bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergence of visual artistic creativity in frontotemporal dementia
Authors: Friedberg Adit , Pasquini Lorenzo , Diggs Ryan T. , Glaubitz Erika Alma , Lopez Lucia , Brown Jesse A. , Rankin Katherine P , Allen Isabel Elaine , La Joie Renaud , Iaccarino Leonardo , Mundada Nidhi S. , Illán‐Gala Ignacio , Bonham Luke W. , Yokoyama Jennifer S. , Miller Zachary A. , Rabinovici Gil D. , Kramer Joel H. , Rosen Howard J. , Tempini Maria Luisa Gorno , Seeley William W. , Miller Bruce L.
Published: December 2022

Background

Emergence of novel visual artistic skills has been described in neurodegenerative disorders, particularly in the frontotemporal dementia – amyotrophic lateral sclerosis (FTD‐ALS) spectrum, but associated clinical and genetic features and the underlying neural mechanisms have not been systematically examined. We aimed to address these gaps.

Method

We performed comprehensive chart review of all 734 participants in the University of California San Francisco FTD Program Project Grant who had a clinical syndrome within the FTD‐ALS spectrum. This review allowed us to ascertain subjects meeting current FTD‐ALS clinical research criteria who had: (1) an emergence of novel visual artistic skills or (2) a change in the style of visual art produced or (3) a significant increase in quantity of visual art produced. Clinical data, imaging studies, and genetic information were collected and analyzed.

Result

Among the 734 patients screened, 45 were excluded due to lack of available research notes. We identified a change in visual artistic creativity in 17/689 patients (prevalence 2.5%). Mean age of FTD symptom onset was 57.4 (±10.4), and the visual artistic creativity (VAC) change was reported an average of 0.7 years (±10.1) prior to FTD symptom onset. Of the 17 patients with VAC, 8 exhibited no prior interest in art, 2 were professional visual artists who experienced a change in artistic style, and 7 reported some prior interest in art but a substantial change of style or quantity. Artistic output was diverse however bright colors and non‐human subjects were prominent. VAC occurred in patients with semantic variant primary progressive aphasia (8), behavioral variant FTD (3), nonfluent variant primary progressive aphasia (2), progressive supranuclear palsy ‐ Richardson’s syndrome (2), corticobasal syndrome (1), and ALS (1). None carried a common pathogenic variant in a FTD gene.

Conclusion

Change in VAC is an uncommon but early positive symptom that occurs in patients across the FTD‐ALS clinical spectrum but appears most common in patients with anterior temporal lobe degeneration. We are pursuing the neural mechanisms of VAC through structural and functional neuroimaging studies.
Brain health index as a predictor of possible vascular cognitive impairment (pVCI) in the Mexican Health and Aging Study (MHAS) 2012‐2015
Authors: Aguilar‐Navarro Sara Gloria , Moctezuma‐Gallegos Rogelio , Yeverino Sara , Arango Silvia Mejia , Funes José Alberto Avila , Mimenza Alberto
Published: December 2022

Background

Vascular dementia is the second most common cause of dementia. Brain health is defined as the capacity to function adaptively in the environment, and its partially determined by cardiovascular risk factors, which are a potential target for the prevention of all cause dementia. We developed a brain health index (BHI) to establish association with possible vascular cognitive impairment.

Method

MHAS is a longitudinal cohort study of Mexican adults ≥50 years. The cardiovascular risk factors (CVRF) considered for the index were: diabetes, hypertension, myocardial infarction, depression, obesity, physical inactivity and smoking. pVCI was defined if scores in two or more cognitive domains in the Cross‐Cultural Cognitive Examination were ≥1.5 standard deviations below the mean on reference norms for self‐respondents or for proxy respondents a score ≥3.4 on the Informant Questionnaire on Cognitive Decline in the Elderly, with limitations in ≥1 instrumental activities of daily living and a history of stroke. A cognitive unimpaired and dementia without stroke groups were included. We compared the groups with ANOVA; a multinomial regression model was developed to predict the association of the BHI with the groups and a Cox regression model to determine

Result

12,427 individuals were included, 513 were identify as dementia without stroke and 75 as pVCI. For pVCI, 57.3% were female, with mean age of 75.28 (SD 9.31) years and education of 3.25 (SD 4.75) years. The mean BHI for the cohort was 2.21 (SD 1.27), for dementia without stroke 2.79 (SD 1.17), and with pVCI 3.28 (SD 1.23). The OR for pVCI was 1.904 (CI 1.4‐2.6, p <0.001) and the HR with a 3 year follow‐up was 1.75 (CI 1.4‐2.17, p <0.001).

Conclusion

The BHI predicted the development of pVCI up to 74.5% in the 3 year follow‐up after adjusting for covariables. This index could potentially be used to identify pVCI in adults with potentially modifiable CVRF. Further studies should be carried out in other populations and with longer follow‐ups.
A fundamental study on the relationship between cognitive function and psychological load while driving in older adult drivers
Authors: Suzuki Mio
Published: December 2022

Background

Although many media outlets have sounded the alarm about dangerous driving by elderly drivers, serious accidents do not occur on a daily basis, and the dangerous events of daily driving have not been clarified. However, serious accidents do not occur on a daily basis, and the risk events of daily driving have not been clarified. Also, the relationship between cognitive function and drivers' cognitive function has not been clarified. In addition, cognitive function fluctuates from day to day, and it is difficult to obtain an accurate picture of cognitive function from a one‐time test. However, in Japan, the system currently determines whether a driver’s license is revoked or not depending on the results of the test, and it is difficult to say that we can properly diagnose the driving of elderly drivers.

