bluuebunny/crossref_metadata_2025 huggingface dataset:
3D bioprinted human neuron‐like spheroids as an in vitro model for neurodegenerative diseases
Authors: Salles Geisa Rodrigues , Dall'Agnol Ferreira Natalia , Pacheco‐Soares Cristina , Porcionatto Marimelia Aparecida
Published: December 2023

Background

The limited number of reproducible in vitro models for neurobiology purposes consists of a difficult challenge, primarily because naturally, in the organism, cells are organized three‐dimensionally. The concept of developing three‐dimensional (3D) models to further elucidate brain organization, mechanisms, and pathways has the importance of reaching characteristic features of native tissue that facilitate the comprehension of complex neurodegenerative diseases, such as Alzheimer’s disease (AD). Bioprinting has revolutionized the concept of three‐dimensionality, producing complex structures and sculptural constructs. This study aims to demonstrate the first steps of a novel 3D bioprinted construct, illustrating that neuron‐like cells organize themselves as spheroids when cultured in a 3D environment.

Method

First, the bioink was prepared by adding human neuroblastoma cells (SH‐SY5Y), differentiated into a more mature neuron‐like phenotype by the addition of 2% retinoic acid, for seven days into a hydrogel consisting of an Alginate/Gelatin solution. As control cells were cultured in the absence of retinoic acid. The constructs were bioprinted and crosslinked by the addition of 2% CaCl2. The swelling degree of printed hydrogel and morphological cytoskeletal organization of the neuron‐like spheroids were evaluated.

Result

The developed hydrogel has a high swellability, increasing water retention upon long‐term immersion (Figure 1A). Swellability is an important feature, indicating the hydrophilicity of the construct, which facilitates cell‐cell interactions and culture medium diffusion into the construct core. Importantly, when cellular organization within the construct was evaluated, we observed that the SH‐SY5Y cells arranged themselves as spheroids (Figure 1B), a valuable tool for investigating the 3D cellular organization. This feature reproduces important natural tissue characteristics, such as producing extracellular matrix components and forming a network of cell‐cell interaction, which cannot be reproduced in 2D structures. Moreover, neurite outgrowth is observed inside the spheroidal construct with differentiated cells (Figure 1B).

Conclusion

The 3D bioprinted construct is highly suitable and advantageous as a neurobiological 3D model. Based on this construct, further studies are being developed to better simulate AD in vitro, building an interactive disease model.

Acknowledgments: This study was supported by São Paulo Research Foundation (FAPESP, grants 2022/08664‐4 and 2018/45605‐8), and Brazilian National Council for Scientific and Technological Development (CNPq, grant 406258/2022‐8).
Brain Arginine Metabolism in Early‐onset Alzheimer’s Disease and Frontotemporal Dementia
Authors: Mein Hannah , Jing Yu , Lladó Albert , Zhang Hu , Liu Ping
Published: December 2023

Background

The semi‐essential amino acid L‐arginine is metabolically versatile with a number of bioactive metabolites that are involved in synaptic plasticity, learning and memory, cerebral blood flow and microtubule stabilization processes. Altered brain arginine metabolism is evident in patients with late‐onset Alzheimer’s disease and has been implicated in the disease pathogenesis. However, the brain arginine metabolic profile is yet to be investigated in early‐onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD).

Method

Using high performance liquid chromatography and liquid chromatography/mass spectrometry, we measured the concentrations of L‐arginine and its downstream metabolites L‐citrulline, L‐ornithine, agmatine, glutamate, glutamine, GABA, putrescine, spermidine and spermine in the hippocampus and frontal and temporal cortices from EOAD (n = 27‐28/region), FTD (n = 27‐31/region) and control (n = 9‐17/region) cases.

Result

There were significantly reduced levels of L‐ornithine in all three brain regions in both groups of dementia cases compared to the controls. Furthermore, the putrescine levels were significantly reduced in all brain regions examined in the FTD cases, and in the temporal cortex and hippocampus of the EOAD cases. In the hippocampus, there were increased L‐arginine levels, but decreased agmatine levels, in both the EOAD and FTD cases relative to the controls.

Conclusion

This study demonstrates for the first time that brain arginine metabolism is altered similarly in both EOAD and FTD cases, and therefore suggests that altered L‐arginine metabolism may be a common mechanism involved in the neurodegenerative processes in these two early‐onset dementias. Further research is required to investigate the mechanisms for these metabolite changes and to explore the therapeutic potential of targeting L‐arginine metabolism in EOAD and FTD.
The effect of light exposure on cognitive outcomes at long term follow up in an at‐risk dementia population
Authors: Schrire Zoe M , Gordon Christopher J , Palmer Jake R , Mowszowski Loren , Michaelian Johannes C , Naismith Sharon L , Hoyos Camilla M
Published: December 2023

Background

Circadian disturbances are a common occurrence in older adult population but are more prevalent in people with dementia. For some individuals, these occurrences begin many years prior to the onset of clinical symptoms and have been suggested as a potential risk factor. As light is the primary synchroniser of the circadian system, the current study aimed to examine if 14‐day light exposure could predict cognitive outcomes of older adults with varying risks of dementia at 2‐year follow‐up.

