bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation and utility of plasma neurofilament light as a biomarker for vascular cognitive impairment
Authors: Kautz Tiffany F , Mathews Julia J , Parent Danielle , Sudduth Tiffany L , Liu Qianqian , Wiedner Crystal , Wang Chen‐Pin , Mbangdadji Djass , Bis Joshua C , Sagare Abhay P , Beiser Alexa S , Pottanat George , Aparicio Hugo J , Thompson Jeffery F , Erickson Kelsey , Jin Lee‐Way , Gonzales Mitzi M , Ghosh Saptaparni , DeCarli Charles S. , Wang Danny JJ , Wilcock Donna M , Rosenberg Gary A , Lu Hanzhang , Kramer Joel H. , Launer Lenore J. , Fornage Myriam , Mosley Thomas H , Maillard Pauline , Gudnason Vilmundur , Singh Herpreet , Helmer Karl G , Schwab Kristin , Greenberg Steven M , Tracy Russell P. , Kivisäkk Pia , Seshadri Sudha , Satizabal Claudia L
Published: December 2022

Background

Neurofilament light chain (NfL) is a broad marker of neuroaxonal injury that is elevated in the CSF in those with vascular cognitive impairment and dementia (VCID). Blood and CSF levels highly correlate, making it an attractive peripheral marker for VCID pathology. As part of the MarkVCID consortium, we sought to evaluate the instrumental validity of plasma NfL using the Quanterix Simoa platform and assess its validity for risk stratification in clinical trials of VCID.

Method

Plasma NfL was measured using HD‐X and HD‐1 Simoa instruments. For instrumental validation, we used samples from the MarkVCID consortium to evaluate intra‐ and inter‐plate reliability, test‐retest repeatability, and inter‐site reproducibility. We used linear regression models to assess the association of NfL with general cognitive function (GCF) as the primary outcome. In secondary analyses we assessed associations with white matter hyperintensities (WMH), an established small vessel disease marker. Models were adjusted for potential confounders. The clinical validation included established cohorts from the CHARGE consortium (i.e., CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196). Additional analyses are underway in MarkVCID sites.

Result

We found low coefficients of variation (average CV<12%), high inter‐site reproducibility (overall ICC = 0.93) and high repeatability in blood samples drawn within 30 days (ICC=0.968). There was high consistency across Quanterix instruments (HD‐X and HD‐1; R2≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in CHARGE cohorts (meta‐analysis β=‐0.11; [95% CI ‐0.06; ‐0.17]), the UKY ADRC (β=‐0.16; [95% CI ‐0.27; ‐0.05]) and the UCD ADRC (UCD: β=‐0.28; [95% CI ‐0.48; ‐0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in CHARGE cohorts and the UCD ADRC (P<0.01).

Conclusion

Our results suggest plasma NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi‐site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH across independent samples, providing evidence that plasma NfL can be a useful biomarker for stratification in VCID trials.
Blood‐based biomarkers for neurodegeneration in non‐Hispanic Black and White older adults: Results from the Einstein Aging Study (EAS)
Authors: Engeland Christopher G , Katz Mindy J. , Qin Jiyue , Wang Cuiling , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Graham‐Engeland Jennifer E , Pavlovic Jelena , Derby Carol A. , Lipton Richard B.
Published: December 2022

Background

With recent technological advancements, neurodegenerative biomarkers (NDBMs) in blood plasma now produce results comparable to those obtained in cerebrospinal fluid, supporting the possibility of less invasive and costly determination of risk status for Alzheimer’s disease (AD). However, most research with these novel biomarkers has been in predominately non‐Hispanic (NH) White samples. Hence, little is known about distributions of these biomarkers among NH Blacks despite their elevated risk for AD.

Method

Blood plasma samples were obtained from 254 older participants in the EAS who were free of dementia (mean age [SD]=77.6[4.9] years; range 70‐93 years; 66.1% female; 46.5% NH Black, 53.5% NH White; 27.2% mild cognitive impairment (MCI) as defined by Jak/Bondi criteria). AD biomarkers [β‐amyloid (Aβ40, Aβ42), pTau181], along with biomarkers of generalized neuronal damage and astrocyte activation [neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), respectively] were quantified in blood using Single molecule array (Simoa) assays on HD‐X Analyzers (Quanterix, Billerica, MA). Comparisons of NDBMs between groups were conducted using Wilcoxon rank sum test in unadjusted analyses, and linear regression models adjusting for covariates including age, gender, education, diabetes history, myocardial infarction, and hypertension.

Result

We observed lower overall levels of NDBMs in NH Blacks vs. NH Whites regardless of MCI status (Aβ40, Aβ42, and NfL (ps<0.05) see Table 1). Among NH Whites, those with MCI had higher Aβ40, Aβ42, and NfL (ps<0.05) compared to cognitively normal individuals; no significant differences by MCI status were observed among NH Blacks (not shown). The above race differences in Aβ40, Aβ42, and NfL remained evident across the full sample in linear regression analyses (adjusted for MCI status and covariates). When stratified by MCI status, race differences remained evident for NfL (regardless of MCI status); for Aβ40, race differences were evident among individuals with MCI only (see Table 2). Although individual analytes differed, the Aβ42/Aβ40 ratio did not differ by race.

