with a diagnosis of a) no cognitive impairment and low pathology (NCI‐LP, Braak stage I/II, n = 12), b) NCI with high pathology (NCI‐HP, Braak stage IV, representing cognitive resilience, n = 8), c) mild cognitive impairment (MCI, n = 10), or d) dementia due to AD (n = 9). Illumina‐based sequencing of total RNA was performed and trimmed reads with a size of 15‐31 bases were analyzed.

Result

Differential expression analysis (FDR ≤ 0.04) revealed 42 miRNAs significantly dysregulated among the NCI (independent of Braak stage), MCI, and AD groups. Two miRNAs, miR‐99a (FDR‐adjusted p = 0.01) and miR‐664b (p = 0.005), were downregulated in AD vs NCI and MCI, while miR‐30a (p = 0.006), miR‐374a (p = 0.004), and miR‐501 (p = 0.005) were significantly upregulated in MCI vs. NCI and AD. Three miRNAs were significantly downregulated in NCI‐HP vs. NCI‐LP: miR‐103a (p = 0.04), miR‐211 (p = 0.03), and miR‐4443 (p = 0.03). These miRNAs may operate in resilience‐related pathways. Correlation analysis revealed that decreasing PCC levels of miR‐664b levels were associated with poorer performance on antemortem tests of episodic memory (r = 0.41, p = 0.009), semantic memory (r = 0.44, p = 0.004), and visuospatial ability (r = 0.45, p = 0.004).

Conclusion

Taken together, these data may identify potential pathogenic or protective miRNA‐related mechanisms contributing to PCC and DMN function during the progression of AD, which may inform biomarker and intervention strategies. Ongoing analysis will identify functional pathway enrichment and miRNA targets.
Interactome‐guided machine learning modeling reveals information embedded in blood plasma protein‐protein interactions in Alzheimer’s Disease patients treated by the complex plasma fraction GRF6019
Authors: Nanasi Tibor , Braithwaite Steven P , Lehallier Benoit
Published: December 2023

Background

The relevance of plasma fraction treatment to reverse age‐related conditions was underlined by our previous pre‐clinical results. In two Phase 2 clinical trials (GRF6019‐201 and GRF6019‐202), patients with Alzheimer’s Disease (AD) were treated with the complex plasma fraction GRF6019, which was determined to be safe and well‐tolerated. Interestingly, no cognitive decline and minimal functional decline were observed. While GRF6019 treatment was associated with a quick and widespread proteomics response, lasting molecular changes were more subtle. Here, we developed new machine learning models guided by protein‐protein interaction (PPI) information to deeper understand the molecular effects of GRF6019 plasma fraction treatment.

Method

More than 7k proteins were measured in 120 plasma samples from treated subjects enrolled in the GRF6019‐201 and GRF6019‐202 trials (n = 21 and 18, respectively) using the Somascan assay. Interacting protein pairs were curated from STRING and OmniPath PPI databases. For each protein‐protein interaction, linear Support Vector Machine (SVM) models were trained to separate before and after treatment samples based on measured protein levels and compared to single‐protein models. Proteins were ranked based on their individual performance and their gain of performance when combined with interaction partners

Result

Proteasome‐associated elements were overrepresented among proteins with top individual performance. Interaction models provided more details about related processes involving ubiquitination. Furthermore, various other immune, hormonal, and neuronal terms found to be enriched among the top interactors.

Conclusion

Complex biological functions can be mapped into pathways which are composed of and regulated by PPIs. Biological functionality can be encoded in concentrations of individual proteins, also in relative concentrations of interacting proteins. Our results indicate that the latter aspect may contain a significant amount of complementary information, not accessible with traditional approaches analyzing proteins as independent entities. Consequently, the development and the application of novel system biology tools on blood plasma proteomics will help to better understand patients’ responses to treatment in clinical trials.
Relationship between Life’s essential 8 scores and cognitive decline in the ELSA‐Brasil cohort
Authors: Vidal‐Ferreira Naomi , Gonçalves Natalia G , Szlefj Claudia , Goulart Alessandra C. , Santos Itamar Souza , Duncan Bruce , Schmidt Maria Inês , Barreto Sandhi Maria , Caramelli Paulo , Feter Natan , Castilhos Raphael Machado , Drager Luciano Ferreira , Lotufo Paulo A , Bensenor Isabela M , Suemoto Claudia Kimie
Published: December 2023

Background

Lifestyle and cardiovascular risk factors were combined in the Life’s simple 7 (LS7) index to evaluate cardiovascular health, and this index has been previously associated with cognitive decline. The Life’s Essential 8 (LE8) is an update of LS7, which now includes sleep health as an additional factor. We aimed to verify the association between LE8 and cognitive decline during X years of follow‐up in 11,390 participants from a racially diverse sample.

