bluuebunny/crossref_metadata_2025 huggingface dataset:
Smoking History and Higher Pack Years Predict Brain Atrophy in 9646 Healthy Individuals
Authors: Meysami Somayeh , Raji Cyrus A. , Hashemi Sam , Garg Saurabh , Akbari Nasrin , Nguyen Thanh Duc , Gouda Ahmed , Chodakiewitz Yosef Gavriel , London Sean , Merrill David A. , Attariwala Raj
Published: December 2023

Background

Smoking is a risk factor for both Alzheimer and vascular dementia. Understanding this risk requires an investigation of how smoking influences brain volume loss on MRI, a biomarker for neurodegeneration.

Method

In total, 9646 healthy participants from 4 sites were scanned on 1.5T MR with a whole‐body MR imaging protocol. Core whole body sequences included whole body coronal T1, STIR from vertex to feet, whole‐body axial DWI from vertex to proximal‐thighs and axial T2 TSE without fat suppression from skull base to pelvis. Brain sequences were T1 MPRAGE and 2D FLAIR. Deep learning volumetric software, FastSurfer, trained on over 134 participants age 27‐66, segmented 96 brain volumes. Smokers versus non‐smokers were compared by gray and white matter volumes normalized to total intracranial volume using a two tailed t‐test. Partial correlation analysis was done between pack years and brain volumes, controlling for age, sex, and total intracranial volume (TIV). The Benjamini Hochberg False Discovery Rate of 5% accounted for multiple comparisons.

Result

Overall, the sample had an average age of 52.9±13.1 years with 3123 individuals (32.3%) self‐reporting a history of smoking with 3.72±10.08 pack years. The remaining 6523 persons (67.7%) were non‐smokers. Participants who smoked were older than non‐smokers (p = 0.024) and 51.55% were men versus 52.8% in the non‐smoker group (p = .218). Individuals with a history of smoking had lower normalized gray and white matter volumes compared to non‐smokers (t = 8.95, p = 4.39e‐19). Adjusting for age, sex, and TIV co‐variates and multiple comparisons, higher pack years of smoking predicted brain volume loss in: total gray matter volume (Partial R = ‐0.06, p = 2.19e‐8), total white matter volume (Partial R = ‐0.06, p = 4.26e‐9), hippocampus (Partial R = ‐0.05, p = 6.26e‐6), frontal cortex (Partial R = ‐0.06, p = 1.34e‐10), temporal lobes (Partial R = ‐0.06, p = 3.24e‐8), parietal lobe (Partial R = ‐0.04, p = 0.0008), orbital frontal cortex (Partial R = ‐0.05, p = 2.19e‐8), posterior cingulate gyrus (Partial R = ‐0.05, p = 2.97e‐7).

Conclusion

Both smoking history and pack years are related to lower whole brain and regional volumes.
Social Assistive Robotics to Motivate Cognitive Training in Patients with Chronic Depression
Authors: Schüssler Sandra , Paletta Lucas , Reininghaus Eva , Macher Michael , Fellner Maria , Russegger Silvia , Lenger Melanie , Pszeida Martin , Orgel Thomas , Draxler Sandra , Häussl Alfred , Nina Dalkner , Spat Stephan , Pötz Gloria , Zuschnegg Julia
Published: December 2023

Background

Approximately 280 million people in the world suffer from depression, which can become chronic and often leads to cognitive problems. International literature shows that depression is known as one of the 12 main modifiable risk factors for dementia, and therefore, cognitive training is essential to foster cognition and to reduce the risk for dementia. In the last years new technologies, like robots, have been developed to support health care professionals with limited resources in their daily practice. The aim of the Austrian project AMIGA is to develop and test a gender‐sensitive and customizable Social Assisting Robotic Technology (SAR) including a cognitive training to enhance cognition and to improve the quality of life of people with chronic depression in psychiatric hospitals.

Method

In the first step of the project, the requirements of the target group will be determined using qualitative and quantitative methods (e.g. survey, interviews). Based on the results, the interactive SAR prototype will be developed which will use human‐robot interactions to motivate users to perform cognitive training with the BRAINMEE‐App on a daily basis. Target group‐specific as well as gender‐sensitive content for holistic stimulation with visual, auditory and interactive elements will be included. The prototype will then be tested in a usability study with 12 end users including patients to revise the robot. At the end, a randomized controlled trial with additional interviews including 60 patients will be conducted to test the final robotic platform.

Result

At the conference, the first results of the project will be presented.

Conclusion

AMIGA is the first project to investigate, on a scientific basis using neuropsychological theories, care requirements and human factor measurement technologies, the fundamental design parameters for interactions with social robotics, which contribute to increasing motivation for cognitive training, to efficiently relieve stress and strengthen the resilience of patients with depression during training. AMIGA, as a research prototype, will lay the foundation for future system developments that provide motivational support for improved adherence to training activities in the mental health care field, which includes depression and other mental illnesses, like dementia and further brain‐related disorders as well as learning disorders.
Distinct immune signatures associated with sex and genotype in the 15m novel hAPP+hAPOE mouse risk model of Alzheimer’s disease
Authors: Delatorre Nicole , Van Rossum Hannah , Brinton Roberta Diaz
Published: December 2023

Background

Alzheimer’s disease research continues to struggle with the translatability of animal models to human patients. Exploring whole systems is integral to early AD biomarker discovery in the pursuit of therapeutics to delay or prevent AD. Previous finds in our lab indicate sex differences in immune transcription levels in human AD brain and in the humanized apolipoprotein E (APOE) mouse model. Herein we investigated the impact of the APOE genotype in a novel mouse model, humanized amyloid precursor protein (APP), and humanized APOE transgenes (Jackson Laboratory).