Method

In this study, we observed the heart rate during driving and examined the changes in psychological load that occur during driving. I observed 80 subjects' driving data.

Result

As a result, it was found that the heart rate of drivers with cognitive decline increased when they were approached by a trivial voice or an unexpected obstacle, followed by a rapid decrease in the heart rate and a state of excessive relaxation.In addition, when they were in the state of excessive relaxation, they slowed down their obstacle avoidance behavior and forgot to activate the blinker.

Conclusion

Therefore, it is necessary to find a way to equalize the tension during driving in order to support the safe driving of elderly drivers.
Spatiotemporal transcriptomic characterization of an amyloid mouse model of Alzheimer’s disease
Authors: Miyoshi Emily , Morabito Samuel , Henningfield Caden M , Michael Neethu , Shabestari Sepideh Kiani , Das Sudeshna , Shahin Saba , AD MODEL , Green Kim N , Swarup Vivek
Published: December 2022

Background

Transcriptomic studies of Alzheimer's disease (AD) have identified both tissue‐level and cell‐type specific gene expression changes. However, with both "bulk"‐tissue and single‐cell approaches, we lose pertinent spatial information, such as cell‐to‐cell proximity or proximity to pathological features. Recently several techniques have emerged, aiming to profile gene expression while preserving the spatial architecture, and we have leveraged one of these techniques—spatial transcriptomics—to interrogate AD gene expression changes in the 5XFAD, an amyloid mouse model, in a spatial and temporal manner.

Methods

We generated spatial transcriptomic (10x Genomics Visium) data from 5XFAD and wildtype mice at the ages of 4, 6, 8, and 12 months (n = 80 total samples, sex‐balanced). Prior to generating libraries, we stained our tissue sections with Amylo‐glo and the conformation‐specific antibody OC to analyze gene expression changes in spatial relativity to amyloid pathology.

Results

We profiled 18,000‐20,000 total genes per sample with 1,800‐2,700 genes per spatial spot and identified brain region‐specific transcriptionally distinct clusters. We also examined the spatial distribution of AD risk genes, identified by GWAS, throughout the disease progression. Further, we identified gene expression changes spatially related to amyloid pathology localization.

Conclusions

We have characterized the 5XFAD transcriptome, identifying spatiotemporal AD gene expression changes and providing further insight into the role of amyloid pathology in the modulation of gene expression in AD.
Alzheimer’s Disease Related Neurodegeneration Partially Mediates Associations Between Air Pollution and Medial Temporal Lobe Atrophy in Older Women
Authors: Petkus Andrew J. , Wang Xinhui , Salminen Lauren , Millstein Joshua , Beavers Daniel P. , Espeland Mark A. , Resnick Susan M. , Gatz Margaret , Braskie Meredith N , Thompson Paul M , Kaufman Joel D. , Younan Diana , Chen Jiu‐Chiuan
Published: December 2022

Background

Ambient air pollutants are toxic to the vascular systems, and recent studies have shown the late‐life exposures may result in neurodegeneration and increased risks for AD. It is unclear if cerebrovascular damage and AD‐related neurodegeneration contribute to the atrophies of medial temporal lobe. Here we assessed whether AD related neurodegeneration and cerebrovascular disease mediated adverse effects of air pollution exposure on MTL atrophy.

Method

Participants included 624 community‐dwelling older women without dementia (mean age 77.4 +/‐ 3.4 years) who underwent two structural brain MRI scans (MRI‐1: 2005‐6; MRI‐2: 2010‐11) as part of the Women’s Health Initiative Memory Study. Regionalized universal kriging was used to estimate annual concentrations of PM2.5 (fine particulate matter) and NO2 at residential locations aggregated to 3‐year averages prior to MRI‐1. The outcome was 5‐year standardized change in the MTL volumes. Mediators included spatial pattern of neurodegeneration of AD (AD pattern similarity scores [ADPS], validated ADNI data) and a proxy of global cerebrovascular damage (small‐vessel ischemic disease [SVID]). Whether the associations between exposures on MTL atrophy were mediated by the initial level or concurrent change in ADPS or global SVID were examined by the structural equation models with latent‐difference scores. All effect paths were adjusted for sociodemographic, lifestyle, clinical characteristics, and intracranial volume.

Result

Living in locations with higher PM2.5 (per interquartile range [IQR] = 3.21µg/m3) and NO2 (per IQR = 6.72ppb) were both associated with greater atrophy of the MTL (βPM2.5 = ‐.27, 95% confidence interval [CI] = [‐.38,‐.16]; βNO2 = ‐.12,95%CI = [‐.22,‐.02]). PM2.5 was associated with increased ADPS (βPM2.5 = .02, 95%CI = [.01,.05]) over time, which partially mediated associations with MTL atrophy (26%, 95% CI = [10%,49%; Figure 1 Panel A). NO2 was positively associated with ADPS at MRI‐1 (βNO2 = .02, 95%CI = [.01,.04]), which partially mediated the association with MTL atrophy (14%, 95% CI = [1%,94%]; Figure 1 Panel B). Global SVID at MRI‐1 or change in SVID did not significantly mediate observed associations between exposures and MTL atrophy (Figure 1 Panels C and D).