Conclusion

NH Blacks exhibited lower overall levels of NDBMs compared to NH Whites, and associations between NDBMs and MCI were in the expected directions only among NH Whites. These race differences suggest that future work is needed to develop generalizable norms for blood‐based NDBMs.
Cognitive impairment one year after hospitalization due to COVID‐19 infection in Brazil: preliminary results.
Authors: Sousa Danielle Calil , Leite Arnaldo Santos , Faria Barbara Caroline Dias , Sacramento Luiz Gustavo Guimarães , Marinho Carolina Coimbra , Caramelli Paulo
Published: December 2022

Background

Persistence of symptoms or development of new symptoms after SARS‐CoV‐2 infection is an increasingly recognized problem and the long‐term post‐COVID‐19 outcome and the effects on cognitive function remain poorly understood. This study aims to investigate the long‐term cognitive effects and impacts of COVID‐19 with a special focus on a population with low education and low socioeconomic status.

Method

Cross‐sectional cognitive assessment of participants with severe forms of Covid‐19 one year after hospital admission. Until now, 187 of 322 patients underwent TICS‐M for brief telephone cognitive screening one year after hospitalization for COVID‐19 in 3 public hospitals in Belo Horizonte, Brazil. This sample was divided into two groups according to scores on the TICS‐M screening test: with or without cognitive impairment. 26 participants were selected by convenience for neuropsychiatric assessment, namely 13 with abnormal TICS‐M scores (cases) and the other 13 controls. They were submitted to the following tests and scales: Addenbrooke’s Cognitive Examination‐Revised (ACE‐R), Symbol Digit Modalities Test (SDMT), Free and Cued Selective Reminding Test (FCSRT‐IR), Hospital Anxiety and Depression Scale (HADS) and Impact of Events Scale‐Revised (IES‐R).

Result

There were no significant differences between groups for age, sex, educational level, need for intensive care unit or use of anticholinergics or sedatives. Although the comparison of SDMT between the groups showed no statistical difference (p = 0.999), all participants showed lower performance compared to normative data. Cases presented lower scores than controls in ACE‐R total (p = 0.034) and in the subdomains Attention and Orientation (p = 0.002), as well as in delayed total recall of the FCSRT‐IR (p = 0.039). Moreover, participants with lower HAD‐D scores had worst performance in Attention and Orientation subdomains of the ACE‐R (p = 0.003).

Conclusion

Our study shows impairment in global cognition, attention, orientation and episodic memory in individuals previously hospitalized for COVID‐19 infection who presented low scores on TICS‐M. Performance in processing speed tests was impaired among both groups in relation to normative data. Cognitive and mood analyses after COVID‐19 infection can provide information for improving healthcare of these individuals.
Juvenile concussion results in accelerated aging:A diffusion MRI investigation
Authors: Lee Jeong Bin , Grande Beatriz Rodriguez , Fournier Marie‐Line , Clément Tifenn , Trotier Aurélien J , Miraux Sylvain , Marchi Nicola , Badaut Jerome , Obenaus Andre
Published: December 2022

Background

Juvenile mild traumatic brain injury (jmTBI) has the potential to elicit cognitive, adaptive, and socio‐behavioral decrements. Unknown is how early life concussions can lead to enduring effects into late adulthood. Studying jmTBI progression from an early concussive event to long term deficits in adulthood is critical for outcome prediction and the development of appropriate treatments. We hypothesized that a single jmTBI leads to an altered brain maturation, thereby producing temporally evolving microstructural deficits that eventually lead to late‐in‐life cognitive and behavioral deficits.

Methods

We investigated the long‐term effects of jmTBI in C57Bl6 mice at postnatal day 17 and mapped the temporal evolution of alteration in long‐term behavior and cognitive outcomes. Diffusion‐tensor MRI (DTI) and structural MRI were examined at 7 temporal epochs from 1 to 18mo post‐concussion. Regional MRI tissue analysis was performed using the AMBC mouse atlas. Confirmatory immunohistochemistry was also undertaken.

Results

jmTBI led to increased glial fibrillary acidic protein (GFAP) and neurofilament‐light (NFL) in blood samples and impaired spatial learning and memory was evident at 18mo. Extensive DTI longitudinal analysis from 1 to 18mo post‐concussion revealed that jmTBI produced temporally dependent deficits that were concurrent with behavioral impairments. DTI findings were concentrated at earlier timepoints (1‐3 m) and were correlated 10 behavioral deficits at 18m.

Conclusion

We demonstrate that a single juvenile concussion early in life leads to lasting behavioral impairments later in life and which are linked to early regional tissue deficits. Our work not only establishes that juvenile concussions are chronic in nature with the potential to produce long‐lasting effects but provides an unprecedented insight into how an early concussions may produce adverse effects later in life.
Contribution of astrocytic MMP9 toward progression of VCID pathology
Authors: Early Alexandria N , Weekman Erica M , Lee Tiffany , Wilcock Donna M
Published: December 2022

Background

Vascular contributions to cognitive impairment and dementia (VCID) is one of the leading causes of dementia. High levels of plasma homocysteine or hyperhomocysteinemia has been characterized as a risk factor for VCID however, the mechanism underlying the connection between hyperhomocysteinemia and development of VCID pathology remains elusive. I hypothesize that hyperhomocysteinemia initiates a pro‐inflammatory cascade that increases the activity of MMP9 causing both perivascular astrocytes to dissociate from their vessels and initiating the degradation of endothelial cell tight junction proteins, leading to blood brain barrier dysfunction and the progression toward VCID pathology.