Methods

To identify immunophenotypes at late‐midlife (15 months: late 40s – early 50s human correlative) a novel hAPP+hAPOE mouse model was utilized: hAPP (5M:5F), hAPP+hAPOE ε3/3 (16M:16F), & hAPP+hAPOE ε4/4 (16M:16F). The brain was hemisected. The left side was processed for multi‐color flow cytometry analysis. Peripheral blood was taken via cardiac puncture. The plasma was isolated and ELISA was used to detect levels of Aβ 40‐42 and pro‐inflammatory cytokines. PBMCs were isolated from the peripheral blood for multi‐color flow cytometry analysis. Microglia (CD45, CD11b), microglia reactivity (MHCII, CD68), phagocytosis (pHrodo), and oxidative stress (CellRox) levels were determined in the brain. Lymphocytes (CD3, CD4, CD8, CD19), lymphocyte activity (CD69), and oxidative stress (CellRox) levels were determined in both the brain and peripheral blood. Midlife endocrine status was determined for the female mice by daily lavage.

Results

hAPP+hAPOE ε4/4 animals exhibited accelerated endocrine aging evidence by increased proportion of irregular cycling mice, compared to hAPP hAPOE ε3/3 animals. Microglial activation marker by MHCII was significantly impacted by sex (p<0.0001) and less so by genotype (p = 0.0551). Microglial function measured by pHrodo was impacted by sex (p<0.0001) with hAPP+hAPOE ε3/3 males exhibiting greater phagocytosis in MHCII+ microglia relative to their female counterpart.

Conclusion

The interaction between the genotypes APP and APOE in combination with sex has a significant impact on immune phenotypes in the late‐midlife brain. These indications offer unique insights for future targeted therapeutics. Our findings support further investigation into neuroimmune activation in mid‐life to delay or prevent AD.
Using spatial transcriptomics to investigate region‐specific gene expression in J20 mice
Authors: Sander Millie , Brown Jonathan T , Lunnon Katie , Ballard Clive G
Published: December 2023

Background

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) share various pathological and symptomatic traits. As such, providing an accurate diagnosis of DLB can be difficult, ultimately impacting patient support and care. It is therefore imperative to establish biomarkers which reliably differentiate between disease states. Plasma‐derived exosomes appear to be promising in this regard. Exosomes are extracellular vesicles, containing cargos from the cell from which they originate. Increased concentrations of exosomal disease‐associated proteins, such as p‐T181‐tau and Aβ‐42, have previously been associated with cognitive decline and disease progression among AD patients (Winston et al., 2016; Kapogiannis et al., 2019).

Method

We aim to quantify exosome‐associated proteins from AD patients, DLB patients and healthy controls in order to establish exosomal signatures to differentiate between disease states. Exosomes are being isolated using differential ultracentrifugation. Nanoparticle track analysis (NTA) and western blots are being used to verify isolation, and ELISA assays against p‐T181‐tau, Aβ‐42 and α‐synuclein will be used to quantify proteins of interest. Plasma samples are being collected at baseline and after a 6 month follow‐up period in order to monitor the stability of these potential biomarkers.

Result

To date, full ethics approval has been granted for this study, and the differential ultracentrifugation protocol has been established. Successful isolation of particles in the size range of exosomes (30 – 100nm) has been confirmed using NTA. ELISA assays will be undertaken in the up‐coming months, with the aim of collecting and analysing baseline results by May 2023.

Conclusion

Exosomes already appear to be a reliable, and relatively non‐invasive biomarker for assessing disease state and progression among dementia patients. Our preliminary findings have shown successful isolation, and we believe the findings could be invaluable with regards to improved diagnosis options for DLB.

References:

Kapogiannis, D. et al. (2019) ‘Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging’, JAMA Neurology. https://doi.org/10.1001/jamaneurol.2019.2462

Winston, C. N. et al. (2016) ‘Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile’, Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring. Elsevier Inc., 3, pp. 63‐72. https://doi.org/10.1016/j.dadm.2016.04.001.
Astrocyte reactivity is associated with synaptic dysfunction across the aging and Alzheimer’s disease spectrum, whereas microglial reactivity is specifically associated with synaptic dysfunction related to cognitive impairment
Authors: Rohden Francieli , Ferreira Pamela C.L. , Bellaver Bruna , Aguzzoli Cristiano Schaffer , Soares Carolina , Povala Guilherme , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Benedet Andrea Lessa , Cohen Annie , Lopez Oscar L. , Ashton Nicholas J. , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Souza Diogo O. , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A.
Published: December 2023

Background

Healthy synapses are the key to proper brain function, ensuring communication between neurons. Recent studies have associated synaptic dysfunction with Alzheimer’s disease (AD) proteins, however, little is known about the role of glial reactivity, another pathology closely linked to AD, in brain synaptic dysfunction (Figure 1).