Method

In this cohort study, LE8 score was measured based on diet, physical activity, nicotine exposure, sleep health, BMI, blood lipids, blood glucose, and blood pressure. Cognition was assessed in three waves four years apart from each other using the CERAD word list, semantic and phonemic verbal fluency, Trail Making Test B (TMT‐B), and a global composite score. We used inverse probability weighting to account for mortality and attrition bias and linear mixed models with random intercepts and slopes to verify the association between baseline LE8 score and cognitive decline. We tested the interaction between LE8 and age, sex, and race.

Result

The mean sample age was 51.4±8.9yo at baseline, 56% were women, and 43% Black. Higher baseline LE8 scores were associated with slower memory (β = 0.001; 95%CI = 0.000,0.002; p = 0.013), verbal fluency (β = 0.001; 95%CI = 0.000,0.002; p = 0.003), executive function (β = 0.004; 95%CI = 0.003,0.005; p<0.001), and global cognitive decline (β = 0.001; 95%CI = 0.001,0.002; p<0.001) (Table 1). Age (p < 0.001), sex (p < 0.001), and race (p < 0.001) were modifiers of the association between LE8 score and global cognitive decline (Figure 1), suggesting that in different socioeconomic profiles, this association might have different manifestations.

Conclusion

Higher baseline LE8 scores were associated with global and domain‐specific decline after eight years of follow‐up. Age, sex, and race were modifiers of this association, suggesting that it might differ based on the participant’s socioeconomic profile.
Florbetapir PET Uptake in White Matter in Aging and Alzheimer’s Disease
Authors: Bhargava Vedanshi , Luo Ji , Chen Yinghua , Ghisays Valentina , Malek‐Ahmadi Michael H. , Sohankar Javad , Lee Wendy , Protas Hillary D. , Reiman Eric M. , Su Yi
Published: December 2023

Background

Amyloid PET tracers, typically used to track cerebral amyloid changes in Alzheimer’s Disease (AD) patients, have been recently suggested to measure cerebral white matter (WM) integrity due to structural similarity between myelin and amyloid. We previously reported significant associations of amyloid neuroimaging marker, Pittsburgh Compound B (PiB) PET, with WM hyperintensities as quantified by MRI and FLAIR data, in AD patients (Su et al. 2018, HAI). The goal of this study was to explore the association between Florbetapir (FBP) PET and WM integrity.

Method

Our study population consisted of 673 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) sorted into the following groups of clinical severity: (1) Normal Controls (NC) participants who are amyloid negative and cognitively normal (CDR = 0) (A‐CDR‐); (2) Preclinical (Pre) who are cognitively normal (CDR = 0) and amyloid positive (A+CDR0); (3) Symptomatic AD who are both CDR and amyloid positive (A+CDR+); and (4) Suspected Other Dementia group consisting of cognitively impaired but amyloid negative participants. We analyzed baseline biomarkers as function of stage of AD and age, comparing groups using ANOVA and Scheffe’s Post Hoc Analysis, and linear regression, respectively. Associations between white matter and amyloid FBP uptake were quantified using Pearson correlation with Least Trimmed Square (LTS) regression. Lastly, rate of change of amyloid and white matter uptake of FBP PET were quantified to assess longitudinal biomarker changes using a one sample t‐test.

Result

Cross‐sectionally, baseline FBP uptake in white matter significantly declines with age (p = 0.027) and advancing disease stage with significant differences found between the Preclinical and Symptomatic AD group (p<2.2E‐06); and NC and Symptomatic AD group (p<0.003). Significant associations were also observed between baseline FBP uptake in white matter and amyloid (p<0.001).

Longitudinally, rate of change of FBP uptake in white matter progressively declined with advancing disease stage while rate of change of FBP uptake in amyloid increased and plateaued in the Symptomatic group of patients.