Method

For in vivo studies, C57BL6 WT and MMP9KO mice were placed on a control diet or a diet deficient in folate, vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia for 4, 8, 12, and 16 weeks. For in vitro, experiments, primary astrocytes from WT and MMP9KO mice were treated with a 50μM homocysteine stimulus or an inflammatory stimulus (TNF‐a, IL‐1b and C1q) for 48 hours and the conditioned media was collected. This homocysteine or inflammatory astrocyte conditioned media was then used to treat WT endothelial cells. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes while histology was used to identify changes in astrocytic end‐feet proteins, tight junction proteins, vascular density and microhaemorrhages. Both gel and in situ zymography were used to assess proteinase activity of MMP9 and related gelatinases. Western blots were used to investigate substrates of MMP9 including claudin, occludin and β‐dystroglycan. Behaviour was assessed using rotarod, novel object recognition and spontaneous alternation testing. Transendothelial electrical resistance and sodium fluorescein assays were used to measure the integrity of endothelial cell tight junctions in vitro.

Result

Studies are underway to examine changes in cognition, microhaemorrhages, neuroinflammation, astrocyte end‐foot integrity, tight junction protein integrity and activity of MMP9.

Conclusion

Collectively, our findings suggest that astrocytic MMP9 may play an integral role in the mechanism associating homocysteine induced neuroinflammation with vascular pathogenesis leading to VCID, highlighting this pathway as an important subject for future study.
Role of extracellular vesicles in early synaptic dysfunction in AD
Authors: Prada Ilaria , Gabrielli Martina , Joshi Pooja , Falcicchia Chiara , D'Arrigo Giulia , Rutigliano Grazia , Tonoli Elisa , Battocchio Elisabetta , Zenatelli Rossella , Tozzi Francesca , Verderio‐Edwards Elisabetta , Radeghieri Annalisa , Arancio Ottavio , Origlia Nicola , Verderio Claudia
Published: December 2022

Background

Synaptic dysfunction is an early mechanism in Alzheimer’s Disease (AD) which involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. We hypothesised that large extracellular vesicles (EVs) released by microglia exposed to and carrying Aβ42 (Aβ‐EVs) may be responsible for these early events in AD.

Method

Combining optical manipulation with time lapse imaging we placed single Aβ‐EVs and ctrl‐EVs (released by microglia not exposed to Aβ) on axons or dendrites of RFP‐positive cultured neuron to test both the dynamics of their interaction with neurons and their effects on the synapse. Then, EVs were stereotaxically injected into the mouse entorhinal cortex (EC), one of the most vulnerable regions in AD, and long‐term potentiation (LTP) was measured in the EC and in its main target region, the dentate gyrus of the hippocampus (DG), through field potential extracellular recordings in cortico‐hippocampal brain slices. Finally, taking advantage of high‐resolution accurate‐mass spectrometry SWATH™‐MS, we investigated the molecular differences between ctrl‐EVs and Aβ‐EVs.

Result

Aβ‐EVs were able to move along the axonal surface more efficiently than ctrl‐EVs and predominantly in an anterograde direction. They locally altered dendritic spine morphology in vitro and impaired LTP in vivo. One hour after injection in the EC, LTP was impaired in the EC of brains injected with Aβ‐EVs but not ctrl‐EVs. However, 24h after Aβ‐EV injection, LTP was impaired also in the DG, indicating a spreading of synaptic dysfunction between the two connected regions. Results were reproduced using large EVs released by microglia exposed to naturally secreted Aβ oligomers, whereas neither Aβ alone nor inflammatory EVs devoid of Aβ were able to propagate LTP impairment. Importantly, when Aβ‐EV motility was limited by annexin‐V coating, no propagation of LTP deficit occurred along the EC‐DG circuit. Proteomic analysis provided insights into the possible molecular mechanisms underneath Aβ‐EV extracellular motion at the neuronal surface.

Conclusion

Our data provide evidence of the involvement of microglial EVs in early synaptic dysfunction, through a new mechanism ‐ extracellular motion at the neuronal surface ‐ not implying EV internalization, paving the way for novel therapeutic strategies.
Development and systematic evaluation of high resolution PD‐weighted, T2‐weighted, and T2 map templates of the MIITRA atlas for use in studies on older adults
Authors: Ridwan Abdur Raquib , Niaz Mohammad Rakeen , Wu Yingjuan , Zhang Shengwei , Bennett David A , Arfanakis Konstantinos
Published: December 2022

Background

Atlas based MRI investigations involving PD‐weighted (PDw), T2‐weighted (T2w) MRI sequences on older adults typically utilized younger adult templates such as those of the ICBM. Additionally, a thorough quantitative assessment of how available standardized PDw and T2w templates perform on aging population has not yet been performed. Here a new standardized high resolution PDw, T2w and T2 map templates of the MIITRA atlas dedicated for studies on older adults was developed using concepts of super‐resolution and sparse‐representation and compared to other available standardized templates in terms of image quality, inter‐subject spatial normalization accuracy and representativeness of the older adult brain.

