bluuebunny/crossref_metadata_2025 huggingface dataset:
Education or Socioeconomic Status: which proxy of cognitive reserve associates better with cognitive function and amyloid imaging results?
Authors: Sohrabi Hamid R , Weinborn Michael , Shemehsavar Soudabeh , Verma Shipra , Dore Vincent , Xia Ying , Taddei Kevin , Rainey‐Smith Stephanie R , Martins Ralph N
Published: December 2023

Background

Cognitive reserve (CR) is partially responsible for inter‐individual differences in developing dementia due to Alzheimer’s disease (AD). However, education years, as the primary proxy of CR, does not capture various life experiences, vocational background, and resources available to those who did not have an opportunity to complete formal education. We compared education years against Hollingshead Four‐Factor Index of Socioeconomic Status (SES‐Adults) to examine the latter’s utility as a better proxy of cognitive reserve. The SES‐Adults is a survey collecting information on marital status, retired/employed status, educational attainment, and occupational prestige for participants and their partners. The survey results are then converted into one of the 5 social class categories including low, working, middle, upper‐middle, and upper socioeconomic status.

Method

A cross‐sectional study was conducted on a cohort of adults and older adults (n = 264) with mean age of 67.96 years. Participants were recruited from a longitudinal study investigating neuropsychological and biological correlates of dementia, namely the Western Australian Memory Study (WAMS). We examined the relationships between education years and the SES‐Adults scores, with cognitive function and amyloid load while controlling for age, gender (male/female), and APOE ε4 carriage. Amyloid load was measured using 18F‐NAV‐469 tracer.

Result

The cohort included 190 females and 74 males with 80 APOE ε4 carriers (available genotyped individuals = 203). Linear regression results showed education years was significantly correlated with both general cognitive function (MoCA) and amyloid load (R2 = 0.2935, Adjusted‐R2 = 0.2513; p<0.026) while controlling for the effects of age, gender, and APOE ε4 carriage. The SES‐Adults was not significantly related to cognition or amyloid load (p = .914). When SES was included in regression model, the relationships between education years and outcome measures turned non‐significant.

Conclusion

We found education years to be significantly related to both cognition and amyloid load. However, no significant results was noted for the SES‐Adults. This cross‐sectional study showed that education is a reliable CR proxy as compared to a comprehensive measure of socioeconomic status(SES‐ Adults) .
Rational design of a vaccine for Alzheimer’s disease using a computationally‐derived conformational epitope to selectively target toxic amyloid‐beta oligomers
Authors: Kaplan Johanne , Napper Scott , Scruten Erin , Gibbs Ebrima , Coutts Juliane , Peng Xubiao , Plotkin Steven S , Cashman Neil R
Published: December 2023

Background

Amyloid‐beta (Aß) vaccines have the potential to protect against disease but also carry the risk of eliciting proinflammatory T cell responses causing meningoencephalitis, and plaque‐reactive antibodies that can increase the risk of brain edema (ARIA‐E). To circumvent these issues and induce an antibody response that selectively targets soluble toxic Aß oligomers (AßO), without inducing potentially detrimental B or T cell responses against plaque or normal Aß, we used our Collective Coordinates computational platform to design a vaccine consisting of a conformational epitope of AßO, coupled to keyhole limpet hemocyanin (KLH) as a carrier protein to provide T cell help.

Method

Mice received 3 immunizations, 4 weeks apart, with vaccine conjugate in alum or QS‐21 as adjuvants. Serum titers of total IgG, IgG1 and IgG2a antibodies to the peptide epitope were measured by ELISA. The selectivity of serum antibodies for toxic AßO versus monomers was evaluated by surface plasmon resonance, and plaque reactivity was assessed by immunohistochemistry on AD brain sections. T helper type 1 (Th1) and type 2 (Th2) responses to the peptide and to KLH were evaluated by ELISPOT analysis of splenic lymphocytes.