Method

We evaluated 123 individuals (67 cognitively unimpaired (CU) and 56 cognitively impaired (CI)) who had available Aβ‐ and Tau‐PET as well as cerebrospinal fluid measures of glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), and presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). ANCOVA adjusted for clinical diagnosis, age, and sex was used to compare levels of CSF biomarkers; whereas linear regressions adjusted for age, sex, clinical diagnosis, and Aβ/tau‐PET were used to test the associations between glial reactivity and synaptic markers.

Result

Demographic information is shown in Table 1. Increased levels of GAP‐43, SNAP‐25, and Ng were observed in CI compared to CU individuals. CSF GFAP was highly associated with both presynaptic and postsynaptic biomarkers in CU and CI groups. CSF YKL‐40 was associated only with presynaptic biomarkers in both clinical groups. On the other hand, CSF sTREM2 showed an association with all synaptic markers but only in the CI group (Figure 2).

Conclusion

We found a heterogeneous association between synaptic markers and glial activation. The presence of GFAP+ astrocytes was associated with dysfunction of presynaptic/postsynaptic markers, whereas YKL‐40+ astrocytes specifically reflected presynaptic dysfunction across aging and AD spectrums. On the other hand, microglial activation reflected synaptic dysfunction associated with dementia symptoms. Our results support recent experimental observations suggesting that clarifying the heterogeneity of different glial cell phenotypes is crucial to advancing our understanding of the role of immune cells in cognitive decline.
The auditory phenotype of behavioural variant frontotemporal dementia
Authors: Johnson Jeremy , Levett Benjamin , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Jiang Jessica , Bamiou Doris‐Eva , Hardy Chris JD , Warren Jason D
Published: December 2023

Background

Patients with behavioural variant frontotemporal dementia commonly exhibit abnormal hedonic and other behavioural responses to sounds, however hearing dysfunction in this disorder is poorly characterised. Here we addressed this issue using the Queen Square Tests of Auditory Cognition (QSTAC) – a neuropsychological battery for the systematic assessment of central auditory functions (including pitch pattern perception, environmental sound recognition, sound localisation and emotion processing) in cognitively impaired people.

Method

The QSTAC was administered to 15 patients with behavioural variant frontotempoal dementia, 24 patients with comparator dementia syndromes (primary progressive aphasia and typical Alzheimer’s disease) and 15 healthy age‐matched individuals. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.

Result

After accounting for nonverbal executive and peripheral hearing performance, patients with behavioural variant frontotemporal dementia showed deficits of environmental sound and auditory emotion recognition and sound localisation, compared both with healthy controls and patients with Alzheimer’s disease. Patients with behavioural variant frontotemporal dementia were further differentiated from primary progressive aphasia patients on their performance across QSTAC (sound recognition and localisation) subtests.

Conclusion

Behavioural variant frontotemporal dementia has a distinct phenotype of auditory cognitive dysfunction which likely contributes to the hearing alterations that many patients with this diagnosis experience in daily life. Our findings call attention to an under‐recognised issue in frontotemporal dementia that warrants further clinical interpretation and the development of management strategies tailored to real‐world acoustic environments.
Cognitive impairment prevention and healthy aging. A multidisciplinary team work
Authors: García‐Lluch Gemma , García Hernán Ramos , Pardo Juan , Gil‐Peinado María , Garcia Cristina Garcia , Climent Marta Sala , de Coca Teresa López , Sánchez‐Roy Rafael , Baquero Miguel , Sendra‐Lillo José , Royo Lucrecia Moreno
Published: December 2023

Background

Cognitive impairment (CI) is often diagnosed at moderate stages, with an estimated time for diagnosis of two years. However, the early diagnosis of CI allows the control of modifiable risk factors to prevent the development of dementia at later ages. In addition, the community pharmacy is a close, accessible, and trustworthy health establishment where the pharmacist often participates in disease prevention, becoming a suitable healthcare center for facilitating the detection of cases of CI

Method

A cross‐sectional observational study was designed using a structured personal interview. Participants were aged 50 or older with subjective memory complaints. Pharmacies in the province of Valencia (Spain) were invited to participate voluntarily by the organization entities. Before the start‐up of the service, the participating pharmacists received specific training. In the personal interview with the patient, after signing the corresponding informed consent, three validated questionnaires were conducted to assess their cognitive status: Memory Impairment Screening (MIS), Semantic Verbal Fluency (FVS), and Pfeiffer’s Short Portable Mental State Questionnaire (SPMSQ). Whenever possible, a fourth questionnaire was carried out: Brief Informant Test (Brief TIN). Data collection was carried out through a computer platform. This project was approved by the Ethics Committee of the University CEU‐Cardenal Herrera (registration number CEEI21/198).

Result

Between February 2021 and July 2023, 44 pharmacies participated, and 534 patients were screened. Of them, 194 (36%) had at least one positive test result, therefore having possible CI. After their corresponding referral to the doctor, 52 (29%) patients were referred to the hospital neurology department, of which 42 (81%) had been diagnosed with cognitive decline. Finally, the average time from the first evaluation by a pharmacist to a diagnosis by the specialist was six months.

Conclusion

Preliminary results of the screening for cognitive impairment show that the community pharmacy is a critical point in the approach to early detection of dementia and that collaboration and coordination between different levels of care is enhanced through such programs.
Inflammatory and synaptic PET imaging in behavioural variant frontotemporal dementia caused by a repeat expansion in C9orf72 (C9orf72‐FTD)
Authors: Clarke Mica TM , Consortium MINDMAPS , Cash David M , Rohrer Jonathan D.
Published: December 2023

Background

Pathophysiological mechanisms associated with neurodegeneration include chronic neuroinflammation and synaptic dysfunction/loss. Radiotracer [11C]PBR28 is a marker of inflammation which binds to a translocator protein expressed by activated microglia. [11C]UCB‐J is a marker of synaptic density which binds to synaptic vesicle protein 2A. We evaluated both tracers as biomarkers of C9orf72‐FTD.