Method

T2‐weighted multi‐echo spin‐echo brain MRI (0.5mmx0.5mmx3mm isotropic, TE=20,40,60,80,100ms) and its corresponding T1‐weighted (isotropic 1mm) data obtained from the 400 non‐demented older adults (65‐95 age range, male:female=1:1) participating in the construction of the MIITRA atlas were used in this work. Additionally, subject T2 maps were constructed by fitting the T2 decay equation. The template construction involved reconstruction of high resolution voxels of T2‐weighted data utilizing nonlocal super‐resolution upsampling technique, mapping of each of the five echo (TE=20,40,60,80,100ms) separately using combined iterative T1‐weighted and DTI spatial normalization based transformations on a super‐resolution grid followed by patch‐based sparse representation to construct our T2‐weighted templates of the MIITRA atlas (Fig.1).The first echo PD‐weighted and the third echo T2‐weighted templates were compared to other available templates in terms of image sharpness and inter‐subject spatial normalization accuracy achieved when used as references for normalization of 30 ADNI PD‐weighted and T2‐weighted participants.

Result

The new PD and T2 weighted templates of the MIITRA atlas demonstrated higher image sharpness compared to the other templates, as exhibited by larger high spatial frequency content in the normalized power spectra (Fig. 2A,B,C,D). Inter‐subject spatial normalization was higher when using the new templates compared to the other templates (Fig.3,4). The new templates required the least spatial deformation for normalizing ADNI data (Fig.5A,B).

Conclusion

We conclude that the new PD‐weighted and T2‐weighted templates of the MIITRA atlas are characterized by superior image quality, require lower deformation and allow for higher spatial normalization accuracy for use in studies on older adults such as the ADNI datasets.
IMPROVING DEMENTIA CARE THROUGH DIGITAL CAREGIVER EMPOWERMENT: DURABLE CLAIMS‐BASED OUTCOMES DEMONSTRATED IN A PRAGMATIC REAL‐WORLD TRIAL
Authors: Soenksen Dirk , Kleinman Nathan
Published: December 2022

Objective

The Ceresti Digital Caregiver Empowerment Program (DCEP) was deployed to 164 family caregivers of Medicare Advantage patients with ADOD. The primary objective of this pragmatic trial was to demonstrate that increasing the knowledge, skills and confidence of family caregivers (e.g., spouses, adult children) via personalized education, proactive coaching and remote monitoring—delivered via an app on a dedicated tablet computer—reduces avoidable patient hospitalizations. Durability of claims‐based outcomes was also studied. Caregiver engagement, caregiver satisfaction and caregiver mental health were also tracked

Methods

Patients were included in the claims analysis if their caregiver was enrolled in the DCEP for at least 45 days. Patient outcomes were compared to outcomes from a 3:1 propensity matched comparison group, post‐index, from the DCEP start date to the end of claims. Comparison group members were matched to enrollees on demographics, pre‐index utilization and costs, and other factors, including the patient’s frailty index. The first 30‐days post‐index were deemed a “transition” period. The impact of the DCEP was determined by comparing the 6‐month pre‐index averages to outcomes from the 30‐day post‐index period using the “difference‐in‐differences” approach (Figure 1).

The index date for program enrollees was their DCEP start date. For matched comparison group patients, the index date was the program start date of the enrollee to whom the comparison group member is matched. The DCEP was personalized for each caregiver/patient dyad using predictive models applied to claims data.

Results ‐ Patient Outcomes

Table 1 summarizes statistically significant (p‐values < 0.05) monthly reductions in utilization and costs for patients enrolled > 45 days, and enrolled high utilizers enrolled > 45 days (PMPM = per member/patient per month). High utilizers are patients with at least one hospitalization or two ED visits in the prior 24 months. Results were durable through 9 months post‐index (Figure 3).

Conclusions

Empowering family caregivers of patients with ADOD in a personalized DCEP provides durable reductions in patient hospitalizations and medical costs.
APOE genotype alters the lipid droplet proteome and modulates droplet dynamics
Authors: Smith Cathryn T , Friday Cassi , Devanney Nicholas , Allenger Elizabeth J. , Cornea Ana Maria L/K , Gordon Scott , Johnson Lance A
Published: December 2022

Background

The microglial immune response is a significant contributor to Alzheimer’s disease (AD) pathophysiology and neurodegeneration. Aging microglia accumulate lipid droplets (LDs), have high levels of reactive oxygen species, secrete pro‐inflammatory cytokines, and are defective in phagocytosis. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late‐onset AD, and is associated with heightened neuroinflammation and increased LD formation. We hypothesize E4 microglia have increased LD formation under basal conditions and a higher capacity to form LDs under stress, resulting in greater pro‐inflammatory cytokine production. We characterized LD development in microglia in the context of APOE genotype and analyzed LD surface proteins and lipid content from control and lipopolysaccharide (LPS) stimulated ApoE3 and ApoE4 mice.

Method

Primary microglia were isolated from mice expressing human ApoE3 and ApoE4. Microglia were exposed to 250uM oleic acid (OA), 10ug/mL LPS, OA+LPS, dead N2A cells, or dead N2As+LPS. ApoE3 and ApoE4 expressing mice were injected with saline (control) or LPS (5mg/kg) and perfused at 24h. Livers were extracted, the LD enriched supernatant fraction was collected after centrifugation, and proteomic and lipidomic analyses were performed.

Result

Primary microglia from ApoE4 mice accumulated more LDs at baseline, with exogenous OA, LPS stimulation, and N2As as a percentage of E3 control across multiple experiments (E3 v E4 p‐values: baseline, 0.0317; LPS, 0.0032; OA, 0.0277; N2A, 0.0192). Western blots on LD fractions confirm LD enrichment by surface protein, PLIN2, along with increased expression of PLIN2 (i.e. more LDs) in E4 LPS mice. Proteomics reveal LD fractions from E4 mice are enriched for proteins involved in innate immunity, while E3 LDs are enriched for proteins involved in lipid b‐oxidation.