Result

A robust antibody response against the conformational AßO epitope was observed with both adjuvants and remained undiminished out to 6 months after the last immunization. Alum gave rise to a predominantly IgG1 response while QS‐21 produced a more comparable IgG1/IgG2a response. The serum antibodies showed the desired binding profile and reacted with AßO only, not Aß monomers or plaque. ELISPOT analysis showed a lack of Th1 (interferon‐gamma) or Th2 (IL‐5) cytokine production in response to stimulation with the AßO epitope thereby indicating that the peptide only contains a B cell epitope. T cell help was provided by the carrier and, as expected, stimulation with KLH induced Th cytokine production.

Conclusion

A vaccine consisting of an AßO‐restricted conformational B cell epitope conjugated to KLH produced a strong Aß antibody response with no measurable pro‐inflammatory T cell response against Aß. In addition, the oligomer selectivity of the antibodies focused the response on pathogenic AßO, potentially reducing the risk of ARIA‐E associated with binding to plaque and vascular deposits of Aß.
The association between depressive symptoms and amyloid positivity
Authors: Wiels Wietse A , Oomens Julie Elisabeth , Engelborghs Sebastiaan , Baeken Chris , Verhey Frans R.J. , Visser Pieter Jelle , Jansen Willemijn J. ,   the Amyloid Biomarker Study group
Published: December 2023

Background

Amyloid deposition and hippocampal atrophy have been linked to late‐life affective disorders, raising concerns for Alzheimer’s Disease (AD). However, biomarker and autopsy studies have been inconclusive. It remains unclear if and in what way depressive symptoms imply an increased risk of amyloid positivity.

Method

Using data from 49 centers in the Amyloid Biomarker Study, we investigated the association between depressive symptoms and amyloid positivity. We included participants with normal cognition (NC) (n = 9776) and MCI (n = 2995). Amyloid positivity was defined using standardized CSF (n = 5926) and PET (n = 6845) measures. Depressive symptoms were obtained through medical history (12%) and various rating scales (88%). Symptoms on rating scales were classified as (1) present/absent using established cut‐off values, (2) severity using center‐based trichotomisation. We examined associations between depressive symptoms and amyloid positivity using generalized estimating equations and evaluated potential moderation by age and APOE‐e4 status.

Result

Mean age was 69 years and 33.8% were amyloid positive. In NC, no association between the presence or severity of depressive symptoms and amyloid positivity was observed, nor was there when including APOE‐e4, sex or education. In MCI, persons with depressive symptoms were ∼10% less often amyloid positive than those without depressive symptoms (p = 0.001), this was even more pronounced in persons with moderately severe symptoms (p = 0.01). We identified an interaction between depressive symptom severity and APOE‐e4 status (p = 0.034). In APOE‐e4 noncarriers with MCI, persons with moderate depressive symptoms were 20% less often amyloid positive than those with no or mild depressive symptoms. In APOE‐e4 carriers with MCI, depressive symptom severity was not associated with amyloid positivity.

Conclusion

In persons with normal cognition, depressive symptoms are not associated with amyloid positivity. In MCI patients, however, those with depressive symptoms were ∼10% less often amyloid positive. This association increased in persons with moderately severe symptoms and appeared to pertain to APOE‐e4 noncarriers. These data suggest that the presence of depressive symptoms in MCI patients is no reliable indicator of amyloid positivity. This may have diagnostic implications for this group.
Promoting memory retention in older adults with and without Alzheimer’s Disease using the mobile app Blank Slate
Authors: Marin Anna , Smith Amy , DeCaro Renée , Hughes Gregory , Rivard Nathaniel , Feinn Richard , Turk Katherine W , Budson Andrew E
Published: December 2023

Background

Spaced retrieval is an effective technique for supporting learning and memory. It involves repeatedly recalling information that one desires to learn after increasingly lengthy intervals of time. It is still unclear how older adults, including individuals with Alzheimer’s Disease (AD), can best implement spaced retrieval in their daily life mostly due to their difficulty in self‐adhering to schedules and their metacognitive deficits. We examined the usability and efficacy of a mobile application called Blank Slate Technologies (BST) for helping older adults with and without cognitive impairment due to AD retain new and old memories using the spaced retrieval technique.