Conclusion

Altogether, our results show declining FBP uptake by white matter, both cross‐sectionally and longitudinally, through the stages of AD and with age. Our results could have methodological implications on the quantification of amyloid burden using WM as a reference region.
Number of completed exercise sessions is associated with slower brain atrophy in MCI over 12 months in the EXERT trial
Authors: Digma Leonardino A , Aslanyan Vahan , Brewer James B. , Bevins Elizabeth A , Katula Jeffrey A. , Chmelo Elizabeth , Hodge Heather , LaCroix Andrea Z. , Shadyab Aladdin H. , Jacobs Diane M. , Salmon David P. , Feldman Howard H. , Pa Judy , Baker Laura D
Published: December 2023

Background

Mid‐ and late‐life exercise has been associated with lower dementia risk. The EXERT trial tested whether aerobic training (AX), compared to stretching/balance/range‐of‐motion training (SBR), could slow cognitive decline in MCI. While no difference was detected between exercise arms, EXERT participants overall showed little cognitive change over 12 months. It is possible that the amount of exercise, rather than the type, may be protective against decline. In this exploratory, post‐hoc analysis of EXERT data, we assessed whether intervention adherence, operationalized as the number of supervised exercise sessions completed, was associated with slower brain atrophy over 12 months.

Method

194 EXERT participants with baseline and follow‐up MRI were included in this analysis. For each participant, the number of supervised exercise sessions of at least 40 minutes in duration completed during the first 12 months was determined. MRI data were processed using FreeSurfer. Repeated measures ANOVAs were conducted using regional volume or thickness as the dependent variable, and the interaction between number of sessions (continuous scale) and study visit as the independent variable. Baseline age and sex, as well as their interactions with time were included in the model. FDR‐adjusted p‐values <0.05 were considered significant.

Result

Greater number of sessions completed was associated with less brain atrophy over 12 months in the hippocampus and parahippocampus, and less ventricular expansion in the lateral and inferior lateral ventricles (Table 1, Figure 1; FDR‐corrected p<0.05 for interaction term). Results remained unchanged when including exercise type (AX vs. SBR), baseline CDR‐SB, or baseline plasma Aβ42/40 in the model. Findings were similar when analyses were restricted to participants who completed the study prior to the onset of the COVID‐19 pandemic.

Conclusion

Our results show that higher adherence to a supervised exercise intervention over 12 months was associated with reduced brain atrophy in adults with amnestic MCI. These findings were obtained in post‐hoc, exploratory analyses, so causality should be interpreted with caution. EXERT was supported by the Alzheimer’s Disease Cooperative Study and funded by the National Institutes of Health grant U19‐AG010483.
Age but not education affects social decision‐making in the Ultimatum Game paradigm
Authors: Cassimiro Luciana , Cecchini Mario Amore , Cipolli Gabriela Cabett , Yassuda Monica Sanches
Published: December 2023

Background

Decision‐making is a key cognitive ability for autonomy and quality of life in old age and it may be influenced by social context. Social decision‐making is often studied through the use of gaming paradigms, where participants allocate resources between themselves and others based on predefined rules. In a version of the Ultimatum Game (UG) decision‐making behaviour was modulated in response to fairness of monetary offers and social context of monetary offers designed to produce either prosocial or punishing behaviours. Previously, patients with behavioural variant frontotemporal dementia were reported to be impaired in the UG when they needed to modulate their decisions in response to social contextual information. The aim of the present study was to investigate whether social decision‐making evaluated by the UG is affected by age and education. It is relevant to know whether sociodemographic variables may bias UG results.

Method

A total of 131 healthy adults participated ‐ 35 were young university students and 96 were older adults. The sample was divided into three age groups (17‐ 22, 60‐ 69, 70‐79 years old) and three education groups (4‐8, 9‐11, 12 or more years of education). Participants completed a health questionnaire and cognitive tests to ascertain normal cognitive status.

Result

Age and education did not affect performance in fair monetary offers. Differences were observed in the unfair conditions. The older group (70‐79) accepted less frequently the Baseline unfair offers (without social context), when compared with the young and the 60‐69 group (young = 60‐69 > 70‐79). Regarding the Prosocial unfair and Punishing unfair conditions, older adults accepted such offers more frequently (young < 60‐69 = 70‐79). In other words, when a prosocial context (for instance, unemployment) was added to unfair monetary offers, older adults accepted them more frequently than younger adults. Education effects were not observed.