Method

The study was a retrospective analysis of 195 participants (age = 67, 60.7% female) who attended the Healthy Brain Ageing Clinic in Sydney. At baseline, participants were neurocognitively assessed and wore an actigraph for 14 days and then completed another neurocognitive test battery at their follow‐up. Binary logistic regression was used to determine if participants converted to either Mild Cognitive Impairment (MCI) or dementia was predicted from light exposure (average and maximum) and average time spent in >1000 lux (OR = 1.00), adjusting for age, sex and years of education. Linear regression was used to investigate the relationship between light variables and differences in verbal memory, processing speed and executive function composite scores from baseline to 2 years.

Result

Light exposure at 2 years prior did not appear to predict cognitive performance. There was a trend towards moderate to bright light increasing risk of cognitive decline.

Conclusion

Further research is needed to understand light exposure and the relationship to circadian rhythms and cognition. As previous light therapy research has been inconclusive, future research will inform treatment approaches.
Biomarker interplay between CSF p‐tau and 18F‐PI‐2620 PET in Alzheimer’s disease and 4R‐tauopathy
Authors: Dilcher Roxane , Wall Stephan , Franzmeier Nicolai , Katzdobler Sabrina , Barthel Henryk , Wagemann Olivia , Palleis Carla , Weidinger Endy , Fietzek Urban , Kurz Carolin Isabella , Ferschmann Chrsitian , Scheifele Maximilian , Eckenweber Florian , Zaganjori Mirlind , Gnörich Johannes , Danek Adrian , Bürger Katharina , Janowitz Daniel , Rauchmann Boris‐Stephan , Stöcklein Sophia , Perneczky Robert , Schoeberl Florian , Zwergal Andreas , Höglinger Günter , Bartenstein Peter , Villemagne Victor L , Seibyl John , Sabri Osama , Levin Johannes , Brendel Matthias
Published: December 2023

Background

Reliable biomarkers for detecting different abnormal tau protein isoforms between neurodegenerative diseases are currently missing. Phosphorylated tau (p‐tau) in the cerebrospinal fluid (CSF) is acknowledged as a 3/4R tau biomarker in AD but not in other tauopathies. The positron emission tomography (PET) radiotracer 18F‐PI‐2620 has the potential to detect abnormal 3/4R‐tau in patients with Alzheimer’s disease (AD) and 4R‐tau in Progressive Supranuclear Palsy (PSP) or Corticobasal Syndrome (CBS). This study investigates the interplay between tau‐PET and CSF p‐tau in AD and 4R‐tauopathies.

Method

In this cross‐sectional analysis, 52 patients with AD, 54 patients with PSP/CBS, and 11 controls underwent lumbar puncture and 0‐60 min dynamic 18F‐PI‐2620 PET scanning. Independent t‐tests assessed group differences in standardized uptake value ratios for the 20‐40min time window (SUVr20‐40) and p‐Tau. Quantitative and voxel‐wise multiple regression analyses tested the association between SUVr20‐40 and p‐tau and group interactions, using R and SPM and controlling for age and sex. ROC analyses were performed to evaluate biomarker performance in differentiating patient groups.

Result

Patients with AD showed elevated CSF p‐tau levels (p<0.05; >61 pg/ml) and SUVr20‐40 in temporal, parietal, occipital, frontal, cingulate‐insula, striatum, and amygdala (p<0.05). In patients with AD the two biomarkers correlated positively (p<0.05). Patients with clinically suspected 4R‐tauopathies did not show elevated p‐tau levels but demonstrated high tau‐PET uptake in the lentiform nucleus (p<0.05), compared to controls and AD. ROC analyses showed that temporal SUVr20‐40 (87.3%) and p‐tau levels (80.8%) were able to differentiate AD from 4R‐tauopathies, while the lentiform nucleus tau‐PET showed moderate performance at discriminated patients with 4R‐tau from those with AD (56.7%) and healthy controls (66.3%). Interestingly, the AUC increased to 70%, when excluding patients with CBS.

Conclusion

The specific combination of CSF p‐tau levels and 18F‐PI‐2620 PET SUVR in disease‐specific regions facilitates biomarker‐guided stratification of AD and clinically suspected 4R‐tauopathies.
Comparative identification of Veterans with mild cognitive impairment or Alzheimer’s disease extracted from clinical notes and administrative data
Authors: Berlowitz Dan , Aguilar Byron J. , Li Xuyang , Shishova Ekaterina , Jasuja Guneet , Morin Peter J , Miller Donald R , O'Connor Maureen K. , Nguyen Andrew H. , Zhang Raymond , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming
Published: December 2023

Background

Registries that identify people with mild cognitive impairment (MCI) or Alzheimer’s dementia (AD) will be critical in targeting interventions to delay disease progression. Optimal methods to identify people for inclusion in such registries remain uncertain. We now compare approaches that rely on International Classification of Diseases (ICD)‐10 codes to the use of natural language processing (NLP) of clinicians’ notes.

Method

We used data from the Department of Veterans Affairs (VA) considering all Veterans aged 50 or older from the fiscal year 2019. People for the “ICD” cohorts were identified based on at least one code for either AD or MCI. For the “NLP” cohorts, we used electronic clinician notes and previously validated algorithms that search for keywords ("Alz*” or “Mild Cognitive Impairment”), excluding false positive cases identified through text screening such as “family history.” The number and overlap of people identified by the ICD‐ and NLP‐based approaches were compared.