Conclusion

Our study supports the mediating role of AD neurodegeneration contributing to MTL atrophy associated with late‐life exposures to air pollutants. Findings support the hypothesis that multiple neuropathological processes of brain aging are affected by air pollution neurotoxicity.
The association of gabapentin use and change of cognitive and functional status in older adults with normal cognition
Authors: Oh GYeon , Moga Daniela C , Fardo David W. , Abner Erin L
Published: December 2022

Background

Although gabapentin has been increasingly prescribed to older adults, the relationship between gabapentin and cognition/functional status is not well studied. Therefore, we aimed to examine the association of gabapentin use and cognitive/functional change in older adults.

Methods

A retrospective cohort study was conducted using National Alzheimer’s Coordinating Center Uniform Data Set (2005‐March 2021). Gabapentin new users with normal cognition at the visit of gabapentin initiation (i.e., index visit) were included. New‐users were matched on year of first enrollment and time of gabapentin initiation since enrollment to randomly select nonusers with replacement. The decline of cognitive/functional status, including Clinical Dementia Rating global score (CDRGLOB), Clinical Dementia Rating sum of boxes (CDRSUM), Mini‐Mental State Examination (MMSE), sum of Functional Activities Questionnaire (FAQ), and mean of FAQ, was assessed from index to index+1 and index+2 visits. The criteria of cognitive/functional status decline were any increase of CDRGLOB, 1 point increase of CDRSUM, 1 point decrease of MMSE, 3 point increase of sum of FAQ, and 0.3 point increase of mean of FAQ. To mitigate confounding and selection bias, stabilized inverse probability of treatment weights and stabilized inverse probability of censoring weights were used. Generalized estimating equations with an exchangeable working correlation structure were used to account for within‐participant correlations and obtain robust standard errors.

Results

We included 496 new‐users (mean age [SD]: 78.0 [7.1]; male 35.9%) and 4,464 nonusers (77.4 [7.1]; 35.1%) with normal cognition at index. Among the participants who had information of seizure history (57.1% of new‐users and 58.0% of nonusers), 2.2% and 1.6% of new‐users and nonusers, respectively, reported having seizure history, indicating that gabapentin is widely prescribed off‐label in older adults. Gabapentin use was significantly associated with cognitive/functional status decline with outcomes, including CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.57 [1.08, 2.31]); CDRSUM at index+1 visit (1.89 [1.16, 3.06]) and at index+2 visit (1.66 [1.05, 2.63]); and mean of FAQ at index+2 visit (2.23 [1.22, 4.07]) (Figure 1).

Conclusions

Gabapentin use was significantly associated with decline in cognitive and functional status among older adults with initially normal cognition. Further studies are needed to examine the association.
Impact of Study Partner Replacement in Mild Cognitive Impairment Clinical Trials
Authors: Dolmadjian Lucy A , Ryan Mary M , Grill Joshua , Gillen Daniel L.
Published: December 2022

Background

In Alzheimer’s disease (AD) clinical trials, including trials enrolling patients with Mild Cognitive Impairment (MCI), participants must enroll with a study partner (SP). SPs ensure compliance and provide study data, including assessments of the participant’s cognition and function. Thus, consistency in SP reporting is essential to trial integrity. We quantified the impact of SP replacement on bias and variance of SP‐reported AD Cooperative Study Activities of Daily Living (ADCS‐ADL‐MCI) scores in a large Phase 3 MCI trial.

Method

We analyzed data from the ADCS Donepezil/Vitamin E MCI Trial. We used logistic regression to estimate the association between SP type (spouse or non‐spouse) and the odds of experiencing an SP change. We used generalized estimating equations (GEE) to longitudinally model the differences in ADL scores recorded at consecutive visits as a function of whether an SP change occurred. All models adjusted for confounding factors, including SP type, participant age, time (in months) since baseline visit, gender, and ADL score at previous visit.

Result

Among the 768 participants, 41 (5%) experienced at least one SP change (Table 1). We estimated that the odds of experiencing an SP change were 60% lower for spousal SP dyads when compared to non‐spousal SP dyads (OR = 0.40; 95% CI: [0.18, 0.88]). Compared to those with consistent SP, participants who experienced SP replacement had, on average, a consecutive visit absolute score difference that was 1.76 points larger in magnitude (95% CI: [0.24, 3.29]; Figure 1). ADL scores were neither systematically larger nor smaller, on average, when a participant experienced a SP change (‐0.60; 95% CI: [‐2.61, 1.41]; Figure 2). The difference in the variance for end‐of‐study change from baseline ADL was higher for those who experienced an SP change compared to those who did not (110.35 vs 86.78; p‐value = 0.25).

Conclusion

Our results suggests that while SP replacement may not result in systematic bias on functional outcomes, it does increase variability. Efforts to reduce replacement or otherwise account for variability may be necessary.
Comprehensive CSF Tau Profiling Identifies Soluble Tau Pathophysiological Stages in Dominantly Inherited Alzheimer Network (DIAN): Implications for the DIAN‐TU Tau Next Generation Platform
Authors: Horie Kanta , Barthélemy Nicolas R. , Li Yan , Sato Chihiro , Gordon Brian A. , Benzinger Tammie L.S. , Sachdev Pallavi , McDade Eric , Bateman Randall J.
Published: December 2022

Background

Brain tau aggregation is a pathological hallmark of Alzheimer’s disease (AD) and the tau microtubule binding region (MTBR) is the core of AD tau tangles. Recently, we identified the enrichment of some specific MTBR species in sporadic AD brain tangles. Corresponding soluble MTBR species in the CSF increased together with clinical progression and tau pathology measured by tau‐PET. Because extracellular MTBR‐tau was discovered in human AD, MTBR‐tau has become a high priority target for antibodies binding this region. In this study, we sought to determine when these MTBR‐tau changes occurred and the relationship to clinical, cognitive and biomarker changes in the DIAN.