Conclusion

In the context of social decision‐making, cognitively unimpaired older adults may show prosocial behaviors more frequently than younger adults. Findings suggested the UG is affected by age but not education.
Multivariate canonical correlation analysis to delineate ATN specific genetic variants in Alzheimer’s disease
Authors: Zhuang Xiaowei , Yang Zhengshi , Cordes Dietmar
Published: December 2023

Background

Genome wide association studies (GWAS) in AD have been focused on clinically diagnosed case‐control subjects, and have identified more than 70 AD risk loci1‐3. The biological mechanisms underlying these genetic variants in AD remain unclear. In this study, we investigated the relationship between subjects’ genetic variants and AD biomarkers within the NIA‐AA ATN framework4 using a single holistic multivariate canonical correlation analysis (CCA) approach.

Method

932 subjects from the ADNI database5 with at least one 1) clinical visit; 2) 18F‐AV45 amyloid PET scan 3) structural MRI scan; 4) CSF sample; and 5) genotyping data were included in this integrated CCA analysis. More specifically, after imputation and quality control steps, 3323 single‐nucleotide‐polymorphism (SNP) with p‐values<1e‐4 in previous AD‐GWAS1 were included as genetic features. Following the ATN framework, subjects’ amyloid status were quantified by CSF‐derived amyloid beta 42 (Abeta42) values and amyloid PET‐derived standardized uptake value ratio (SUVR) values in major cortices; subjects’ tau status was represented by CSF‐derived phosphorylated tau values; and subjects’ neurodegenerative status were quantified using MRI‐derived cortical thickness measures from AD‐meta‐ROIs6. Total 16 measures were included as ATN biomarkers. Using CCA, we sought to estimate pairs of canonical components along which genetic variants and ATN biomarkers co‐vary in a similar way in these subjects7,8. Statistical significance of each canonical component was determined through the permutation inference9. We further examined SNPs and biomarkers that are most strongly correlated with each significant CCA component identified.

Result

CCA analysis reveals two significant components that relate AD risk SNVs to ATN biomarkers (r = 0.6381 (p = 0.0002) and r = 0.5776 (p = 0.0046), Fig.1). The first component is most significantly contributed by amyloid biomarkers (Fig.2(A)), and top associated SNVs are centered around the APOE, APOC1, TOMM40, PVRL2 genes on chromosome 19 (Fig.2(B)), which are overrepresented in pathways related to amyloid formation and catabolic process. Furthermore, tau biomarkers significantly contribute to the second CCA component (Fig. 2(A)), and top associated SNVs are additionally involved in the regulation of neurofibrillary tangle assembly pathway.

Conclusion

Using multivariate CCA method, we identified specific genetic variants covaried with the amyloid (A), tau (T) and neurodegeneration (N) biomarkers in AD, respectively.
Recruitment and Retention in the Puerto Rico Alzheimer’s Disease Initiative
Authors: Feliciano‐Astacio Briseida E. , Rajabli Farid , Prough Michael B. , Hamilton‐Nelson Kara L. , Adams Larry D. , Mena Pedro R. , Tejada Sergio J. , Sanchez Jose Javier , Celis Katrina , Silva‐Vergara Concepcion , Whitehead Patrice , Acosta Heriberto , Feliciano Nereida I , Chinea Angel , McInerney Katalina , Vance Jeffery M. , Cuccaro Michael L. , Beecham Gary W. , Pericak‐Vance Margaret A.
Published: December 2023

Background

Puerto Ricans, the second largest US Latino group, are underrepresented in genomic studies of Alzheimer disease (AD). We describe a multi‐source ascertainment approach, networking with community and governmental stakeholders, as part of the Puerto Rico (PR) Alzheimer Disease Initiative (PRADI) whose goal is to increase recruitment and retention of PR individuals in genomic research.The National Alzheimer’s disease Action Plan 2015‐2025 served as a framework for PRADI group that aims to fill two of the goals of the plan: increase research and education.