Method

Three individuals with C9orf72‐FTD (mean age 62.7 years) underwent two PET scans between 3 and 13 months apart using [11C]PBR28 and [11C]UCB‐J. Dynamic PET data were acquired for 90 minutes following injection of each tracer. Arterial plasma input functions were generated from arterial blood samples. Participants also had volumetric MRI scans for each PET scan. Age‐matched controls from different cohorts underwent the same procedures (n = 5 for [11C]PBR28; n = 17 for [11C]UCB‐J).

Regions of interest (ROIs) were defined on co‐registered T1‐weighted MR images using the CIC anatomical atlas. [11C]PBR28 BPND values were generated using a simplified reference tissue model with a cerebellar reference region. [11C]UCB‐J DVR‐1 values were generated using regional VT normalised to the VT in the centrum semiovale. ROI volumes were expressed as a percentage of total intracranial volume. W‐scores computed from each control cohort, using age and gender as covariates, illustrated the magnitude of differences between cases and controls. W‐scores >1.65 were considered abnormal for [11C]PBR28 and ←1.65 for [11C]UCB‐J and MRI.

Result

[11C]PBR28 w‐scores indicated significant neuroinflammation in FTD but varied between cases. Differences in BPND were greater than in volume in frontal/temporal/cingulate cortices in the individual with the longest disease duration (DD) (16‐17 years). Inversely, in the individual with the shortest DD (1‐2 years), there were greater differences in volume than BPND in most ROIs.

[11C]UCB‐J w‐scores indicated significant synaptic dysfunction/loss and were lower than w‐scores of volume in all cortical ROIs. In the individual with the longest DD, differences in [11C]PBR28 were greater than in [11C]UCB‐J in most ROIs. An inverse pattern again observed in the individual with the shortest DD suggests synaptic dysfunction/loss may precede significant neuroinflammation.

Conclusion

Inflammatory and synaptic PET may provide more sensitive biomarkers of C9orf72‐FTD than MRI. Variability in PET signal within this genotype may be explained by DD.
Designing new musical technologies for wellbeing – exploring the needs and preferences of those living with dementia
Authors: Christensen Justin , MacRitchie Jennifer , Neokleous Michael , Jackson Katherine , Timmers Renee , De Witte Luc
Published: December 2023

Background

Music has been found to provide numerous health and wellbeing benefits for people living with dementia. It is also quite open in terms of the forms of engagement it affords, offering numerous different ways to listen, play and create. Although technology has the potential to reduce barriers that people with dementia face when attempting to engage with music, little has been designed with them in mind. This study seeks to understand: i) the needs, rewards, and barriers that people with dementia and their carers face when engaging with music in their daily lives, and ii) how any specifically designed future musical interfaces will look and react.

Method

A survey using a mixture of qualitative and quantitative questions was distributed online to people living with mild cognitive impairment or dementia and to those that provide care for them. Questions asked about motivations and contexts for engagement, barriers and enabling factors, the comparative importance of various musical activities, and the technologies people living with dementia currently use and why.

Result

The main tools for listening include smartphone apps, radio, virtual assistants, and YouTube. Most participants listen to music on multiple devices, with its ease of use, accessibility, and convenience for their current listening environment frequently influencing their choice. They also presented a wide range of motivations for engaging with music, but a majority of participants agreed that “feeling like myself” is their most important motivator. Most participants thought it was very important for devices to offer choice. It should also have a simple way for them to turn it off or switch to a safe song if they hear a distressing song or it experiences signal loss.

Conclusion

The findings highlight that people living with dementia have diverse individual motivations for music, and they want it to perform different functions at different times (e.g. sometimes aiding in their relaxation and sometimes connecting them with others). The findings point to fruitful future directions for technology development: i) ready‐to‐use tools that can adapt to changing interests, and ii) tools that make it easy to access choice and variety while safeguarding against distress from unwanted or unexpected events.
CSF tau markers are associated with fine memory discrimination in older adults with amnestic MCI in the EXERT trial
Authors: Fenton Laura E. , Aslanyan Vahan , Jacobs Diane M. , Salmon David P. , Brewer James B. , Rissman Robert A , Feldman Howard H. , Shadyab Aladdin H. , LaCroix Andrea Z. , Baker Laura D , Pa Judy
Published: December 2023

Background

Cognitive assessments sensitive to the integrity of the medial temporal lobe, an area vulnerable to early tau deposition, may serve as a low‐cost, effective marker of underlying tau burden in older adults at risk of Alzheimer’s dementia. The current post hoc analyses from the EXERT study examined the relationship between CSF phosphorylated tau181 (p‐tau181), total tau (t‐tau), hippocampal volume, and cognitive performance on three distinct memory assessments in older adults with amnestic mild cognitive impairment (aMCI).