Method

Twenty healthy older adults and 20 older adults with mild cognitive impairment (MCI) or dementia due to AD engaged with the BST app each day for four weeks to practice retrieving recently learned information (facts about the country Georgia) and older, fading information (celebrity names that they knew but had difficulty recalling). Automatic notifications prompted participants to access the BST platform and review their assigned flashcards for a few minutes daily. Over time, each participant reviewed the information they were most likely to quickly forget. At the end of the four weeks, participants took two recognition tests, spaced one week apart. Recognition performance on the two tests was measured across all item types.

Result

Healthy and AD participants correctly recognized respectively 86.2% and 85.4% of the items studied using the app, compared to 57.6% and 54.1% of the items not studied on the app. A week after the training, the effect of the BST training was sustained such that both healthy and AD participants correctly recognized 85.3% and 78.6% of the items studied on the app compared to 58.1% and 53.0% of the items not studied on the app.

Conclusion

Thanks to its reminder notifications and customized learning schedule, the BST app is an effective and easy‐to‐use platform to help improve and sustain long‐term memory retention in the aging population and in individuals with AD at different stages of the disease. Future research should examine the efficacy of the BST app also for improving the free recall of information.
Memory impairment due to recurrent vascular insults in mice was rescued by pleiotrophin
Authors: Gupta Mayank , Talukdar Ankita , Hussain Rehab , Diwakar Latha
Published: December 2023

Background

Small vessel infarcts, ischemic attacks, microbleeds are considered a common cause of vascular dementia appears as white matter hyperintensities (WMH) in MRI of many patients. However, we don’t know how these WMH contribute to cognitive decline, and little is known about the underlying pathogenesis of Blood Brain Barrier (BBB) dysfunction. Thus, in the current study we have developed a mouse model with recurrent small vessel strokes leading to memory dysfunction and BBB loss. Further, we infused pleiotrophin (PTN) a trophic factor important for maintaining pericyte, the component of BBB for regulation of cerebral blood flow to rescue from multiple vascular insults.

Method

3‐4 months old C57/BL6J male mice was implanted with cannula into intracerebroventricular cavity. ET‐1 (Endothelin‐ 1), a 21 amino acid vasoconstricting peptide was injected through guide cannula into the ventricle for a period of 9 weeks at an interval of 21 days. Another set of mice were given 3 doses of ET‐1 along with PTN two days earlier and 3 days after along with ET‐1 injection. Mice were assessed for memory deficits with different behavioral task after 9 weeks. Animals were perfused and brain was processed for immunohistochemistry to assess vascular pathology.

Result

Mice injected over a period of three weeks with ET‐1 showed discrepancies in the blood vessel integrity and loss of pericytes potentiating multiple vascular insults cause BBB dysfunction leading to memory impairment. However, maintaining PTN level during ET‐1 injections in mice significantly improved memory function in novel object task and contextual fear conditioning test as well as protected BBB. These data suggest that rescue of BBB integrity by PTN infusion during chronic vascular insults prevents memory decline in mice.

Conclusion

Repeated vasoconstriction by ET‐1 in small vessels lead to BBB breach resulting in irreversible learning and memory deficits. This could be rescued by PTN treatment restoring BBB structure and memory function intriguing to further study novel therapeutic targets.
Specific memory binding indexes and their potential to discriminate between Alzheimer´s disease biomarker‐positive and biomarker‐negative older adults with amnestic mild cognitive impairment
Authors: Horakova Hana , Mazancova Adela Fendrych , Matuskova Veronika , Veverova Katerina , Laczó Jan , Hort Jakub , Vyhnalek Martin
Published: December 2023

Background

The Memory Binding Test (MBT) and Face‐Name Associative Memory Exam (FNAME‐12) are challenging tests based on relational memory binding paradigm. Recent studies support their sensitivity to subtle memory changes; however, their specificity to Alzheimer´s disease (AD) related memory deficit has not been studied. This study aimed to explore differences in MBT and FNAME‐12 scores between patients with amnestic mild cognitive impairment (aMCI) due to AD (aMCI‐AD), those with aMCI with non‐Alzheimer´s etiology (aMCI‐nonAD), and cognitively normal older adults (CN) as a control group, and to compare the potential of the challenging tests and the standard Rey Auditory Verbal Learning Test (RAVLT) to discriminate between the aMCI groups.