Conclusion

E4 microglia accumulate more LDs compared to E3 microglia under all conditions tested. The proteomic profile of E4 liver LDs support the hypothesis that E4 expression increases inflammation under basal conditions, and upon stimulation, causes a more robust response. Increased LD formation is present in non‐aged, non‐diseased E4 cells, suggesting preclinical dysfunction associated with the highest risk APOE genotype. A better understanding of LD dynamics within these cells and their functional implications can provide targets to improve E4‐related outcomes.
Association of long‐term exposure to air pollution and dementia risk: the role of homocysteine, methionine
Authors: Rizzuto Debora , Hooshmand Babak , Vetrano Davide Liborio , Wu Jing , Grande Giulia
Published: December 2022

Background

Growing evidence associates long‐term exposure to air pollution with dementia. The biological mechanisms behind this association are yet unclear. We aimed to investigate the role played by homocysteine and methionine in the association between air pollution and dementia.

Method

Data from 2512 dementia‐free individuals were derived from the ongoing Swedish National study on Aging and Care in Kungsholmen (SNAC‐K). Two major air pollutants (particulate matter ≤2.5µm, PM2.5 and nitrogen oxides, NOX) were assessed yearly from 1990, using dispersion models for outdoor levels at residential addresses. The hazard of dementia was estimated using Cox models. The potential mediating or modifying effects of homocysteine and methionine were analysed through the counterfactual approach.

Result

Over a mean follow‐up time of 5.18 years (SD: 2.96), 376 incident dementia cases were identified. We observed an up to 70% increased hazard of dementia per unit increase in PM2.5 levels during the previous five years (HR: 1.71; 95%CI: 1.33‐2.09). We found that approximately 50% (95%CI: 8.9‐97.7) of the total effect of PM2.5 on dementia was due to mediation (7.5%; 95%CI:1.8%‐13.3%) and/or interaction (50%; 95%CI: 5.0%‐ 94.9%) with homocysteine. Higher levels of methionine reduced the dementia risk linked to PM2.5 exposure by 31% (HR: 0.69; 95% CI: 0.56 – 0.85). No statistically significant mediation effect was found through methionine in the association between PM2.5 and dementia. Similar but attenuated results have been obtained for NOx.

Conclusion

High levels of homocysteine enhanced the dementia risk associated with air pollution exposure, whereas high methionine reduced such a risk.
Stable Isotope Labeling Kinetics (SILK) tracing of neurofilament light in stem cell‐derived neurons
Authors: Giovannucci Tatiana A. , Leckey Claire A. , Bateman Randall J. , Zetterberg Henrik , Mills Kevin , Wray Selina , Paterson Ross W.
Published: December 2022

Background

Neurofilament light polypeptide (NfL) is a basic component of intermediate filaments in neurons that is released from damaged and/or degenerated neuronal axons. As such, NfL levels in CSF and serum are elevated in several neurodegenerative diseases, and have been proposed as a promising biomarker of axonal damage. However, whether NfL’s extracellular release results from passive events or active mechanisms remains largely unknown. Kinetic labeling at the step of protein translation can inform about active translation vs. passive release processes and provide protein metabolism half‐lives and rates of production and clearance.

Method

Our aim was to develop a method to study NfL turnover rates using stable isotope labeling kinetics (SILK) in human induced pluripotent stem cell (iPSC)‐derived neurons. We added 13C6‐leucine, the tracer, to the neuron cultures (“pulse”) for four weeks, followed by medium exchange with 12C6‐leucine, the tracee, for an additional four weeks (“chase”). Samples were collected during both the pulse and chase phases of the experiment. 13C6‐leucine incorporation and the levels of labeled NfL in cell lysates and conditioned media from two independent neuronal inductions were analyzed by ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) and the tracer‐to‐tracee ratio (TTR) and mole percent excess (MPE) calculated.

Result

We detected ten leucine‐containing peptides unique to NfL in neuronal cell lysates, which are present within the rod‐domain of the protein. These peptides showed different rates of 13C6‐leucine incorporation (reaching up to 69% MPE).

Conclusion

Preliminary data on the monitoring of these peptides suggest that NfL is turned over at a slow rate in iPSC‐. Tracking of both intracellular and extracellular NfL in neurons derived from healthy control individuals, as well as cells with mutations implicated in neurodegenerative diseases, are expected to shed light into the dynamics of NfL turnover in both physiological and pathological conditions. This will be critical for interpreting NfL in response to disease‐modifying therapies.
Altered HDL Cholesterol Efflux Capacity and LCAT Activity is APOE‐Specific in Alzheimer Disease and Mild Cognitive Impairment Patients
Authors: Hong Brian V. , Agus Joanne , Zheng Jack Jingyuan , Lebrilla Carlito B. , Jin Lee‐Way , Maezawa Izumi , Harvey Danielle J. , Zivkovic Angela M.
Published: December 2022

Background

High‐density lipoproteins (HDL) in circulation perform a crucial role in maintaining cholesterol homeostasis by removing cholesterol from peripheral tissues for excretion. High HDL has been linked with a lower risk of developing Alzheimer’s Disease (AD). However, the concentration of HDL only partially accounts for the variation in the ability of HDL to perform their primary function to efflux cholesterol. Apolipoprotein E (APOE) is the strongest genetic risk factor for AD, and its role in regulating cholesterol is implicated in AD. However, the complex relationship between APOE genotype and the function of peripheral HDL in AD patients remains largely unknown.