Result

Overall, 144,942 Veterans documented with either ICD coding or clinical notes using NLP as probable AD patients were identified; 32,498 (22.4%) people were identified by ICD codes and 141,816 (97.8%) people by clinical notes. Only 20.3% of the Veterans were identified by both clinical notes and ICD; 77.5% were identified by clinical notes alone and only 2.2% by ICD alone. In contrast, for the 134,699 Veterans with MCI, 95,324 (70.8%) people were identified by ICD codes and 79,232 (58.8%) people by clinical notes. Veterans identified by both ICD and clinical notes consisted of 29.6% of the sample, compared to 41.2% by ICD and 29.2% by clinical notes.

Conclusion

Identification of patients with MCI or AD in electronic clinical notes using NLP is an alternative approach for developing a disease registry to the traditional methodology based on ICD coding in administrative databases. The differences in case identification between NLP‐ and ICD‐based approach may have reflected a clinical practice pattern in making clinical judgments regarding MCI and AD and documenting MCI and AD assessments in clinical notes as opposed to administrative records among the US Veterans.
Lipidomic dysfunction accompanied phosphatidylethanolamine deregulation is a potential detection biomarker and drug target for early Alzheimer’s disease of obesity population
Authors: Qi Shaohua , Yang Li , Li Xuping , Yin Zheng , Zhao Hong , Willa Hsueh , Xia Weiming , Wong Stephen T.C.
Published: December 2023

Background

White adipose tissue in obesity produces bioactive factors associated with an unprecedented risk of cognitive impairment. Extracellular vehicles (EVs) mediate crosstalk between adipose tissue and central nervous system (CNS) of obese patients results in lipid dysfunction interweaved with numerous signaling pathways to affect CNS. Our study aims to uncover the biomarkers to reflect unbalanced lipid homeostasis during the early phase of Alzheimer’s disease (AD) and investigate novel targets for developing early‐stage AD therapeutics.

Method

Clinically collected human white adipose tissues from 7 lean and 12 obese donors were forward to gas chromatography‐mass spectrometry tandem analysis for lipidomic data acquisition. Principal component analysis, quantitative comparison, and systemic assay were applied to dissect and profile the lipidomic data and identified phosphatidylethanolamine (PE) as the absolute distinguishing index of obese individuals. More than 1,000 bioactive compounds were then screened and analyzed to identify hits that can recover the PE flux balance while simultaneously suppressed the expression of pathology proteins for early stage of AD. We selected a high‐ranking drug hit for validation with in vitro and in vivo systems, including the 3D Alzheimer’s disease in a dish (3DDS) assay and 3xTg and 5xFAD mice. Pathology and behavior assessments were performed to confirm the anti‐AD effect of the repositioned drug.

Result

Our analysis indicates that the disturbance of PE homeostasis can serve as a potential biomarker to discriminate lipidomic dysfunction from healthy controls while PE also can be used to predict the conversion from mild cognitive impairment to AD. We screened our drug compound library and verified a known drug, ebselen, as a potential anti‐AD drug with in silico analysis and high content screening using 3DDS assay and transgenic mouse models. Pathology and behavior assessments with the AD mouse models generated robust evidence supporting the druggability of lipid homeostasis against early‐stage AD.

Conclusion

EVs mediated crosstalk between adipose tissue and CNS of obese patients in promoting cognitive impairment and mechanically disturbing lipid quiescent states in the CNS. Maintaining lipid homeostasis, particularly the PE level in the CNS via pharmacology strategy, would open up a new avenue for combating AD.
Response of the elderly to cognitive intervention through brainHQ training software; LatAm‐FINGERS Mexico
Authors: Martínez‐Galindo Joyce Graciela , Salinas‐Contreras Rosa Maria , Vigil‐Martinez Ana , Sosa‐Ortiz Ana Luisa
Published: December 2023

Background

Computerized training has been used to improve cognitive functioning and has been shown to be effective in a wide range of populations. However, its use in elders can be complicated due to many factors including schooling, motivation, perception of difficulty and unfamiliarity with the technology. For the multidomain dementia prevention program LatAm‐FINGERS, the brainHQ software is being used to perform the cognitive training. The aim of this work is to show the perception of participants about this program.

Method

Twenty‐five urban‐Mexican elders cognitively healthy but with risk factors for dementia, are receiving the cognitive training through brainHQ. They indicated in a 5‐point Likert scale (1 = low, 5 = high) how enthusiastic and fearful they felt to begin the training and how difficult it has been. They also reported if they used a smartphone, a computer or a tablet before and how comfortable they felt using it.

Results

Participants were between 60‐77 years old, with an average age of 70.9 ± 4.7 years old and an average schooling of 9.33 ± 3.5 years, 56% were females. Most of the sample (92%) uses smart technology, mainly smartphones, but only 8% feels very comfortable using it, 55% reports regular comfort and 37% feels not comfortable at all. When asked about brainHQ training, over half of the sample (56%) reported high enthusiasm, 68% reported little fear and more than half reported some degree of difficulty (see figure 1). No significant differences between men and women were found. Using Spearman`s test, a significant negative correlation between schooling and perceived difficulty was found (rho = ‐.68, p = .03), but not between schooling and enthusiasm or fear.