Method

We designed a mass spectrometry‐based method to quantify more than a dozen tau species in CSF. To profile MTBR‐tau, we conducted the immunoprecipitation using the anti‐MTBR antibody, E2814 which is bi‐epitopic to R2 and R4 regions and a tau drug in clinical trial. We analyzed CSF from 227 mutation carriers (MCs) (152 asymptomatic, 77 symptomatic) and 141 non‐carriers enrolled in the DIAN‐observational cohort.

Result

CSF MTBR‐tau specifically increased in MCs and changed at different times over the disease course. The change of MTBR‐tau299 (residue 299‐317) in R2‐3 occurred at an estimated years to symptom onset (EYO) of −22, close to the first detection of change in p‐tau217 occupancy (EYO −21). The increase of MTBR‐tau354 (residue 354‐369) in R4 saturated in late clinical stages, potentially due to the deposition into brain tangles. Notably, the ratio of MTBR‐tau299/354 which expected to recapitulate tau pathophysiology highly correlated with p‐tau217 occupancy, an early amyloid marker, in especially asymptomatic MCs (r = 0.82). This indicates MTBR‐tau and p‐tau217 could be useful as biomarkers to assess anti‐MTBR therapies in tau‐PET negative populations.

Conclusion

We identified a soluble measure of tau tangles, CSF MTBR species, with changes many years before symptom onset and continuing through symptomatic stages, suggesting early pre‐symptomatic prevention trials can be implemented with anti‐MTBR‐tau antibodies, such as E2814. These results have been utilized to design the tau next generation platform in the DIAN Trials Unit (DIAN‐TU) E2814 drug arm to target soluble MTBR‐tau in independent cohorts of asymptomatic and symptomatic mutation carriers.
Characterization of behavioral changes, MRI brain volumetry and brain metabolic profile of 5xFAD mouse model of Alzheimer’s disease
Authors: Heikkinen Taneli , Karhunen Petri , Stenius Taina‐Kaisa , Kosunen Henni , Lehtimäki Kimmo , Shatillo Artem , Oksman Juho , Dudek Mateusz , Miszczuk Diana
Published: December 2022

Background

5xFAD mice (B6SJL‐Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax)) express five AD linked mutations in human APP (K670N/M671L, I716V and V717I) and PSEN1 (M146L and L286V) transgenes. APP and PSEN1 mutations cause human like AD pathology by overproducing Aβ42, leading to plaque accumulation in the brain. The objective of this study was to characterize the behavioral changes, brain volumetry and metabolic profile, beta amyloid accumulation and other biomarkers in 5xFAD mice.

Method

14 female and 15 male transgenic mice and 11 female and 10 male wild‐type mice were used for the study. The mice were subjected to behavioral tests including open field (OF), elevated plus maze (EPM), Y‐maze tests (YM), nest building (NB) and radial arm water maze (RAWM). Brain volumes and hippocampal metabolic profile were measured using MRI and MRS. In addition, the FDG PET and functional ultrasound (fUS) imaging were performed. In vivo measurements were performed at 4‐10 months and brain samples were collected at 6 and 11 months for analysis of beta amyloid levels.

Result

RAWM and NB showed a significant deficit in 5xFAD mice. OF, YM and EPM did not reveal significant phenotype. FDG uptake was significantly reduced in 5xFAD, and hippocampal metabolic profile was altered at 6 months.

Conclusion

These data suggest that the 5xFAD mice exhibit cognitive and metabolic changes resembling those observed in AD. These deficits were evident starting from 6 months of age. The 5xFAD mice offers a tool to investigate potential treatment effects in a model of beta amyloid over expression.
Differential expression of Mical2 and its activator (Sema3a) in Alzheimer’s disease mouse model
Authors: P A Haseena , Kommaddi Reddy Peera , Ravindranath Vijayalakshmi
Published: December 2022

Background

Micals are actin regulatory enzymes which can enhance depolymerization of actin filaments (F‐Actin). Activated Micals catalyze the selective oxidation of methionine residues, Met44 and Met47 within the D‐loop of F‐actin. The oxidation of methionine residues disrupts the interaction between G‐actin monomers, thus facilitating F‐actin depolymerization. Dendritic spines are enriched with filamentous actin (F‐actin) where it regulates the formation, elimination and structural plasticity of spines. Early stage of AD is associated with loss of dendritic spines and F‐actin from synapses, leading to memory deficits. However, the potential mechanism involved in the loss of F‐actin remains largely unknown. Therefore, we aimed to elucidate the role of Micals and semaphorins in actin depolymerization at the synapse of AD mouse model.

Methods

Total RNA was isolated from the cortex, hippocampus and entorhinal cortex of adolescent, young, and middle aged wildtype and APP/PS1 mice as well as from the synaptosomes of respective age groups. The cDNA is synthesized and qRT‐PCR is performed using SYBR green reagents with specific primers to Micals and Semaphorins. Data was analyzed using two tailed non parametric test with a p value of <0.05 signifies the result.