Method

We isolated HDL from plasma of 194 age‐ and sex‐matched, ApoE genotyped participants (non‐demented controls, n = 83; mild cognitive impairment, n = 40; AD dementia, n = 71) using two‐step flotation ultracentrifugation, followed by size exclusion chromatography. HDL cholesterol efflux capacity (CEC) and lecithin‐cholesterol acyltransferase (LCAT) activity were measured. We further explored the relationships between HDL functional capacity and cognitive, functional, and imaging scores.

Result

Regardless of diagnosis, ApoE3/E4 carriers had significantly lower CEC index (p = 0.003) and LCAT activity (p < 0.001) vs. ApoE3/E3 carriers. When participants were stratified by APOE genotype and diagnosis, ApoE3/E3 MCI patients had significantly lower CEC index than controls (p = 0.042). In contrast, the CEC index of ApoE3/E4 AD patients was paradoxically increased compared to controls (p = 0.016). ApoE3/E3 MCI and AD patients had lower LCAT activity than controls (p = 0.012 and p = 0.004, respectively), but there were no differences in LCAT activity in ApoE3/E4 participants by diagnosis group. LCAT activity was positively correlated with verbal memory score (p = 0.033) and negatively correlated with clinical dementia rating (p = 0.025).

Conclusion

To our knowledge, our study revealed for the first time an APOE genotype‐dependent alteration in peripheral HDL functional capacity among AD and MCI patients compared with non‐demented controls and an association between HDL LCAT activity and cognitive and functional scores.
Evolution of awareness for cognitive decline across several cognitive domains in stable vs clinically progressing participants.
Authors: Gagliardi Geoffroy Pierre , Vannini Patrizia , Mimmack Kayden J.
Published: December 2022

Background

Awareness of memory impairment has been shown to vary across the AD spectrum with an initial heightened awareness at the preclinical stage, and a subsequent loss of awareness with AD progression (Hanseeuw et al.,2020). Whether there are potential differences in the evolution of awareness for cognitive domains other than memory is unknown. In this study, we investigated the evolution of awareness in visuospatial, language, planning, divided attention and organization in cognitively older adults that later progressed versus those who remained stable.

Methods

Our study included 621 cognitively normal (CN) ADNI participants (Tab1). Individuals were considered Stable or Progressors (n = 147) on the basis on the Clinical Dementia Rating scale global score (stable: scores at first and last observation both 0, progression:last score≥0.5). Cognitive complaints were recorded using the Everyday Cognition (ECog) questionnaire, using both participant’s and informant’s average complaints in each of the six subscales: divided attention, language, memory, organization, planning and visuo‐spatial. Generalized linear mixed‐effect models were run to predict complaints within each subscale, using time, the source of complaint (informant vs participant), and their interaction as independent variables, adjusting for age, gender and education. Jonhson‐Neyman Points (JNP) were computed for significant interactions, and simple slopes analyses were performed.

Results

Stable participants displayed a similar evolution of both informant and participant complaints (Fig1, left panels). Among progressors, all models showed significant interactions with participants expressing greater, and subsequent lower complaints than informants (Fig1, right panels). JNP analyses revealed that, while on some subscales this transition occurred only after/close to progression (i.e., divided attention, language, memory and organization), it could be observed years before progression in others (i.e., planning and visuo‐spatial).

Conclusions

Progressive participants expressed greater, and then lower complaints as compared to their informant, demonstrating a transition from heightened to reduced awareness over time. Our results attest that, while most studies are focusing on memory awareness, other domains might also show early changes in awareness. This advocates for including the informant’s appraisal in the examination process, as well as to expand the focus to other cognitive abilities.
Linking histology to post‐mortem 7T MRI measures of neurodegeneration
Authors: Sadaghiani Shokufeh , Ravikumar Sadhana , Ittyerah Ranjit , Lim Sydney A , Chung Eunice , Bedard Madigan L , Xie Long , Das Sandhitsu R. , Schuck Theresa , Grossman Murray , Lee Eddie B , Tisdall Dylan M , Prabhakaran Karthik , Detre John A. , Mizsei Gabor , Trojanowski John Q , Irwin David J. , Wisse Laura EM , Wolk David A. , Yushkevich Paul A.
Published: December 2022

Background

Neurodegenerative disorders are associated with different pathologies that often co‐occur and have differential contribution to the pattern of cognitive impairment. The majority of these pathologies cannot be detected or measured by in‐vivo methods; therefore, recognition of the topographic patterns of them and association with MRI findings may provide probabilistic non‐invasive biomarkers. We investigated the association of cortical and medial temporal lobe subregional thickness measured from postmortem MRI and semi‐quantitative pathologic measures in order to provide a methodological approach for linking pathological and radiological measures.

Method

22 brain hemispheres from donors with Alzheimer’s disease (AD) spectrum diagnosis were included. T2‐weighted images were obtained on 7 Tesla scanner (0.28 mm isotropic) and patches of cortex around 16 anatomical locations were segmented using semi‐automated active contour segmentation in ITK‐SNAP. Immunohistochemistry evaluation was performed using previously validated antibodies to detect amyloid‐β, phosphorylated tau, phosphorylated TDP‐43 deposits and pathological conformation of α‐synuclein on contralateral hemispheres. Neuronal loss was visually assessed. Thickness measures at each location were associated with pathology measures at corresponding or closest to corresponding anatomical location. Multivariate linear models were used for statistical analyses.