Conclusion

In general, the participants have a good attitude towards the use of brainHQ, although they reported not feeling very comfortable with the use of intelligent technologies, they were enthusiastic about starting the training, and most of them were not afraid. However, the perceived difficulty could hinder training, especially in those with less schooling, therefore, it is important to develop strategies that encourage them to continue with the program to obtain the benefits of computerized training.
The generalizability of proposed reference values for plasma neurofilament light chain in cognitively healthy adults in Thailand
Authors: Rianaree Juthamas , Anukoolwittaya Prakit , Hiransuthikul Akarin , Hemachudha Pasin , Hemachudha Thiravat , Thanapornsangsuth Poosanu
Published: December 2023

Background

Despite being an established biomarker for quantifying neuroaxonal injury in research, the clinical utility of neurofilament light chain (NFL) for assessing individual patients is limited, primarily due to the confounding effect of aging on its levels. Although many studies reported age‐specific cutoff values in neurologically healthy population of European descent in high‐income countries, evidence suggests that the value of neurodegenerative biomarkers may differ in ethnically and socioeconomically underrepresented populations. In this study, we aimed to evaluate the acceptability of the reported NFL cutoff values for local clinical use by examining specimens from healthy Thai cohorts.

Method

This study enrolled participants without neurological disorder and normal cognitive examination from two distinct cohorts in Bangkok, Thailand, ranging in age from 40 to 90 years old. Plasma levels of NFL were quantified using the single molecule array. By utilizing reference data from previous studies (Simrén et al., 2022; Bornhorst et al., 2022), the proportion of participants exceeding the proposed cutoff values were estimated and compared to the expected values. Furthermore, the cohort was stratified by age group and methods similar to prior studies were employed to determine age‐specific cutoff values.

Result

One hundred and three participants were included, comprising of 69 females (67%), with a median age of 65.4 years (interquartile range (IQR): 56.7, 70.3) and a cognitive z‐score of 0.11 (IQR: ‐0.44, 0.63). Using the reference threshold from prior studies, plasma NFL were elevated in 4 participants (3.9%, 95% confidence interval: 1.0‐9.6%) which is consistent with the expected prevalence of 5% (as 95th percentile cutoffs were used). Subsequently, we determined age‐specific plasma NFL cut‐off values for each decade through quantile regression, values ranging from 7.2 pg/mL for 40‐50 years to 58.2 pg/mL for >80 years.

Conclusion

Our initial findings suggest that the previously established cutoffs for plasma NFL may be applicable in Thailand. Nonetheless, further studies with a larger and more diverse sample size may be necessary in order to fully validate the generalizability of these cutoffs and potentially establish more specific thresholds for local use.
Cognitive and sleep evaluation of Myotonic dystrophy type I: A protocol for a case‐control study
Authors: MISHRA RINKLE , Gupta Anu , Garg Divyani , Padma Vasantha , BHATIA ROHIT , Macken William L , Dalal Ashwin , Ahmad Tanveer , Reyaz Alisha , Pitceathly Robert D. S. , Thangaraj K , Hanna Michael G , Vishnu Venugopalan Y ,   ICGNMD Consortium
Published: December 2023

Background

Myotonic dystrophy type 1 (DM1) is one of the most common inherited muscular dystrophies in adults. It is caused by CTG repeat expansions in the 3' untranslated region (UTR) of the DMPK gene on Chromosome 19. Apart from muscle, the disease can involve the eye, heart, brain and endocrine system. Cognitive and sleep disturbances are common but poorly recognized non‐motor manifestations of DM1.

Method

We plan to recruit 30 genetically proven DM1 patients from the prospective MRC‐funded International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) cohort. Neuromuscular phenotyping will be done by the same neuromuscular expert. The muscle strength will be assessed by the Medical Research Council scale and Muscular Impairment Rating Scale (MIRS). We will exclude patients with severe depression. An age and sex‐matched control group of 30 healthy participants will be included to evaluate patients’ cognitive profiles. A comprehensive neuropsychological evaluation (NPS) to assess multiple cognitive domains will be conducted on all patients. A prescheduled sleep history, Epworth Sleepiness Scale (ESS), Pittsburg sleep quality index (PSQI) and full‐night diagnostic polysomnography will be done in all patients.

Result

The outcomes include the NPS domains comparing cognitive impairment compared to controls and the severity and type of sleep apnea (apnea‐hypopnea index [AHI])

Conclusion

The study will investigate the DM1 cognitive profile and its relationship with sleep disturbance using motor scales, neuropsychological assessment and polysomnography.
Anatomical characterization of pT217‐tau in aged rhesus macaque association cortices: Relevance for trans‐synaptic propagation in sporadic Alzheimer’s Disease
Authors: Datta Dibyadeep , Mentone SueAnn , Morozov Yury , van Dyck Christopher H , Arnsten Amy F. T.
Published: December 2023

Background

Tau pathology in Alzheimer’s Disease (AD) targets higher cortical circuits, with evidence that phosphorylated tau propagates from the entorhinal cortex (ERC) to “seed” pathology throughout the neuronal network affecting the dorsolateral prefrontal cortex (dlPFC) with advanced neurodegeneration. Recent discoveries indicate that phosphorylated tau (pT217‐tau) can be captured in CSF and plasma as an early biomarker of ensuing disease. However, the role of pT217‐tau in brain tau pathology is unknown, especially as soluble tau species are dephosphorylated postmortem in humans. Rhesus macaques naturally develop the same qualitative pattern and sequence of tau and amyloid pathology, with neurofibrillary tangles comprised of paired helical filaments, identical to human AD. Perfusion fixed monkey tissue preserves phosphorylation state and allows imaging of molecular location and interactions with nanometer resolution not possible in humans due to postmortem degradation. The current study examined the ultrastructural localization of pT217‐tau in ERC and dlPFC of the aged rhesus macaques, focusing on potential evidence of propagation between neurons, and exposure to the extracellular space.