Results

The mRNA expression levels of Micals and Semaphorins in entorhinal cortex, hippocampus, and cortex of wildtype and APP/PS1 as well as in the synaptosomes of age matched animals were measured by qRT‐PCR. We found that Semaphorin3a showed differential mRNA expression levels in entorhinal cortex of adolescence and young adults of APP/PS1 mice in comparison to wildtype littermate controls. Further, we detected that the synapse specific mRNA levels of Mical 2 and Semaphorin3a are significantly decreased in adolescent APP/PS1 mice in comparison to WT mice. However, we did not detect any significant alteration in the mRNA expression levels of Mical1, Mical3 and Semaphorin3f in APP/PS1 mice at different age groups in comparison to WT littermate controls.

Conclusion

Altered expression levels of actin regulatory proteins like Micals and Semaphorins at the dendritic spines could play critical roles in Aβ mediated F‐actin depolymerization in Alzheimer's disease pathology.
Evaluating Digital Twins for Alzheimer’s Disease using Data from a Completed Phase 2 Clinical Trial
Authors: Walsh Jonathan R. , Roumpanis Spyros , Bertolini Daniele , Delmar Paul
Published: December 2022

Background

Complex Alzheimer’s Disease (AD) clinical trials that require a large number of subjects leads to long trial timelines and significant costs. Our novel methods can accelerate randomized clinical trials (RCT) by reducing the required number of subjects using a combination of deep learning‐based predictive models and statistical methods while meeting regulatory requirements. Our method leverages historical control clinical data in a way that allows for faster trials without sacrificing the reliability of traditional RCT analyses. A Phase 2 study on crenezumab (the ABBY study, NCT01343966) in mild‐to‐moderate AD was used to retrospectively assess the validity of this approach for AD clinical trials and the potential impact on future studies.

Method

A probabilistic deep learning model of AD progression was used to predict longitudinal outcomes using baseline data for 184 subjects from the placebo arm of the ABBY study. These clinical predictions are called Digital Twins, and are comprehensive outputs across several outcomes, including the 12‐component Alzheimer’s Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog12), the Clinical Dementia Rating Sum‐of‐Boxes (CDR‐SB), labs, and vitals. After Digital Twins were created blind to subject outcomes, they were compared to observed outcomes across visits and statistical metrics were computed to evaluate the utility of predictions in accelerating this Phase 2 clinical trial. The Pearson correlation coefficient defines the extent to which Digital Twins can provide a reduction in subjects in a clinical trial.

Result

Using the 18‐month outcomes for the change in ADAS‐Cog12 and CDR‐SB scores from baseline, the Digital Twin predictions had a correlation of 0.46 (ADAS‐Cog12) and 0.37 (CDR‐SB) with the observed values from subjects that took placebo. These values suggest that in similarly designed studies, this approach can yield 21% (ADAS‐Cog12) or 14% (CDR‐SB) smaller studies when maintaining randomization, or 35% (ADAS‐Cog12) and 24% (CDR‐SB) smaller control arms when maintaining treatment arm size.

Conclusion

When used with appropriate statistical analysis methods, Digital Twins offer the ability to accelerate RCTs by requiring fewer subjects to achieve a desired power. Because these methods follow regulatory guidance, they can be applied in large pivotal studies to reduce trial timelines, costs, and potentially bring effective therapies to market faster.
Brain age estimation by structural MRI in superagers: a BrainAGE approach in elderly people with youthful episodic memory
Authors: Pascual Marta Garo , Gaser Christian , Strange Bryan A
Published: December 2022

Background

Age‐related episodic memory decline is not the only trajectory of healthy ageing. Superagers are the living proof that an 80yo can have the memory of a 50‐60yo. We aim to estimate the biological brain age of superagers using the BrainAGE approach to understand the underlying ageing process. In the context of normal ageing, resistance refers to the avoidance of ageing effects and will translate into a deceleration of the ageing process, whereas resilience is the successful coping with age‐related changes and will translate into a similar estimated brain age and chronological age. We tested these hypotheses in this study.

Method

A sample of 63 superagers (mean age 81.8 years ± 1.8 std, 60.3% women) and 55 age‐matched controls (mean age 82.4 years ± 1.9 std, 63.6% women) from the Vallecas Project cohort in Madrid, Spain, were selected according to their episodic memory score in the Free and Cued Selective Reminding Test. Superagers scored at or above the mean value of a 50‐56yo person, whereas controls scored within one standard deviation for their age. BrainAGE (“Brain Age Gap Estimation”) aggregates to a single value the complex multidimensional aging pattern within the whole brain by applying established kernel regression methods to anatomical brain magnetic resonance images (Franke and Gaser 2019). The BrainAGE score was calculated for both groups as the difference between chronological age and estimated brain age. Positive values indicate an acceleration of the ageing process and negative values indicate a deceleration of the ageing process.

Result

The BrainAGE score of superagers was ‐0.5 years, showing that their estimated brain age is lower than their chronological age whereas the estimated brain age of the control group is similar to their chronological age. The difference in BrainAGE between the superager and the control group is significant (p = 1x10‐6). This result indicates a deceleration in the brain ageing process of superagers compared to age‐matched controls.