Result

The mean age of donors at death was 80.2±10.7 years (range 63‐99) and 8 (36%) were female. The median Braak stage was 5 (range: 2‐6). Linear models including regional Tau and TDP43 scores and age showed significant relationships between increased regional tau score and reduced thickness in anterior temporal pole, entorhinal, angular and superior parietal cortices. (Table 1, Figure 1) Linear models including Braak stages, TDP43 scores and age showed significant correlation between Braak stage and thickness in anterior temporal pole and entorhinal cortices and BA35 region of medial temporal lobe.

Conclusion

The aim of the current study is to validate methods for development of 3D pathology maps which can be directly linked to local neurodegeneration measures. As the primary result of such an effort, the present study demonstrates an association of semi‐quantitative measures of AD pathology and with local tissue loss in several common AD regions despite limited range of pathology in these cases. These promising results provide support for future studies directly linking pathology with post‐mortem measures of structure.
Sex differences implications in hippocampal volumetry during midlife
Authors: Caillaud Marie , Foret Janelle T , Gallagher Isabelle , Haley Andreana
Published: December 2022

Background

Sex differences in adult brain morphology are frequently reported. Hippocampal and medio‐temporal (MTL) cortices in women and men are frequently implicated in Alzheimer’s Disease (AD) pathology, and women are disproportionally more affected by AD than men. Modifications in these regions’ volumetry are described during aging and in pathology, but their specificities during midlife regarding sex are still debated. Also, the multifaceted interactions between sex and dementia risk factors in these brain areas are not fully established. The aim of this study is to precisely identify the differences between women and men in the volumetry of hippocampal and MTL subregions, as well as the moderation effects of risk factors for dementia such as hypertension (diastolic blood pressure), hypercholesterolemia, obesity (body mass index), physical inactivity, and inflammation (C‐Reactive Protein), on sex.

Method

Data from 210 cognitively healthy participants were analyzed (106 women; 104 men; age 40‐65). Automatic segmentation was performed to determine the volume of the bilateral anterior and posterior hippocampus, and of entorhinal, perirhinal (BA35 and BA36), and parahippocampal cortices (ASHS‐PMC‐T1 atlas). The total intracranial volume was obtained to calculate adjusted‐volumes for every participant. An analysis of covariance (ANCOVA) was performed to compare women and men subregions’ volumes, corrected for age. Linear regressions were performed to analyze the interactions between sex and dementia risk factors on the volumetry of these regions.

Result

Women and men were significantly different in the volume of the left (p < .001) and right (p < .001) hippocampus, on the right BA35 (p = .008), and on the left (p < .001) and right (p < .001) parahippocampal cortices. No significant interaction was highlighted between sex and risk factor variables.

Conclusion

Beyond basic demography, sex is essential to consider in research, as women and men appear to be inherently different in their brain morphometry, even from midlife. Volumetric differences in AD‐linked brain regions, regardless of potential dementia risk factors, may be an innocuous sex‐specific feature at the preclinical phase. In this regard, women’s vulnerability to AD may not occur until later in aging, potentially linked to hormonal decline.
Tau levels are higher in objective subtle cognitive decline, but not subjective memory complaint
Authors: Thomas Kelsey R. , Weigand Alexandra J. , Edwards Lauren C. , Edmonds Emily C. , Bangen Katherine J. , Ortiz Gema , Walker Kayla S. , Bondi Mark W.
Published: December 2022

Background

The 2018 NIA‐AA Alzheimer’s disease (AD) Research Framework states that subtle cognitive decline in cognitively unimpaired individuals can be measured by subjective report or evidence of objective decline on neuropsychological measures. Both subjective memory complaint (SMC) and objective subtle cognitive decline (Obj‐SCD) have been shown to be associated with future cognitive decline and AD biomarkers. We examined whether there are tau PET differences in a) SMC‐ vs. SMC+ participants, b) Obj‐SCD‐ vs. Obj‐SCD+ participants, and c) participants with overlapping/discrepant SMC and Obj‐SCD classifications.

Method

Participants without MCI or dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 236) were classified at baseline as positive or negative for SMC (SMC‐ n = 77; SMC+ n = 159) based on the first 12 items of the Cognitive Change Index and/or classified as positive or negative for Obj‐SCD (Obj‐SCD‐ n = 173; Obj‐SCD+ n = 63) based on previously defined neuropsychological criteria. Analyses of covariance, adjusting for age, sex, APOE ε4 status, and pulse pressure, examined group differences in tau PET (AV‐1451) using a composite SUVR for regions consistent with Braak stage III/IV. Chi‐squared tests examined tau positivity rates across groups.