Method

We used immunohistochemistry paired with high spatial‐resolution immunoelectron microscopy (immunoEM) in aged rhesus macaques (18‐33 years) to localize pT217‐tau in ERC layer II, which show the earliest signatures of tau pathology in AD and dlPFC layer III critical for working memory.

Result

pT217‐tau immunolabeling was predominantly observed in postsynaptic compartments and accumulated on the calcium‐storing smooth endoplasmic reticulum spine apparatus near axospinous asymmetric glutamatergic synapses in dendritic spines. We observed extensive, trans‐synaptic pT217‐tau trafficking between interconnected neurons within omega‐shaped bodies and endosomes, specifically near excitatory, but not inhibitory synapses. Within dendritic shafts, pT217‐tau aggregated on microtubules often in concordance with autophagic vacuoles indicative of neurite dystrophy.

Conclusion

pT217‐tau accumulates in ERC and dlPFC subcompartments known to be the earliest to show pathology in humans. The data provide the first evidence of pT217‐tau trafficking between neurons to “seed” tau pathology in higher brain circuits, potentially interfacing with the extracellular space to become readily accessible and captured in CSF and blood as a robust AD biomarker. Illuminating patterns of neurodegeneration with pT217‐tau could potentially guide earlier intervention of therapeutics that might mitigate tau hyperphosphorylation in AD.
Meeting the needs of care partners of people living with ADRD from historically underserved communities
Authors: Gelmon Sherril B , Reed Jenn Hollandsworth , Colon Anaeliz Mina , Lara Sofia Chapela , Prince Devlin , Dawson Walter D
Published: December 2023

Background

Care and support for people living with Alzheimer’s disease and related dementias (ADRD) is mostly provided unpaid by family, friends, or neighbors. The multiple stressors associated with caregiving often produce substantial care partner burdens. The responsibility for caregiving falls disproportionately on those who rely on and provide unpaid care and support, such as women, individuals of low socioeconomic status, and historically and currently underserved racial and ethnic populations. This study was designed to learn from individuals with lived experience of caregiving, with an emphasis on historically and currently underserved communities, for whom culturally appropriate services for people living with ADRD may be non‐existent or difficult to access.

Method

The study population was care partners of people living with dementia who identify with historically and currently underserved communities. The four communities identified for this study were Black, Indigenous, Asian, and Latin Americans. The team developed strategies for recruitment of focus group participants with input from community‐based organizational leaders who provide ADRD support services in Portland, Oregon. Focus groups were convened with care partners from each of these four communities, as well as one with individuals who identified with other communities.

Result

Care partners from all populations reported lacking supports to help manage care‐related activities. Specific needs and types of supports varied across populations, due to cultural traditions, multiple systemic inequities, and legacies of structural racism. The findings suggest multiple unmet care partner needs across all populations, including information on ADRD, financial and psychological supports, leisure activities, in‐home health, and respite. While many care partners were generally satisfied with their clinical care and involvement in research studies, nearly all identified potential areas of additional supports.

Conclusion

The findings suggest a need for changes in policy and practice to better support care partners of people living with ADRD from underserved populations. Policymakers must take a collaborative approach with care partners in developing and implementing new policies that can improve care partner experiences. To ensure equitable service provision, specific and unique supports for care partners from underserved communities that may have difficulties accessing culturally appropriate services should be offered.
Feasibility of a Non‐pharmacological Intervention for Impaired Financial Capacity in Mild Cognitive Impairment
Authors: Nowrangi Milap A. , Outen John D. , Rosenberg Paul B. , Kim John
Published: December 2023

Background

A pilot trial of financial literacy training (FL) and computerized cognitive training (CCT) was conducted to assess tolerability, feasibility, and the effect on financial capacity (FC) in participants with normal cognition and MCI.

Methods

Cognitively normal and MCI participants were randomized to receive either targeted FL content (N = 4) (Savvy Saving Seniors (“SSS”) workshop) narrated and presented online or the active control CCT (N = 3) (BrainHQ, ©Posit Science) over 6‐weeks. “SSS” participants were instructed to complete 25‐minute sessions twice per week and BrainHQ participants were instructed to complete 60‐minute sessions three times per week.

Results

No significant differences were found between baseline and follow‐up in either group. Table 1. Two out of 3 BrainHQ participants reported that their processing speed had improved and they felt challenged and experienced positive cognitive benefits. Three out of 4 “SSS” participants reported that they felt stimulated and challenged and that the activities were a good use of their time. All “SSS” participants agreed their financial literacy had improved. The most common reported benefits were accomplishment, enjoyment, and increased alertness. The most common reported discomforts were frustration, boredom and one participant complained of eye strain.