Method

We developed collaborative relationships with community and governmental organizations that serve the elderly and AD patients from 37/78 (47%) municipalities of PR to identify potential research participants. Trust and transparency were central to our interactions with community groups. We educated patients and caregivers about AD and their possible contribution to science. Bringing academia to the community encouraged participation. Additionally, we established relationships with multiple neurologists across PR caring for AD patients and their families. For recruitment and enrollment PRADI team members visited families in the homes, daycare facilities and clinics. All participants were assigned diagnoses by a clinical adjudication committee comprised of neurologists and neuropsychologists with expertise in AD and related dementias (ADRD)

Result

Since 2016 we have enrolled 1, 281 individuals. Among these 752 are unrelated individuals (193 AD, 170 mild cognitive impairment (MCI), 306 cognitively unimpaired (CU) and 83 with other diagnoses (OD). 529 individuals (195 AD, 76 MCI, 178 CU and 80 OD) were part of 155 multiplex AD families. Most families are from Eastern and Northern PR regions, reflecting dense population areas with large cities. Longitudinal follow‐up of the first 167 participants for diagnostic updates is complete. 64 individuals were ascertained in the continental US (cUS). Of the 167 individuals in the longitudinal follow‐up (3‐5 years), 7.2% progressed from either CU to MCI or AD, or MCI to AD.

Conclusion

The PRADI group multisource ascertainment approach enabled recruitment and retention of participants both in PR and the cUS. Longitudinal clinical data across the cohort further enriches the impact of genomic studies in a diverse population.
The effect of our physical or cognitive program for the elderly with mild cognitive impairment: the eighteen months’ follow‐up after intervention, third version, showed an improvement in RBMT story retention delayed and Raven’s colored progressive matrices
Authors: Kanemaru Akiko , Kato Takayuki , Kawaji Yoshie , Honda Takuya , Makita Ayaka , Uno Shizuna , Higuchi Wakana , Shimizu Aya , Enomoto Yoji , Kanemaru Kazutomi
Published: December 2023

Background

To prevent or slow down a cognitive decline in the elderly is an important issue. Therefore we have conducted an intervention study with our rehabilitation training program of physical or cognitive rec‐xercise (the made‐up word from recreation+exercise) (REPCREC) for the elderly with mild cognitive impairment (MCI).

Method

This study design is a non‐randomized controlled trial. The ninety‐one individuals have been enrolled and eighty‐seven those have undergone our study, where they have been divided into four groups: the cognitive (group A: n = 22), physical (group B: n = 27), both cognitive and physical (group C: n = 30) training and control (group D: n = 8). The three training groups received the each session once per week up to twelve times. Before and after the intervention, and 3, 6, 12 & 18‐months after the intervention, we have evaluated the following items: physical function, GDS and neuropsychological tests [MMSE, RBMT, TMT, Ravenʼs Colored Progressive Matrices (RCPM), Rey‐Osterrieth Complex Figure Test (ROCF), story retention, coding and Miyake’s paired verbal associate learning test (MPVALT)]. A one‐day booster program has been provided at the time of evaluation. For statistical analysis, Fisher’s exact test and Kruscal‐Wallis test for the baseline data, and linear mixed model (LMM) analysis have been performed.

Result

At the baseline, no difference between groups except RCPM (p = 0.017). LMM analysis revealed the significant time‐course differences in RBMT Story Retention Delayed (RBMT‐SRD), RCPM, ROCF recall, coding and MPVALT related words (MPVALT‐RW) (p = 0.003, 0.001, 0.000, 0.000 and 0.001, in order). Furthermore, LMM analysis showed the interaction effects in RBMT‐SRD and RCPM. Therefore, we have conducted the LMM analysis of each group, where groups A and B showed improvements in RBMT‐SRD (p = 0.003 and 0.040, in order) and where group A and C showed improvements in RCPM (p = 0.001 and 0.016, in order).

Conclusion

The improvement in RBMT‐SRD and RCPM may have shown that our program REPCREC can have the better effects on non‐verbal intelligence, visuospatial abilities, memory, attention, working memory etc. for the elderly with MCI. However, in ROCF recall, coding and MPVALT‐RW, all the groups have shown the similar time‐course, which might suggest merely an interventional effect of the evaluation using those neuropsychological tests.
Larger hippocampal and temporal lobe volume may associate with early rapid forgetting in cognitively healthy individuals with a predisposition to Alzheimer’s disease
Authors: Rising Shant , Woo Rachel , Nolty Anne , Chui Helena C , Butler Ryan , Kang Jimmy , Spezzaferri Mitchell , Sin Caleb , Buennagel David P , Aguda Shelly , Minazad Yafa , Kim Sung , Kloner Robert A , Fonteh Alfred N. , Arakaki Xianghong
Published: December 2023

Background

Growing need exists to link volumetric brain analysis to functional cognitive performance in early prediction of Alzheimer’s disease.