Method

The study used baseline data from 41 older adults with aMCI in the EXERT trial who consented to lumbar puncture and had CSF data available (mean age = 74.10±11.98 years, mean education = 16.24±2.39 years, 61% female). P‐tau181 and t‐tau levels were quantified using Lumipulse from CSF samples. Structural brain images were processed using NeuroQuant. Hippocampal volume measures were averaged across hemispheres and adjusted for intracranial volume. Memory measures included the computerized Cogstate Behavioral Pattern Separation of Objects task (BPSO; fine memory discrimination), the Auditory Verbal Learning Test (AVLT; long delay free recall), and the Logical Memory test (delayed recall). Linear regression models were adjusted for age, sex, and education.

Result

Lower CSF p‐tau181 was significantly associated with better fine memory discrimination (β = ‐0.11, SE = 0.03, p<0.01). Lower CSF t‐tau was significantly associated with better fine memory discrimination (β = ‐0.09, SE = 0.03, p = 0.01). Larger hippocampal volume was significantly associated with better fine memory discrimination (β = 0.08, SE = 0.02, p<0.01), better AVLT delayed recall (β = 1.69, SE = 0.32, p<0.01), and better Logical Memory delayed recall (β = 1.69, SE = 0.40, p<0.01). Neither p‐tau181 or t‐tau were significantly associated with AVLT delayed recall or Logical Memory delayed recall.

Conclusion

Fine memory discrimination measured via the computerized BPSO test was associated with CSF p‐tau181, CSF t‐tau, and hippocampal volume, while more traditional verbal memory tests of list learning and story recall were associated only with hippocampal volume. The BPSO test may be a sensitive indicator of early pathology in individuals with aMCI with underlying tau burden. EXERT was supported by the Alzheimer’s Disease Cooperative Study (ADCS) and funded by the National Institutes of Health Grant U19 AG010483.
Using multimodal, low‐cost data to efficiently identify clinical subgroups and classify Alzheimer’s diagnosis
Authors: Ren Yueqi , Shahbaba Babak , Stark Craig E.L.
Published: December 2023

Background

With increasingly greater prevalence of Alzheimer’s disease (AD) worldwide, cost‐ and time‐efficient methods for identifying at‐risk individuals are needed. Survey, simple neuropsychological, and demographic information are low‐cost, but their lower levels of sensitivity or specificity when considered individually are problematic. However, past work has demonstrated the usefulness of statistical machine learning tools for predicting clinical diagnosis using multimodal data. To better understand and quantify Alzheimer’s risk and progression at follow‐up using lower‐cost data, we apply statistical and machine learning tools to screen, cluster, and classify individuals from the National Alzheimer’s Coordinating Center (NACC) dataset.

Method

Previously, we developed hierarchical classification strategies to use lower‐cost data for 3‐class prediction (unimpaired, AD‐MCI, and AD‐dementia). Building upon this idea, here we leverage a Gaussian mixture model to infer subgroup identities of subjects and use subgroup identity to further aid classification. Individuals belonging to homogeneous subgroups consisting primarily of a single diagnosis are more likely to also be given that diagnosis. This approach enables confidence in screening given a threshold for identifying the primary diagnosis within each cluster. Additional classification is performed on subjects that belong to heterogeneous subgroups. The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA‐funded ADRCs.

Result

The proposed method unmasks the clinical subgroup trends within the sample and allows for detailed longitudinal risk tracking. We identified five subgroups within the sample, representing five clinical clusters. These subgroups include predominantly unimpaired individuals, mixtures of unimpaired and MCI, MCI and AD‐dementia, and individuals predominantly with AD‐dementia. A large proportion of individuals can be confidently screened based upon subgroup identity. Using only baseline visit information, predictions of clinical diagnosis post‐clustering is highly reflective of conversion to a worse diagnosis within 18 months. Changes in the conversion rate to a more severe diagnosis are dependent on the cluster identity.

Conclusion

Using cost‐ and time‐efficient data enables more effective screening and tracking of disease progression. The proposed approach of clustering, screening, and prediction yields a measure of confidence in predictions of clinical diagnosis and allows for greater understanding of clinical profiles and progression.
T1 MRI reveals differential hippocampal atrophy in Lewy Body Disorders with and without Alzheimer’s copathology
Authors: Cohen Jesse S , Phillips Jeffrey S , Das Sandhitsu R. , Rhodes Emma , Cousins Katheryn A Q , Yushkevich Paul A. , Wolk David A. , Weintraub Daniel , Irwin David J. , McMillan Corey T
Published: December 2023

Background

Lewy body disorders (LBD) include Parkinson disease (PD), Parkinson disease dementia (PDD), and dementia with Lewy bodies (DLB). LBD are the second leading cause of neurodegenerative dementia after Alzheimer’s disease (AD). An estimated 50% of LBD patients have coexisting AD pathology (LBD+AD), which correlates with shorter time to dementia and death. Autopsy evidence suggests that verbal memory impairment correlates with the severity of hippocampal tau pathology in LBD. However, it is unknown whether greater hippocampal tau burden in LBD+AD causes neurodegeneration detectable by in vivo structural MRI, and whether hippocampal atrophy explains verbal memory impairment.