Discussion/Conclusions

We demonstrated good efficacy, tolerability, and adherence in delivering FL education and CCT interventions in cognitively normal and MCI participants.
The effect of BDNF Val66Met on memory, CSF total‐tau, CSF ptau181 and CSF Aβ42 in early sporadic Alzheimer’s disease
Authors: Thomson Diny , Rosenich Emily , Maruff Paul , Lim Yen Ying
Published: December 2023

Background

Allelic variation in the brain‐derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer’s disease (i.e., Aβ+ older adults), and pre‐symptomatic dominantly inherited Alzheimer’s disease (DIAD). In DIAD, Met66 was also associated with greater increases in CSF levels of total‐tau and phosphorylated tau (p‐tau181). This study sought to determine the extent to which BDNF Val66Met is also associated with changes in episodic memory and CSF total‐tau and p‐tau181 in Aβ+ older adults in early‐stage sporadic AD.

Method

Aβ+ Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who did not meet criteria for AD dementia were included. Only participants with at least one follow‐up neuropsychological and CSF assessment were included. Episodic memory was measured by the ADNI Memory Composite and CSF samples were collected via lumbar puncture to determine levels of total‐tau, p‐tau181 and Aβ42. A series of linear mixed models were conducted to investigate changes in each outcome variable over 10 years, covarying for CSF Aβ42 (except when examining changes in CSF Aβ42), APOE ε4 status, sex, age, baseline diagnosis and years of education.

Result

When followed over 10 years, Aβ+ Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF total‐tau (d = 0.30) and p‐tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent rates of change in CSF Aβ42 (Table 1; Figure 1).

Conclusion

In non‐demented Aβ+ older adults, Met66 carriers showed greater memory decline and greater increases in both CSF total‐tau and CSF p‐tau181 over 10 years compared to Val66 homozygotes, despite showing equivalent changes in CSF Aβ42. This suggests that Met66 carriage, which is associated with lower BDNF availability and lower neurotrophic support, may confer greater vulnerability to Aβ‐related increases in tau compared to Val66 homozygosity in the early stages of sporadic AD.
Relationship among cerebral Aβ burden, cognitive function and diabetes
Authors: Yi Hyon‐Ah
Published: December 2023

Background

Diabetes mellitus (DM) increases the risk of brain atrophy and dementia. We aimed to reveal whether DM could affect cognitive function and the pattern of amyloid retention in cognitively impaired patients. Also we tried to show whether the existence of DM could cause subcortical structural abnormalities with cognitive dysfunction.

Method

We included consecutive 56 controls and 145 cognitively impaired people (CI, 50 MCI and 95 mild to moderate Alzheimer’s disease (AD) patients). All participants of this cross‐sectional study underwent blood tests, detailed neuropsychological evaluations, 3D T1‐weighted MRI at 3‐Tesla and 18F‐FBB‐PET. We estimated the cerebral Aβ burden quantitatively using volume‐of‐interest analysis and segmented the volumes of six subcortical structures, using FMRIBs integrated registration and segmentation tool Multiple linear regression analysis adjusted for age and gender was performed to evaluate the relationship among cerebral Aβ burden, cognitive function and diabetes.

Result

All subcortical structures, except for the globus pallidus, were smaller in CI compared with controls on adjusting for age and gender. CI with DM was associated with the lower volumes of caudate nucleus and putamen than CI without DM patients. Although there was no significant difference of MMSE score within two groups, the performance of frontal‐executive and memory functions was negatively correlated with subcortical structural volume loss in CI with DM. There was no difference between cerebral Aβ burden using composite SUVR and MMSE score in CI patients. However we found higher amyloid retention in CI with DM patients.

Conclusion

The co‐morbidity of DM in AD patients might cause more specific subcortical volume loss beyond diffuse cerebral atrophy and the resultant cortical‐subcortical dysfunction could make cognitive dysfunction worse, especially frontal‐executive and memory functions. Also, CI with DM patients showed higher cerebral amyloid retention, which might be the accelerating factor of cognitive deterioration.
Allostatic load profiles of stress to predict Alzheimer’s disease: an accessible opportunity to identify risk at early stages
Authors: Souza‐Talarico Juliana Nery , Perkhounkova Yelena , Hein Maria
Published: December 2023

Background

Alzheimer’s disease (AD) can start decades before symptoms appear, yet detection at preclinical stages remains a challenge due to a lack of screening tools that are both accurate and accessible. The multi‐system Allostatic Load index (AL), a stress‐related marker of cumulative biological risk, is associated with β‐amyloid (Aβ), tau proteins, and hippocampal atrophy, potentially linking AL to AD. If this is correct, a low‐cost and readily accessible peripheral blood AL‐based screening tool can offer an opportunity to identify individuals at risk for AD in primary care facilities. Here, we determined the AL profiles that predict the conversion risk from mild cognitive impairment (MCI) to AD by 36 months before diagnosis and associated with hippocampus volume (HV) reduction.

Methods

Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, we analyzed longitudinal data from 385 older adults with MCI at baseline, 12, and 36 months. Blood neuroendocrine (cortisol, LH, prolactin, testosterone) and immunologic (C‐reactive protein,fibrinogen,IL‐13,IL‐16,IL‐18,IL‐3,IL‐6,MCP‐3,MCP4,TNF‐alpha,insulin‐like growth factor) stress‐related biomarkers obtained at baseline and 12 months were transformed into AL indexes to generate the following profiles: 1)Decreasing AL: high at baseline and decrease over 12‐months; 2)Increasing AL: low at baseline, increase; and 3)Sustained High AL: high at baseline, remain high or increase. The ADNI consensus diagnosis determined the AD conversion and brain MRI assessed HV. Models were adjusted for socioeconomic and APOE4 covariates.