Conclusion

Superagers showed a slowing of the structural brain age‐related changes compared to the control group. These results suggest that superagers, selected for their youthful episodic memory, show whole‐brain resistance to the ageing process.
Biomarker‐based development for optimized ACI‐24, a novel candidate vaccine for the treatment and prevention of Alzheimer’s disease
Authors: Sol Olivier , Lê Bénédicte , Valatsou Elena , Delpretti Saskia , Rongere Julien , Vukicevic Marija , Gray Julian JG , Hliva Valerie , Kosco‐Vilbois Marie , Pfeifer Andrea , Streffer Johannes
Published: December 2022

Background

Amyloid plaques and neurofibrillary tangles are the neuropathologic hallmarks of Alzheimer’s disease (AD) with the key constituents being Amyloid Beta (Abeta) and Tau protein, respectively. However, the initiation and propagation of neurodegeneration and neurotoxicity in Alzheimer’s disease remains incompletely understood despite recent important progress in clinical trials. It is apparent that small aggregates such as Abeta oligomers or fragments such as Abeta 1‐42 and pyroglutamate Abeta3‐42 (pGlu‐Abeta3‐42)) are of key importance for disease initiation with significant implications for translational medicine and success in clinical trial development.

Method

ACI‐24 is a vaccine targeting Abeta for the treatment and prevention of AD. Initial clinical data have demonstrated safety and an initial pharmacodynamic response, both in sporadic AD and people with Down syndrome (DS), a specifically vulnerable population predisposed to developing AD. Preclinical data have recently demonstrated that a new, optimized formulation of ACI‐24 has significantly improved immunogenicity against key toxic species, i.e., Abeta oligomers, Abeta 1‐42 and pGlu‐Abeta3‐42. Recent clinical trial results in AD, specifically with monoclonal antibodies targeting Abeta, have successfully employed translational biomarkers, including Amyloid PET, as key decision markers and predictors of clinical benefit.

Result

We present an innovative translational clinical trial design to understand the immunogenic properties of optimized ACI‐24 in sporadic AD and in people with DS. The biomarker‐based design, including multiple interim analyses, will enable (I) assessment of early safety and immunogenicity, (II) dose selection for early and meaningful readouts on translational biomarkers including Amyloid PET, (III) the safe transition into the more vulnerable DS population and (IV) informed transition into pivotal studies.

Conclusion

The Alzheimer’s disease field needs new treatments and clinical trial approaches. Vaccination is a proven approach to managing diseases affecting global populations. The field of biomarker‐based translational medicine has been mobilized by the recent understanding of how to clinically evaluate targeting of toxic Abeta fragments and aggregates in trials using monoclonal antibodies. Here, we demonstrate how we utilize these advances in an innovative clinical trial design for an efficient, evidence‐based translational medicine approach to test optimized ACI‐24 as a novel Abeta vaccine candidate.
Telomere Length Variation in the Lewy Body Diseases and its Relationship to Epigenetic Age
Authors: Imm Jennifer L , Harvey Joshua , Smith Adam R. , Pishva Ehsan , Lunnon Katie
Published: December 2022

Background

The Lewy body diseases (LBDs), Dementia with Lewy bodies (DLB), Parkinson’s disease (PD) and Parkinson’s disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha‐synuclein in neurons, forming Lewy bodies (LBs). As both the LBDs and the shortening of telomeres are well established with aging it is reasonable to hypothesise some involvement of telomere shortening in the LBDs. There are few studies addressing telomere length changes in the LBDs and as these studies are often conflicting, we aim to rectify this disparity and establish whether there is a relationship between disease diagnosis, LB Braak staging and epigenetic age.

Method

Bulk cingulate gyrus and prefrontal cortex tissue was used to determine absolute telomere length using quantitative real‐time PCR. Alongside sample DNA, standards for either telomeric repeats or a housekeeping gene, ribosomal phosphoprotein P0 (36B4), for which the copy number was known were run. Calculation of absolute telomere length was achieved by dividing the telomere copies per reaction by the corresponding 36B4 copies per reaction. This value was then further divided by 92 to give the length per individual telomere. Linear regression was used to determine significance within each brain region controlling for age, gender and cellular composition. DNA methylation was assessed using the Illumina EPIC array and epigenetic age was derived using the Horvath skin and blood clock.

Result

We have used 136 PD, 307 PDD, 178 DLB and 302 control samples in two different brain regions in order to determine the relationship between telomere length, epigenetic age, neuropathology and clinical diagnosis.

Conclusion

We have studied how telomere length varies not only in relation to epigenetic age in post‐mortem brain samples but also how it relates to clinical diagnosis and neuropathology in the LBDs.
NLRP3 regulates microglial metabolic function in Alzheimer’s disease
Authors: McManus Roisin M. , Komes Max P , Griep Angelika , Santarelli Francesco , Schwartz Stephanie , Khalil Michelle‐Amirah , Lauterbach Mario , Gomez‐Cabrero David , Tegner Jesper , Hiller Karsten , Latz Eicke , Heneka Michael T.
Published: December 2022

Background

Our laboratory has demonstrated that the NLRP3 inflammasome has a critical part in the microglial innate immune response to Alzheimer’s disease (AD)‐related peptides, triggering the production of cleaved‐caspase‐1 and IL‐1β. NLRP3 activation was found in post‐mortem tissue from individuals with AD (Heneka et al., 2013) and in transgenic mouse models of AD expressing amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice). However, APP/PS1 mice deficient for NLRP3 were protected from AD‐pathology and neuroinflammation. Here, we set out to determine the genes and pathways under the influence of NLRP3, beyond the established release of IL‐1β and ASC that could be contributing to the progression of AD.

Method

Single cell RNA sequencing was performed on CD11b+ cells from the brains of aged wildtype, APP/PS1, NLRP3−/− and APP/PS1.NLRP3−/− mice. Microglia were prepared from the brains of 1‐day old wildtype and NLRP3−/− mice to assess real‐time metabolic function, phagocytosis assays and flow cytometric analysis. Targets were investigated in the post‐mortem brain tissue of those with and without AD. In a separate series of experiments, microglial cells and APP/PS1 mice were treated with novel NLRP3‐targeted inhibitors to confirm findings.