Method

Using a case‐control design, we studied 87 patients with clinical diagnoses of LBD (PD, n = 52; PDD, n = 12; DLB, n = 23) with available T1 MRI and AD biomarkers or, and cognitively‐normal controls (n = 131). AD copathology was defined hierarchically by: a) AD “intermediate” or “high” by ABC neuropathologic criteria; 2) positive amyloid PET; and 3) CSF total tau:β‐amyloid1‐42 ratio > 0.3 (autopsy‐validated cutpoint). The Automated Segmentation of Hippocampal Subfields (ASHS) pipeline was applied to subjects’ T1 MRIs. Hippocampal volume (HV) was compared between controls, LBD‐AD, and LBD+AD, and correlated with verbal memory scores. Linear regression was used to test the association of AD copathology (independent variable) and HV (dependent variable), covarying for age, sex, education, and clinical diagnosis.

Result

Statistically significant differences (ANOVA p = 0.002) in bilateral HV (expressed as percentage of intracranial volume) were seen between groups (mean 0.456for controls, 0.444±0.045 for LBD‐AD, and 0.416±0.063 for LBD+AD). Tukey’s test showed significant differences between LBD+AD vs controls (p = 0.001) and LBD+AD vs. LBD‐AD (p = 0.047). Linear regression showed statistically significant association of LBD+AD with bilateral HV (p = 0.034). Among all LBD patients, hippocampal volume positively correlated with verbal memory (immediate recall: r2 = 0.24, p = 0.033, delayed recall: r2 = 0.22, p = 0.042, recognition discrimination r2 = 0.58, p<0.001).

Conclusion

In patients with LBD, AD copathology is associated with increased hippocampal atrophy as measured by in vivo T1 MRI, which correlates with greater verbal memory deficits. This work supports the that AD copathology impairs cognition in LBD via hippocampal neurodegeneration.
Core outcome set for economic evaluation of dementia interventions: A consensus exercise with health economists who incorporate economic evaluations into dementia trial
Authors: Nguyen Kim Huong , Comans Tracy , Trepel Dominic , Saha Sanjib
Published: December 2023

Background

Healthcare decision‐makers worldwide are increasingly seeking to optimise allocation of resources to dementia and the incorporation of economic evaluations into randomised control trials provide definitive information for such decisions. Economic evaluations are rapidly increasing in number in dementia and standardisation of methods ensure comparability of economic evidence.

Method

Core outcomes sets (COS) aim to provide international recommendations on outcome measurement in trials and currently there exists no COS for economic evaluations of dementia interventions. Our systematic searches identified over 100 economic evaluations of dementia interventions, and critical appraisal demonstrates opportunities for greater standardisation of applied economic methods. This study aims to agree standardised methods for economic measures of a) health outcomes and b) resource use that should be measured and reported in future trial‐based economic evaluation in dementia.

Result

The COS for the economic evaluation of dementia interventions will be developed from two main steps:

First, a systematic review (currently being finalised) extracts information on how costs and benefits are estimated, analysed and reported. All studies published before December 2022, and confirmed as trial‐based economic evaluation, are included. Included studies all contain economic measures and we will report participant characteristics (type of dementia, severity), study design and evaluation types, type of interventions, mode of data collection and instrument(s) used to derive the health outcomes and resource uses.

Second, which speaks specifically to action research at AAIC 2023, we will conduct a Delphi consensus focus groups with economists who have collaborated with dementia‐trial teams. Data extracted during the systematic review will be presented to provide a basis for the consensus recommendations on measures commonly required for economic evaluation in dementia. In the case where consensus was not reached, we may conduct additional consensus exercises. We will also consider country contexts (high versus low‐middle income, or country‐level financing and reimbursement mechanisms) in finalising recommended COS of health and resource use measures.

Conclusion

Findings from COS for economic evaluations of dementia intervention will be published in a dementia‐focused journal and more broadly communicated to a broad range of stakeholders.
Ante‐mortem magnetic resonance imaging grey‐white matter contrast regional signatures of Alzheimer’s disease neuropathology
Authors: Almeida Francisco , Coelho Ana , Quintas‐Neves Miguel , Teylan Merilee A. , Mock Charles , Kukull Walter A. , Crary John F. , Oliveira Tiago Gil
Published: December 2023

Background

Grey matter (GM), white matter (WM) contrast (GWC) in T1‐weighted MRI has been shown to decrease with age in healthy populations and cognitive impairment in clinical Alzheimer’s Disease (AD). However, the neuropathological determinants of this signal remain unknown. Here, we aimed to study whether GWC is associated with AD neuropathology and longitudinal hippocampal atrophy.

Methods

157 patients with neuropathological, clinical data and ante‐mortem MRI were selected from the National Alzheimer’s Coordinating Center database. Cortical volume and GWC (WM/GM intensity) in T1/MRI were obtained with Freesurfer 6.0. Hippocampal volume was divided into anterior, intermediate and posterior regions using a lab‐based algorithm. Correlational analysis was conducted for GWC with age, and GWC residuals after linear regression with age for volume, BRAAK stage (neurofibrillary tangles), CERAD score (neuritic plaque density) and Cognitive Dementia Rating Sum‐of‐Boxes (CDR‐SB). APOE genotypes were compared using one‐way‐ANOVA.

Results

GWC was negatively correlated with age in widespread brain areas (p < 0.05, FDR), but only the entorhinal cortex showed a positive correlation between volume and GWC. There were no significant correlations between GWC and BRAAK stage, CERAD score, CDR‐SB or differences according to APOE genotype. Entorhinal GWC correlated positively only with the posterior hippocampal volume in BRAAK III‐IV.