Results

41.6% of participants with Sustained High AL converted to AD, while 27.9% with Decreasing profiles remained MCI (p = 0.01). Increasing AL showed higher conversion risk than Decreasing profile (OR: 3.96). Sustained High AL was associated with faster HV reduction (p = 0.04). AL and blood Aβ models were compared for prediction accuracy.

Conclusion

The odds of converting to AD were almost four times higher among participants with Sustained High AL profiles with faster hippocampus reduction than Decreasing AL profiles, suggesting that elevated AL profiles might be a risk factor and a potential mechanism explaining MCI conversion to AD. These findings set the foundation for exploring accessible bio‐behavioral screening tools to sign risk in vulnerable individuals in primary care facilities and refer them to specialized clinics for timely intervention.
Dynamic Changes in Quantitative MRI‐based Biomarkers of Alzheimer’s Disease and Its Association with Cognitive Decline – A Longitudinal Study
Authors: Fan Xiang , Cai Yuan , Zhao Lei , Liu Wanting , Luo Yishan , Shi Lin , Mok Vincent Chung Tong
Published: December 2023

Background

Alzheimer’s disease (AD) resemblance atrophy index (AD‐RAI) is an MRI‐based machine learning‐derived composite index reflecting the multi‐region atrophy severity of AD. We investigated the association between the serial change of AD‐RAI and cognitive progression overtime among cognitive unimpaired (CU) and mild cognitive impairment (MCI) subjects and compared it with other conventional MRI biomarkers (i.e., hippocampal volume (HV), hippocampal fraction (HF), brain parenchymal volume (BPV) and fraction (BPF)), which have been used in the past as imaging biomarkers for AD.

Method

We selected eligible subjects from the Alzheimer’s Disease Neuroimaging Initiative [ADNI] databases and included those aged 55 to 90 years, diagnosed with CU and MCI at baseline with 4‐year follow‐up. We defined converters as those who had significant clinical cognitive progression in the 4‐year follow‐up (i.e., CU to MCI, or MCI to AD dementia), while non‐converters were those who remained stable in the 4‐year follow‐up. A total of 318 subjects, including 203 non‐converters and 115 converters, were recruited in total. The following data were extracted for further analysis: AD‐RAI, HV, HF, BPV, and BPF. We used a linear mixed‐effects model (LMM) and generalized linear mixed‐effects models (GLMM) in SPSS 26.0 to explore the serial changes of the imaging biomarkers and interaction effects over time.

Result

LMM showed that AD‐RAI of converters increased significantly faster than non‐converter over time (P < 0.001), and HV, HF, and BPF of converters decreased significantly faster than non‐converters over time (P < 0.001, P < 0.001, P = 0.004, respectively). Besides, the annualized hippocampal atrophy rate was 1.2% for non‐converter and 3.3% for non‐converter when using the corresponding HV at baseline as the reference. Figures showed the means with error bars of 95% CI of each biomarker. In GLMM, we further found that dynamic AD‐RAI over time had the highest classification accuracy (74.2%) for predicting converters when compared with other imaging biomarkers (≤ 70.2%).

Conclusion

Serial AD‐RAI outperforms other conventional biomarkers in correlating with cognitive progression. It may be used as a surrogate marker for monitoring disease progression or treatment response in AD.
Baseline demographic and clinical characteristics of Longitudinal study of Early onset dementia And Family members
Authors: Jung Na‐Yeon , Kim Hee Jin , Lee Sun Min , Park Kee Hyung , Cho Hanna , Kim Yeshin , Jang Jae‐Won , Kang Heeyoung , Lee Jin San , Kang Sung Hoon , Yoon Soo Jin , Kim Hang‐Rai , Park Kyung Won , CHUNG EUNJOO , Park Young Ho , Jang Hyemin , Lim Jae‐Sung , Kim Geon Ha , Jeong Jee Hyang , Choi Seong Hye , Cho Su Hyun , Kim Seung Joo , Kwon Jay Cheol , Lee Juyoun , Kang Kyunghun , Kim Jaeho , Kim Hee‐Jin , Kim Si Eun , Yi Hyon‐Ah , Park Ji Yoon , Moon So Young , Kim Eun‐Joo
Published: December 2023

Background

Patients with early‐onset dementia (EOD) tend to be different from patients with late‐onset dementia in their rarities, atypical presentations, higher genetic predisposition and diverse etiologies. Although EOD has devastating impacts on patients and families, and their societies, there are few longitudinal observational studies providing sophisticated clinical, biomarkers and genetic information of EOD. Here, we introduce a Longitudinal study of Early onset dementia And Family members (LEAF) which was launched in April 2021.

Method

LEAF was originally designed to enroll at least 400 patients with EOD consisting of patients with Aβ‐positive EOAD (LEAF‐AD), FTD (LEAF‐FTD), and other EOD (LEAF‐Others) with annual follow‐up. Family members with a clear family history have also been enrolled in family cohort. Participants undergo a standardized clinical assessment and brain MRI and amyloid PET. We collect plasma, serum, and DNA for biomarkers and genetic studies. Clinical evaluations and blood collections are annually performed, and brain MRIs are followed up every two years.