Result

Single cell RNA sequencing analysis found a unique cluster of microglia with pathways related to phagocytosis and glutamate metabolic signaling in APP/PS1.NLRP3−/− mice. Metabolic analysis found that NLRP3−/− microglia had enhanced mitochondrial and metabolic function. NLRP3−/− microglia had greater Aβ phagocytosis than the wildtype cells, which was strictly associated with cellular utilization of glutamate and glutamine. Importantly, we were able to replicate these findings in human cells and using NLRP3‐specific inhibitors in vitro and in vivo.

Conclusion

We have identified a new mechanism where loss of NLRP3 influences glutamine/glutamate‐related metabolism, which was associated with enhanced phagocytic activity. This pathway is conserved between mouse and man. Critically, we can mimic this effect pharmacologically using NLRP3‐specific inhibitors. Together, our data strengthens NLRP3 as a master‐immune regulator and an important target in the treatment of AD and dementia.
Concordance and discordance in disease severity classification between clinician judgments and cognitive testing scores for Alzheimer’s disease in the United States Veterans Affairs Healthcare System
Authors: Li Mingfei , Wang Ying , Aguilar Byron J. , Morin Peter , Berlowitz Dan , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming
Published: December 2022

Background

The current standard of practice for assessment of Alzheimer’s disease (AD) severity in the Department of Veterans Affairs (VA) Healthcare System is primarily based on clinical examination and cognitive testing. We aimed to assess the consistency between clinician judgements of AD severity compared with that classified by cognitive test scores in the VA system.

Method

We identified medical notes for patients with mild, moderate, or severe AD from the VA electronic healthcare records (EHR) database between March 2008 and October 2021, using the natural language processing technology. Mini‐Mental Status Exam (MMSE) and Montreal Cognitive Assessment (MoCA) scores from the corresponding medical notes with physician judgments were classified and used for comparisons of severity levels. A binary variable was coded to indicate concordance or discordance for each paired comparison.

Result

We screened clinical notes from 51,809 AD patients and analyzed 8,888 clinical notes that had either an MMSE or MoCA test score from 5,150 AD patients (3.5% female; average age at 78.1±9.4 years). Clinician judgements and test‐score‐based classification of AD severity were concordant in 53.2% of comparisons (weighted Kappa = 0.39, 95% CI:0.38‐0.41, p = 0.009); whereas clinician judgments were less severe in 25.7% and more severe in 21.1% comparisons, relative to the test‐score‐based severity level. Clinician judgments were concordant with 54.1%, 51.8%, and 53.0% cognitive test‐score‐based classifications, of mild, moderate, and severe AD, respectively. Concordance was observed in 55.9% clinician judgments involving internist, 53.0% involving psychiatrist or neurologist, and 51.7% involving psychologist specialties, and in 50.4% involving nurse practitioners. Among discordant severity classifications, clinician judgments tended to be less severe than test scores (Figure).

Conclusion

Examination of VA EHR reveals that nearly one half of clinician judgments of AD severity are discordant with severity classification based on the MMSE or MoCA test scores. Discordance is more pronounced in the moderate relative to mild and severe AD categories but does not vary substantially over clinicians’ specialty background. Research will aim to find plausible explanations for the variation of concordance vs discordance by further examining the relative contributions of patient, clinician, and system characteristics in the process of AD clinical assessments.
A standardized protocol for detection of Amyloid Related Imaging Abnormality (ARIA) on 3T Philips Magnetic Resonance Imaging (MRI)
Authors: Pinter Nandor K , Ganji Sandeep , Johnson Brian , Huijbers Willem , Ajtai Bela , Dorn Ryu , Alnaji Baraa , Harlock Sarah , Westphal Erica , Friel Harry , Mechtler Laszlo
Published: December 2022

Background

ARIA is a common side effect of aducanumab, the first anti‐amyloid pharmacotherapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer’s disease. Regular MRI is required by FDA to detect and monitor different forms of ARIA during initiation of therapy. MRI protocols must be a) high resolution to detect abnormalities with high sensitivity, b) fast to accommodate workflow and ensure patient compliance and c) standardized to maximize data acquisition consistency across sites. Based on a vendor agnostic protocol recommendation by Benzinger et al (CTAD 2021), we propose specific parameters for 3T Philips systems, for an accelerated and enhanced protocol.

Method

The protocol was developed on a 3T Philips Elition X scanner, using 32‐channel head coil, and included 3D T1, 3D FLAIR, 2D DWI, 2D T2* and multi echo 3D Susceptibility Weighted Imaging (SWI) sequences.

Result

Acquisition voxel resolution of 3D T1, 3D FLAIR, T2* and DWI matches current recommendations. 3D SWI resolution is 0.7x0.7x2mm. Compressed‐SENSE (C‐SENSE) acceleration is applied on 3D T1, 3D FLAIR, T2* and 3D SWI. SENSE is applied on DWI (Figure 1). Total acquisition time including the additional 3D SWI scan is 11 minutes, 6 minutes faster than the original recommendation. Qualitative assessment of images showed high signal‐to‐noise and contrast‐to‐noise. Images were free of acceleration related artifacts. Automated slice prescription localizer ensures better reproducibility for longitudinal assessment.