Method

Sixty‐seven Czech Brain Aging Study participants (aMCI, n = 37; CN, n = 30) underwent neuropsychological assessment (including the MBT and FNAME‐12), laboratory evaluation, and brain magnetic resonance imaging, and were further classified as aMCI‐AD (n = 18) or aMCI‐nonAD (n = 19) based on the results of amyloid positron emission tomography or AD cerebrospinal fluid biomarkers. The groups were compared using the multivariate analysis of covariance controlling for sex, age, education, and global cognition.

Result

In MBT, aMCI‐AD patients scored the lowest on the paired cued recall scores (CR) (aMCI‐AD<aMCI‐nonAD<CN, ps≤0.003). In FNAME‐12, aMCI‐AD patients scored the lowest on the CR of face‐occupation pairs (aMCI‐AD<aMCI‐nonAD<CN, ps<0.001). On the CR of face‐name pairs, both aMCI groups scored lower than CN (p<0.001); however, they did not differ from each other [p = 0.525; (aMCI‐AD = aMCI‐nonAD)<CN]. In RAVLT, aMCI‐AD patients did not differ from the aMCI‐nonAD patients, except for the delayed free recall (FR) (p<0.001). Adding the RAVLT delayed FR as covariate, the differences in the MBT and FNAME‐12 paired CR scores remained significant. To discriminate aMCI‐AD from aMCI‐nonAD, the MBT paired CR and FNAME‐12 CR of face‐occupation pairs yielded areas under the curve (AUCs) of 88% and 85%, respectively, which was comparable to RAVLT delayed FR (87%). Controlling for RAVLT, the AUCs were 91% for MBT and 88% for FNAME‐12.

Conclusion

Our findings support excellent discriminative ability of selected MBT and FNAME‐12 scores for AD‐related memory deficit and suggest their potential for differential diagnosis of memory deficit in older adults in addition to the standard RAVLT.
Automated lexical analysis of story recall in healthy controls
Authors: Ip Martin Ho Kwan , Cousins Katheryn A Q , Nevler Naomi , Liberman Mark Y , Grossman Murray , Cho Sunghye
Published: December 2023

Background

Impaired episodic memory is one of the earliest and most prominent symptoms of Alzheimer’s disease (AD). Examining how patients produce words and phrases in story recall tasks is useful for tracking and understanding progression of their disease. Traditional approaches rely on manual assessments of recalled stories which can be limited, time‐consuming, and not applicable in large‐scale studies. Here, we implement an automated, computational approach to measure verbal episodic memory in a digitally recorded story recall task performed by young healthy speakers using natural language processing models.

Method

We analyzed digitized speech samples of pre‐recorded immediate and delayed Craft Story recall tasks performed by healthy speakers (n = 67, mean age = 20.31 years, SD = 2.17, 45 (67%) females). All transcripts were transcribed by trained annotators and automatically scored for number of verbatim and paraphrase recall, total recall score ( = verbatim+paraphrase), and semantic distance from the original story (degree of semantic similarity between the original craft story and the recalled story based on the Word2vec module in python). We also calculated total word count and number of unique words, and rated all recalled words for word familiarity, concreteness, and semantic ambiguity based on published norms. Number of pauses and total durations of speech and silent pauses were also measured.

Result

We found larger semantic distance between successive words in the delayed recall task compared with immediate recall within speaker (p<.001). Delayed recall also elicited lower total recall scores than immediate recall (p = .03). Comparing the effect sizes of semantic distance vs. total recall scores, our model comparison showed a smaller prediction error for semantic distance (AIC = 95.45) than total recall score (AIC = 736.18). In addition, speakers in the delayed recall task performed more paraphrase recall, had higher total word count, number of unique words, more ambiguous words, and produced more speech (all p‐values<.001).