Method

In cognitively healthy older adults (N = 40; M age = 71.7±7.7 years), we established amyloid/tau ratios from cerebrospinal fluid, thus finding a small group with pathological amyloid/tau ratios (PAT, n = 11) and normal ratio (NAT, n = 29). Approximately 40% of the PAT group were expected to convert to mild cognitive impairment within 4 years. It was hypothesized that reduced performance on the California Verbal Learning Test‐II (CVLT‐II) Short Delay Free (SDFR) and Cued Recall (SDCR) task would be associated with smaller hippocampal and temporal lobe volume (obtained via NeuroQuant).

Result

Hippocampal total, left, and right percentiles were found to be negatively associated with SDFR in the PAT group, r(38) = ‐.67*, ‐.66*, and ‐.63*, but not in the NAT group, r(38) = ‐.21, ‐.04, and ‐.35, such that a larger hippocampus was associated with fewer remembered words after a short delay on a list learning task in those with pathological amyloid/tau ratios. Temporal lobe volume was also found to be negatively associated with SDFR and SDCR in the PAT group, r(38) = ‐.67* and ‐.69*, but not in the NAT group, r(38) = ‐.36 and ‐.34, such that a larger temporal lobe was associated with fewer remembered words after a short delay on a list learning task (even when cued) in those with smaller amyloid/tau ratios. Two hierarchical multiple regression analyses, one including amyloid/tau ratio and the other including amyloid only, found that age and sex associate with ∼20.4% variance of the performance on the CVLT‐II SDFR task while temporal lobe volume increased associative value by 16.1% in the former [F (1, 35) = 8.871, p < .05] and by 15.4% in the latter [F (1, 35) = 8.430, p < .05].

Conclusion

Our findings suggest there may be early compensation in brain structures among cognitively healthy individuals whose CSF biomarker suggest increased risk for the development of symptomatic Alzheimer’s disease, such that hippocampi and temporal lobes increase in size during early pre‐Alzheimer’s stages despite reduced performance on memory tasks.
Further Preclinical Development of a Bio‐therapeutic Against Porphyromonas gingivalis for the control of Systemic and Neuro‐inflammation related Dementia and Alzheimer’s Disease
Authors: Nara Peter Lloyd
Published: December 2023

Addressing novel mechanisms and effective therapeutic treatments for cognitive decline, Dementia and Alzheimer’s Disease is a major public health need. Keystone Bio have identified that specific virulent strains of Porphyromonas gingivalis (Pg) and the release of specific virulence factors/toxins in the oral cavity as the primary driver/causation of systemic/neuro‐vascular inflammation/degenerative diseases i.e., cognitive decline/dementias/Alzheimer’s disease (Nara et. al 2021). A recent landmark finding was reported in a sub‐cohort analysis from a Phase 2/3 GAIN trial (n = 238) demonstrated that lowering the load of Pg in the mouth leads to a significant improvement of cognitive slowing at both 24 and 48 weeks in participants with mild to moderate AD. Another study showed lowering the load of Pg in the mouth had a favorable effect on AD‐related brain atrophy (https://doi.org/10.1002/alz.12378). Pg OMVs and systemic system diseases has many well‐defined examples such as: cardiometabolic diseases‐ Pg OMVs attenuate insulin induced Akt/GSK‐3_ signaling in hepatic HepG2 cells, thereby causing changes in glucose metabolism in the liver and promoting the development of diabetes and increase vascular permeability by cleaving endothelial cell connexins such as PECAM‐1, thereby promoting cardiovascular diseases.

Keystone Bio has further developed both a companion diagnostic (CDx) and a clinical, proof‐of‐concept tested, first generation, safe, efficacious, precision, bio‐therapeutic murine monoclonal antibody (KB‐001) for the diagnosis, treatment and monitoring against the oral bacteria and major virulent factor/toxin of Pg. The antibody engagement is with the later stages of the complex virulent factor/toxin secretion containing outer membrane vesicles from the bacteria thereby interfering/stopping all necessary metabolic, host defense, energy‐producing sources, adherence and biofilm formation and integrity (Nara et. al 2021). The talk will review what now seems like a solid case for causation in the role of virulent/toxin secreting strains of in neuro‐inflammation leading to cognitive decline, dementia, Sporadic Alzheimer’s disease and possibly Parkinson’s.