Conclusion

Imaging protocol standardization is necessary to ensure consistent accuracy for diagnosing ARIA. Broad recommendations leave room for variability, therefore specific parameters are needed to achieve cross‐platform standardization. Our protocol is applicable for 3T Philips systems with compressed‐SENSE capability and 32‐channel head coil. The recommended C‐SENSE values maintain image quality with shorter exam time. This is more comfortable for patients and easier to fit into the workflow. The higher sensitivity of SWI can improve thresholds for therapy monitoring and provide additional quantitative measurements.
AB1601 topline results – Phase 2 study of ABvac40 in patients with amnestic mild cognitive impairment (a‐MCI) or very mild Alzheimer’s Disease (Vm‐AD).
Authors: Molina Elisabet , Castillo Sergio , Lacosta Ana M , Allué Jose A , Fandos Noelia , Montañés María , Romero Judith , Sarasa Leticia , Boada Mercè , Sarasa Manuel
Published: December 2022

Background

Immunotherapy against amyloid β (Aβ) has emerged as a promising treatment option for Alzheimer’s disease (AD). Araclon‐Biotech is developing an active vaccine against Aβ40 peptide, one of the most abundant peptides in senile plaques and the dominant peptide in vascular deposits, that has been associated with earlier onset of dementia. The immunogen peptide of ABvac40 (Aβx‐40) does not contain the epitope recognized by T cells whose activation was considered the primary cause of aseptic meningoencephalitis. In Phase‐1 (NCT03113812), ABvac40 generated a long‐lasting antibody response after only three‐monthly‐immunizations.

In 2017 Araclon‐Biotech initiated a Phase‐2, 24‐month, multicenter, randomized, double‐blind, placebo‐controlled trial in patients with a‐MCI or Vm‐AD to investigate the safety, tolerability, and immune response of repeated subcutaneous injections of ABvac40 as well as explore the effect of treatment on biomarkers and cognition (Part A) (NCT03461276). In July 2020, a protocol amendment was approved whereby the blind phase (Part A) was shortened from 24 to 18‐months and an additional 18‐months cross‐over study (Part B) was added.

Method

Patients initially receiving placebo during Part A will be crossed over to receive ABvac40, whereas patients initially receiving ABvac40 will be given matching placebo plus a booster. Assignment to treatment groups will remain blinded for investigators and patients until the end of Part B. It is noteworthy that when the blind will be opened (18‐month visit), the average follow‐up will be of 23 months (close to the 24 months initially planned).

Result

124 patients aged 55 to 80 have been included (a‐MCI, n = 80; Vm‐AD, n = 44). Baseline demographics and characteristics were reasonably well balanced. A total of 101 patients have completed Part A and 77 of which have finally transitioned to Part B. Part B is progressing as scheduled.

Conclusion

Top line results for Part A will be presented in the congress.
A biomarker profile of elevated CSF p‐tau with normal tau PET is associated with increased tau accumulation rates on PET in early Alzheimer’s disease
Authors: Groot Colin , Smith Ruben , Stomrud Erik , Binette Alexa Pichet , Leuzy Antoine , Wuestefeld Anika , Wisse Laura EM , Palmqvist Sebastian , Janelidze Shorena , Strandberg Olof , Ossenkoppele Rik , Hansson Oskar
Published: December 2022

Background

Different tau biomarkers become abnormal at different stages of Alzheimer’s disease (AD), with CSF p‐tau typically being elevated at subthreshold levels of tau‐PET binding. To capitalize on the temporal order of tau biomarker‐abnormality and capture the earliest changes of tau accumulation, we selected a group of amyloid‐β‐positive (A+) individuals with elevated CSF p‐tau levels but negative tau‐PET scans and assessed longitudinal changes in tau‐PET, cortical thickness and cognitive decline.

Method

Individuals without dementia (i.e., cognitively unimpaired (CU) or mild cognitive impairment, n=231) were selected from the BioFINDER‐2 study. These subjects were categorized into biomarker groups based on Gaussian mixture modelling to determine cut‐offs for abnormal CSF Aβ42/40 (A; <0.078), CSF p‐tau217 (P; >110 pg/ml) and [18F]RO948 tau‐PET SUVR within a temporal meta‐ROI (T; SUVR >1.40). Resulting groups were: A+P‐T‐ (concordant, n=30), A+P+T‐ (discordant, n=48) and A+P+T+ (concordant, n=18). We additionally used 135 A‐ CU individuals (A‐ CU) as a reference group (Tables 1 and 2). Differences in annual change in regional tau‐PET SUVR, cortical thickness and cognition between the A+P+T‐ group and the other groups were assessed using general linear models, adjusted for age, sex, clinical diagnosis and (for cognitive measures) education.

Result

Longitudinal change in tau‐PET was faster in the A+P+T‐ group than in the A‐ CU and A+P‐T‐ groups across medial temporal and neocortical regions, with the medial temporal increases being more pronounced. The A+P+T‐ group showed slower rate of increases in tau‐PET compared to the A+P+T+ group, primarily in neocortical regions (Figures 1 and 2). We did not detect differences in yearly change in cortical thickness (Figure 3) or in cognitive decline (Figure 3) between the A+P+T‐ and A+P‐T‐ groups. The A+P+T+ group, however, showed faster cognitive decline compared to all other groups.

Conclusion

These findings suggest that the A+P+T‐ biomarker profile is associated with early tau accumulation, and with relative sparing of cortical thinning and cognitive decline compared to A+P+T+ individuals. Therefore, the A+P+T‐ group represents an interesting target‐group for early anti‐tau interventions and for examining the emergence of tau aggregates in early AD.