Conclusion

Our findings suggest that automated speech analysis can provide informative and cost‐effective measures from a recorded story recall task. The study provides an automated and quantitative way to better measure memory abilities by including semantic distance. Future work will test procedures in patients with AD or other neurodegenerative diseases.
Genetic Architecture of Cortical Thickness and White Matter hyperintensities: Evidence of Gene‐Environment Interaction with Cardiovascular Health and Late‐Life Depression
Authors: Zhukovsky Peter , Tio Earvin S. , Coughlan Gillian T , Mulsant Benoit H. , Voineskos Aristotle N. , Felsky Daniel
Published: December 2023

Background

Modifiable risk factors account for over 40% of dementias, offering potential for intervention. However, the impact of these risk factors, including depression and vascular disease, on brain health in the context of variable genetic influences is not well understood. Here we map the genetic landscape of brain structure, testing for gene‐by‐environment (GxE) interactions and relevance to cognitive performance in mid‐ and late‐life.

Method

We conducted genome‐wide association studies (GWAS) to identify genetic variants associated with cortical thickness in over 34,500 UK Biobank participants. We used postmortem bulk RNA sequencing of frontal cortex paired with antemortem MRI in a late‐life sample (n = 66) to directly corroborate implicated GWAS loci. Focusing on GWAS‐significant loci, we tested for GxE interactions and associations with cognition in 25,254 Canadian Longitudinal Study of Ageing (CLSA) participants.

Result

We identified 367 loci in the UK Biobank participants (age 45‐81), associated with global or regional cortical thickness (p<5×10−8), with genetic correlations between pairs of anatomical regions identifying three distinct modules. Corroboration with postmortem bulk RNA sequencing and MRI in a late‐life sample confirmed effects of STMN4, ARL17A and ARL17B genes on cortical thickness. Ten GWAS‐implicated loci from the UK Biobank were also associated with executive function or memory in CLSA, including rs1562330, a locus linked to the STMN4 gene. Notably, 37 variants also showed significant interactions with cardiovascular health or depression (P<2×10−4).

Conclusion

These findings advance our understanding of the genetic architecture of brain structure and show that modifiable factors alter the effects of heritable genetic background on brain and cognitive health.
Sex differences in marmoset neurocognitive aging, a nonhuman primate model for brain aging and age‐related neurodegenerative diseases
Authors: Rothwell Emily , Cobo Carmen Freire , Varghese Merina , Hof Patrick R , Lacreuse Agnès
Published: December 2023

Background

Nonhuman primate models of human aging are necessary to understand functional decline and identify vulnerabilities to aging pathologies. Longitudinal studies are critical and common marmosets (Callithrix jacchus) are ideal as they have a short lifespan (∼12 yr) and naturally develop neuropathology relevant to Alzheimer’s disease (AD).

Method

We studied 28 marmosets (14 females) from midlife (∼5 yr old) to old age across four years. Simple discrimination and reversal learning was used to evaluate cognitive performance. Additional yearly tests included motor, stress reactivity, and social behavior assessments. A subset of animals (n = 17, 9 females) were studied for AD‐relevant neuropathology in post‐mortem tissue of the dorsal lateral prefrontal cortex (dlPFC) and CA1 of the hippocampus.

Result

Multilevel models revealed age‐related changes for cognitive performance with improved reversal learning during the first three years due to practice followed by decline in the final year with the onset of old age. Cognitive decline was steeper and began earlier for females compared to males. Based on cognitive trajectories which were highly variable across individuals, we categorized marmosets as cognitively impaired or non‐impaired. Mild amyloid β (Aβ) deposition was observed in the dlPFC and CA1 but did not differ between males and females. Aβ burden was higher in cognitively impaired compared to non‐impaired marmosets, but this difference did not reach statistical significance. However, cognitively impaired marmosets showed signs of accelerated brain aging including higher astrogliosis associated with Aβ deposits and dendritic spine loss, both in the dlPFC and hippocampus. In addition, increased activation and changes in microglial phenotypes were observed in the dlPFC.