Conclusion

GWC is highly modulated by age, but not by classical AD neuropathology, APOE genotype or dementia severity in this cohort. Entorhinal GWC correlates with entorhinal and posterior hippocampal volume, suggesting it might reflect an early pathophysiological process distinct from classical AD neuropathology.
Association between brain [18F]FDG‐PET signal and genetic cell markers in the brain tissue
Authors: Machado Luiza Santos , Ant Marco , Bastiani De , da Rocha Andreia Silva , Bellaver Bruna , Soares Carolina , Povala Guilherme , Rahmouni Nesrine , de Souza Débora Guerini , Pascoal Tharick A. , Souza Diogo O. , Rosa‐Neto Pedro , Benedet Andrea Lessa , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Ferreira Pamela C.L. , Zimmer Eduardo R.
Published: December 2023

Background

Brain glucose hypometabolism, indexed by [18F]FDG‐PET, is considered a biomarker of neurodegeneration in Alzheimer’s disease (AD). However, other brain cells, such as astrocytes and microglia, also consume considerable amounts of glucose and may contribute to the [18F]FDG‐PET signal in the brain. Thus, the cellular source of the [18F]FDG‐PET signal remains controversial. Here, we aimed to evaluate whether canonical markers of different brain cell types (neuron, oligodendrocyte, astrocyte, and microglia) associate with brain [18F]FDG‐PET signal in humans and a rat model of human amyloidosis.

Method

[18F]FDG‐PET images were acquired in ten‐month‐old APP/PS1 (TgF344‐AD, n = 8) and wild‐type (WT, n = 6) rats. Next, we evaluated the gene expression of NeuN, Olig2, GFAP, S100B, and IBA1 in the frontal and temporoparietal cortices and cerebellum. Association maps integrating mRNA with brain [18F]FDG‐PET signal were conducted at the voxel level using RMINC. [18F]FDG‐PET and brain tissue mRNA (GFAP, ACSA2, S100B, GLAST, IBA1, CSF1R, TREM2, Olig2, Cldn11, NeuN) of cognitively unimpaired patients were obtained from ADNI and Allen Brain Atlas database, respectively. In humans, mean regional [18F]FDG‐PET SUVr (reference region: pons) and mRNA expression were used to evaluate their association using a gaussian model. Differences were considered statistically significant at p<0.05 (t>2).

Result

GFAP and S100B mRNA levels in the temporoparietal and frontal cortices positively correlated with brain [18F]FDG‐PET signal (local maxima, GFAPt(13) = 9.4, S100Bt(13) = 6.6; Fig1B‐C). No associations were found with TREM2, Olig2 and NeuN (t(13)<2; Fig1D‐F). We expanded our analysis by comparing gene astrocyte markers and astrocyte gene cell markers in humans. At the regional level, we found that FDG‐PET SUVr and astrocyte mRNA were positively associated: S100B (R‐squared = 0.34), GFAP (R‐squared = 0.33), GLAST (R‐squared = 0.31) and ACSA‐2 (R‐squared = 0.31; Fig1G).

Conclusion

Our findings suggest astrocyte mRNA markers are more closely associated with brain [18F]FDG‐PET signal than neuronal, oligodendrocyte, and microglial mRNA markers.
Sex‐ or depression‐specific relationships with CSF sAPPα, sAPPβ and their associations with CSF sTREM2 in older adults
Authors: Nunzio Pomara , Plaska Chelsea Reichert , Bruno Davide , Ramos‐Cejudo Jaime , Osorio Ricardo S , Heslegrave Amanda , Pillai Anilkumar , Imbimbo Bruno P , Zetterberg Henrik , Blennow Kaj
Published: December 2023

Background

Female sex and depression are associated with increased risk for Alzheimer’s disease (AD) but the mechanisms for the increased risk remain poorly understood. Increased brain amyloid deposition and microglial activation have both been implicated; however, the role of sex‐ and depression‐related effects on microglial activation remain understudied.

Both sAPPα and sAPPβ, cleavage products of non‐amyloidogenic and amyloidogenic APP cleavage, respectively, have been reported to induce microglial activation. These observations prompted us to examine the relationships between sex, depression, and levels of sAPPα and sAPPβ. CSF levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is a possible proxy for phagocytic anti‐inflammatory TREM2‐dependent microglial activation, was also examined.

Method

Fifty‐one cognitively intact subjects (31 subjects with late‐life major depression (LLMD) and 20 controls) aged 60 years and older, completed a 3‐year longitudinal study. Independent‐samples Mann‐Whitney‐U tests were used to examine group differences by diagnosis, sex, and APOE genotype for sAPPα and sAPPβ.

Result

There were no significant differences between subjects with LLMD and Controls in CSF sAPPα or sAPPβ levels. Irrespective of diagnosis, females had significantly higher levels of both sAPPα (p = 0.016) and sAPPβ (p = 0.010) compared to males. sAPPα and sAPPβ were significantly correlated with each other (rho = 0.930, p<0.001). In the whole sample, sTREM2 correlated with both sAPPα (rho = 0.462, p = 0.001) and sAPPβ (rho = 0.504, p<0.001). When examining the relationships as a function of diagnosis, sAPPα was found to be associated with sTREM2 in Controls only (rho = 0.474, p = 0.035) while sAPPβ correlated with sTREM2 in LLMD only (rho = 0.370, p = 0.048). When examining the relationship as a function of sex, we found that sTREM2 significantly correlated with both sAPPα (rho = 0.629, p = 0.002) and sAPPβ (rho = 0.673, p = 0.001) in females but not in males (sAPPα: rho = 0.310, p = 0.109; sAPPβ: rho = 0.341, p = 0.076).