Result

Obj‐SCD+ participants had higher tau levels (p = .035, ηp
2 = .019) and higher rates of tau positivity (15.8% Obj‐SCD‐ vs. 30.2% Obj‐SCD+) than Obj‐SCD‐ participants. Neither tau levels (p = .381, ηp2 = .003) nor tau positivity rates (18.2% SMC‐ and 20.1% SMC+) differed for SMC groups. There was little agreement between SMC and Obj‐SCD (42%; κ = 0.01, p = .811). Participants with only Obj‐SCD had the highest tau PET levels and differed from participants with only SMC (p = .022). Tau levels in SMC+/Obj‐SCD+ participants did not differ from those with only Obj‐SCD (p = .216). Tau positivity rates across SMC‐/Obj‐SCD‐, SMC+/Obj‐SCD‐, SMC‐/Obj‐SCD+, and SMC+/Obj‐SCD+ groups were 10.5%, 18.1%, 40.0%, and 25.6%, respectively.

Conclusion

Participants with Obj‐SCD had greater tau burden than those without Obj‐SCD, but SMC was not associated with higher tau levels. The combination of SMC and Obj‐SCD did not have higher tau levels than Obj‐SCD alone. Findings add to the evidence that the Obj‐SCD classification is associated with AD biomarkers and faster cognitive decline in ADNI participants, but further work is needed to validate this approach in more representative/diverse cohorts.
Independent and interactive effects of APOEε4 and β‐amyloid on cortical thickness in Alzheimer’s disease
Authors: Tennant Victoria R , Rajagopalan Priya , Thomopoulos Sophia I , Thompson Paul M
Published: December 2022

Background

The apolipoprotein (APOE) ε4 allele is a major risk factor for Alzheimer’s disease (AD) and potentiates β‐amyloid (Aβ) accumulation. Both APOEε4 and Aβ individually contribute to neurodegeneration in the aging brain. Here, we investigate the independent and interactive effects of APOEε4 and global Aβ load on cortical thickness and disease severity across the AD continuum.

Method

We used FreeSurfer v7.1.1 to derive brain morphometry measures from regions‐of‐interest (ROIs) in 796 subjects (N=475 controls (CN), N=77 participants with mild cognitive impairment (MCI), N=244 with dementia; Table 1) to analyze associations between cortical thickness, APOEε4, and Aβ using available T1‐weighted MRI scans from ADNI phases 2 and 3. Multiple linear regression models were run, covarying for age and sex, to examine the effects of APOEε4 status, global Aβ, and their interaction on morphometric measures from ROIs known to be vulnerable to Aβ deposition in aging and disease (Figure 1‐ adapted from La Joie et al.).

Result

In the MCI and dementia groups, higher global Aβ was associated with lower cortical thickness in middle temporal, fusiform, and parietal regions (p<0.05), but was not associated with cortical thickness in controls. In the dementia group, there was a significant effect of Aβ (p<0.001) and an APOEε4 by Aβ interaction (p=0.01) in the inferior parietal gyrus (Figure 2). The interaction effect requires replication due to the multiple hypothesis testing.

Conclusion

Unlike in healthy aging, as disease severity increases, the interactive effect of Aβ and APOEε4 status significantly affects cortical thickness in regions associated with Aβ deposition. This suggests that APOEε4 differentially affects cortical thinning during different stages of disease severity.
Learning Streamline Embeddings with Variational Autoencoder for Intersubject Bundle Comparison in Alzheimer’s Disease
Authors: Feng Yixue , Chandio Bramsh Q , Chattopadhyay Tamoghna , Thomopoulos Sophia I , Owens‐Walton Conor , Garyfallidis Eleftherios , Jahanshad Neda , Thompson Paul M
Published: December 2022

Background

Tractograms generated from diffusion MRI (dMRI) can be used to evaluate white matter abnormalities in Alzheimer's Disease patients (AD). However, the large quantity of streamlines causes problems for downstream analysis. Here we use a variational autoencoder (VAE) with a 1D convolutional layer (ConvVAE) to embed streamlines in a 2D latent space. The generative nature of ConvVAE allows us to apply Euclidean distances directly to embeddings and perform intersubject fiber bundle comparisons.

Method

Multi‐shell dMRI from 141 subjects ‐ 87 cognitively normal controls (CN), 44 with mild cognitive impairment (MCI), 10 with dementia (AD) ‐ from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were preprocessed using the ADNI3 dMRI protocol. 30 white matter tracts were extracted from whole brain tractograms per subject using DIPY's RecoBundles. A control subject with 51,654 streamlines was used to train the ConvVAE with Evidence lower bound (ELBO) loss. We evaluated results by visualizing 2D embeddings and reconstructed streamlines. K‐nearest neighbor (KNN) clustering with Euclidean distance (k=5) was performed on the control subject in a bundle labeling task, to evaluate the alignment between embeddings and generated bundle labels.

Result

2D embeddings for the control subject used for training and a randomly selected MCI and AD subject are shown in Fig. 1, colored by bundles (top) and hemisphere (bottom). Embeddings for each bundle are aligned between subjects, reflecting the shape, size and orientation of the bundle in the streamline space. Embeddings, streamlines and reconstruction for 4 left hemisphere bundles are plotted in Fig. 2. Linearly interpolated points sampled from the latent space translate into smooth transitions in the streamline space, so Euclidean distance can be used in downstream tasks. The fitted KNN model was evaluated on all other subjects where the weighted accuracy for each group was 80.56% (CN), 78.59% (MCI) and 75.76% (AD).

Conclusion

ConvVAE generates 2D embeddings that preserve bundles' spatial and shape information. It learns a smooth latent space from streamlines, which allows for meaningful decodings from sampled points and can be directly applied to new data. Distance‐based algorithms can be used in downstream tasks, such as bundle labeling and intersubject comparisons.