Result

We have currently recruited a total of 296 participants with EOD. Aβ‐positive AD spectrum (n = 202) consists of EOAD dementia (82%), MCI (17%), and SCD (1%). FTD (n = 61) includes bvFTD (59%), svPPA (31%) and nfvPPA (10%). Other EOD (n = 33) is composed of leukodystrophy (12%), early onset neurodegenerative dementia other than EOAD, or FTD (66%), and EOD with unclear etiology (22%). The mean age was 60.4 for EOAD, 64.3 for FTD, and 58.2 for other EOD. The prevalence of women was higher in the EOAD and FTD, while the prevalence of men was higher in other EOD. The prevalence of APOE 4 was significantly higher in EOAD than in FTD and other EOD. Family histories of dementia were reported 32% in EOAD, 35% in FTD, and 44% in other EOD. We have, so far, identified 8 pathogenic variants (1 of EOAD, 3 of FTD, and 4 of other EOD) and enrolled two families as family cohort.

Conclusion

LEAF is the first nationwide multicenter, hospital‐based longitudinal study for EOD in Korea, and this will ultimately shed light on prevention and management of EOD and EOD‐related social issues.
Association between Grip Strength and Future Cognitive Function in male
Authors: Soung YongGwon , Kim Yeshin , Hong Jin Yong , Park Kyung Won , Kim Eun‐Joo , Yoon Soo Jin , Jeong Jee Hyang , Yoon Bora , Kim Hee Jin , Lee Jong‐Min , Choi Seong Hye , Jang Jae Won
Published: December 2023

Background

Frailty is an aging‐related syndrome of physiological decline, and has been associated with cognitive function.

Grip strength, could be used as a marker for frailty and older adult health status. Frailty has been associated with cognitive function. However, its mechanism has not been fully investigated.

We aimed to investigate the association between grip strength with cognitive function.

Method

We prospectively recruited 184 participants who underwent a grip strength test, cognitive function test. Data was collected from the Korean Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study which started in 2014. Frailty was represented by grip strength (kg). Cognitive function was assessed using Mini‐Mental State Examination(MMSE) and The Consortium to Establish a Registry for Alzheimer’s Disease‐K(CERAD‐K).

Multiple linear regression models were used to analyze the associations between grip strength and cognitive function. We adjusted age, gender, years of education, and BMI.

Result

Among 184 participants, 119 (64.7%) were cognitively normal. 32 (17.4%) were diagnosed with mild cognitive impairment and 33 (17.9) were a probable AD. Mean age of the participants was 69.4 (8.2) years. 43.5% of the participants were female. Grip strength was positively associated with MMSE at 1 year later in male (ß = 0.182 p = 0.004). In terms of cognitive domain, verbal and visual memory, language, visuospatial, and frontal‐executive functions were related to grip strength (vebal memory: ß = 0.037 p = 0.022, visual memory: ß = 0.046 p = 0.002, language: ß = 0.055 p<0.001, visuospatial: ß = 0.068 p = 0.0213, frontal‐executive: ß = 0.050 p<0.001).

Conclusion

Weakness of grip strength is associated with decreased future cognitive function. This support concept that grip strength could be a marker for cognitive decline.
Longitudinal Effective Connectivity Changes in the Default Mode Network in Young‐Onset Alzheimer’s Disease Variants
Authors: Kantar Mahasen El , Novelli Leonardo , Schott Jonathan M , Razi Adeel
Published: December 2023

Background

Young‐Onset Alzheimer’s disease (YOAD), a rare form of Alzheimer’s disease occurring before the age of 65, presents as a typical amnestic variant (memory problems) and posterior cortical atrophy ([PCA], visuospatial problems). The DMN is a core resting state network that increases activity during rest but decreases activity during external focused tasks (Buckner et al., 2008). Whilst functional connectivity studies demonstrate altered default mode network (DMN) connectivity in YOAD, the directional influence of one brain region on another, i.e., effective connectivity, remains uncharacterised (Lehmann et al., 2013).

This study investigated the DMN’s effective connectivity changes from baseline to 12 months in amnestic and PCA variants. The association between connectivity and cognition was also examined at follow‐up.

Method

Resting‐state functional MRI data of 28 amnestic and 14 PCA patients was included.Regions of interest included: medial prefrontal cortex, posterior cingulate cortex, bilateral angular gyrus and bilateral hippocampus. Spectral dynamic causal modelling (Friston et al., 2014) and Parametric Empirical Bayes (PEB, Friston et al., 2016) were used to infer individual and group level effective connectivity, respectively. PEB was also used to examine the association between connectivity and cognition at follow‐up. Cognition was measured via the Mini‐Mental State Examination (MMSE).

Result

In the amnestic variant, mostly decreased longitudinal effective connectivity was found, suggesting network dysconnections (disrupted brain connections; Delbeuck, 2013). In the PCA variant, a combination of increased and decreased longitudinal effective connectivity was found, suggesting early DMN changes. These changes may indicate early Alzheimer’s disease‐like brain and cognitive changes (Zhong et al., 2014). The PEB analysis demonstrated associations between the DMN effective dyconnections and cognition, illustrating brain‐behaviour dependencies.

Conclusion

The findings of this study indicate diverse longitudinal DMN effective connectivity patterns across YOAD variants. Our findings support the model of amnestic Alzheimer’s disease and PCA onset and progression, whereby the amnestic variant targets the DMN connectivity early, but PCA targets the network in later stages (Seeley, 2017). This accounts for differences in memory deficits amongst variants. Long term clinical implications of this study include the increased knowledge of YOAD network spread and its effect on cognition, which may ultimately contribute to drug development and network‐based biomarkers.