Conclusion

Mean CSF sAPPα and sAPPβ levels between Controls and LLMD showed no group differences but were significantly increased in females compared to males. Females but not males showed significant positive associations between CSF sTREM2, sAPPα and sAPPβ. Future studies should determine if these results are associated with differences in microglial activation and to the increased risk for AD and depression in females.
Role of peripheral inflammation in driving central nervous system inflammatory signature in pathogenesis of Alzheimer’s disease
Authors: Sanchez‐Molina Paula , Bogachuk Alina , Soto‐Faguás Carlos M , Woltjer Randy L , Cowley Sally A , Quinn Joseph F , Ajami Bahareh
Published: December 2023

Background

Alzheimer’s disease (AD) impacts an estimated 6.5 million people in the United States, however, it cannot yet be prevented, slowed or cured. Although the sporadic AD form comprises around 95% of cases, animal models of familial AD are the ones used for basic and translational research. Most of these models are based on human mutations that cause amyloid‐β (Aβ) pathological accumulation. However, the failure of the majority of Aβ‐related clinical trials, has begged the necessity of an alternative approach to address AD. Interestingly, most of the genetic and non‐genetic risk factors for developing sporadic AD are associated with inflammation. Thus, it has been suggested that microglia, the immune cells in the central nervous system, play a key role in the pathogenesis of AD, and that people with systemic inflammatory diseases have a higher incidence of developing AD. In this context, we hypothesize that a specific subset of cells in peripheral blood contributes to AD development through its communication with microglial cells in the brain parenchyma.

Method

To address this hypothesis, we analyzed peripheral blood mononuclear cells (PBMCs) from sex‐ and age‐matched healthy and AD subjects using mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE‐seq) technologies. Moreover, we used in vitro and histological approaches to study interactions between PBMCs and human microglial cells.

Result

Our preliminary data show a different proportion of peripheral blood immune cell types between healthy controls and AD patients. Remarkably, a specific inflammatory subset of immune cells characterized by the upregulation of pro‐inflammatory signaling pathways and cytokines was detected in blood of AD patients. In addition, T cells in contact with microglia were detected in the parenchyma of AD brains by histological analysis, suggesting adrive of microglial cells towards an inflammatory phenotype that could contribute to AD pathology. We corroborated the pathogenic component of AD blood as healthy PBMCs developed an inflammatory phenotype after stimulation with AD plasma.

Conclusion

Together, our data demonstrate the importance of peripheral immune cells in AD disease and reinforce that studying AD as a multifactorial disease could be key to its prevention and treatment.
Comparison of Vascular Health in Super‐Agers and Cognitively Normal Adults 80 Years and Older
Authors: Trammell Antoine R , Parker Monica W , Wingo Aliza P. , Wingo Thomas S. , Johnson Kirstin M , Binford Bill , Hajjar Ihab , Goldstein Felicia C
Published: December 2023

Background

Unraveling factors associated with cognitive resilience and super‐agers might reduce expected increases in Alzheimer’s disease and related dementia (ADRD). Vascular disease can impair the cerebral circulation and increase risk for cognitive decline and ADRD. However, data in persons aged 80+ suggests that maintained vascular health can preserve key brain regions for normal cognition.

Method

Using National Alzheimer’s Coordinating Center (NACC) data from January 2005 ‐ December 2020, we found 9,581 participants age 80+ (white: 8,296 vs. AA: 1,285,p<.0001) at the baseline visit. We defined cognitive groups per global Clinical Dementia Rating (CDR) and Memory subscale scores. Normal cognition (NC) was defined as a global CDR and memory subscale score = 0. To identify super‐agers (SA), we utilized data‐derived cutoffs from cognitive test performances consistent with prior reports. The operationalized definition was created from: 1) Mean Craft delayed recall scores in 50–60‐year‐olds with NC; 2) Craft scores among age 80+ with NC group were standardized to the mean score for age 50‐60 with NC; and 3) Standardized mean scores for non‐memory measures (trail making test‐B, phonemic fluency, and multilingual naming test) for age 80+ with NC. SA were defined as age 80+ with episodic memory performance (Craft scores) ≥ 1 standard deviation (SD) of the standardized mean for the age 50‐60 group and non‐memory scores ≥ 1 SD of the standardized mean for the 80+ age group.

Result

We identified 4.5% (n = 431) SA and 27.7% (n = 2,654) NC (p<.01) to compare vascular variables. Compared to NC, SA were younger (83.5±3.4 vs. 84.7±4.0, p<.01), had more education (16.5±2.8 vs. 15.2±3.1, p<.01), higher diastolic blood pressure (DBP) (73.9±10.5 vs. 71.9±10.5, p<.01), and mean arterial pressure (MAP) (95.5±11.8 vs. 93.5±11.5, p<.01). Pulse pressure (PP) was similar for both groups (67.5±17.1 vs. 68.1±10.5, p = .33).

Conclusion

Our results suggest that vascular health could impact cognition in aged 80+ adults. SA may have higher cerebral perfusion (CP) per MAP. Although DBP can decrease with aging, higher values in our sample may contribute to CP. The PP in our sample is similar to reported values for healthy 70‐year‐old adults. Further study of vascular health and super‐aging is needed.