Conclusion

Like humans, aging marmosets displayed intra‐individual variability in cognitive decline, neurodegeneration and neuronal aging. Female marmosets showed greater vulnerability to cognitive impairment, which is translationally relevant to the higher prevalence of AD in women. While trajectories of cognitive decline did not strongly map onto Aβ burden for females or males, evidence of accelerated brain aging was found in the impaired marmosets. This study highlights the value of marmosets as a nonhuman primate model of AD to identify vulnerabilities to aging pathologies, such as sex differences.
Longitudinal changes of self‐ and informant‐reported cognitive decline in elderly with regard to clinical progression and amyloid‐status
Authors: Kuhn Elizabeth , Stark Melina , Kleineidam Luca , Wolfsgruber Steffen , Boecker Henning , Bürger Katharina , Düzel Emrah , Fliessbach Klaus , Gaertner Florian , Heneka Michael T. , Laske Christoph , Perneczky Robert , Peters Oliver , Priller Josef , Schmid Matthias , Schneider Anja , Spottke Annika , Teipel Stefan , Wiltfang Jens , Jessen Frank , Wagner Michael
Published: December 2023

Background

Self‐ and informant‐reports of cognitive decline have been previously associated with a higher risk of cognitive decline in elderly. Yet, few studies assessed their longitudinal changes over time with regard to both incident mild cognitive impairment (iMCI) and Alzheimer’s disease (AD) pathology. This study aims at describing these links to better understand which trajectories are indicative of higher AD‐risk.

Method

We used data from 501 participants followed‐up annually (2.51±1.35 years) in the DELCODE project. All were cognitively unimpaired, and had an amyloid measurement available, at inclusion. Among them, 145 were amyloid‐positive, and 65 progressed to iMCI during the follow‐up period (31 iMCI‐Aß+). The SCD‐Interview was used to measure (i) the number of cognitive domains in which the participants or its relative perceived a decline (i.e., self‐ and informant‐SCD‐I), and (ii) the number of fulfilled SCD‐plus criteria. Linear mixed‐effect models were used to assess SCD trajectories over time, according to four groups defined by amyloid status and clinical progression (Stable‐Aß‐, Stable‐Aß+, iMCI‐Aß‐ and iMCI‐Aß+). Analyses were adjusted for age, sex and education; and their interaction with time.

Results

Both self‐SCD‐I levels and SCD‐plus scores decreased significantly over time, without significant differences between groups (Figure 1A, 1B). Conversely, informant‐SCD‐I levels did not significantly change over time in the whole sample, although slopes significantly differed between groups. Compared to the Stable‐Aß‐ group, there was a greater increase over time of informant‐SCD‐I report only in iMCI‐Aß+ [est 0.16, SE 0.05, p<.001] (Figure 1C). The resulting discrepancy score (Self‐SCD‐I minus Informant‐SCD‐I) tended to decrease over time with significant differences between groups. Compared to the Stable‐Aß‐ group, the discrepancy score showed a faster decrease over time in iMCI‐Aß+ [est ‐0.21, SE 0.056 p<.001] (Figure 1D).

Conclusion

Longitudinal patterns in subjective reports of cognitive decline might help identify preclinical AD subjects at higher risk of clinical progression. Specifically, an increase of informant‐reported cognitive decline over time may indicate objective cognitive decline in amyloid‐positive subjects. Conversely, the decrease of self‐reported cognitive decline over time, regardless of the group, may reflect generally reduced concerns after inclusion, or result from current limitations in longitudinal SCD assessment.
Effect of early‐ and mid‐life cognitive enrichment on Alzheimer’s disease pathology and late‐life cognition
Authors: Simone Stephanie M. , Wagner Maude , Peterson Rachel , Krasnova Anna , Andrews Ryan M , Armstrong Nicole M. , Widaman Keith F. , Zaheed Afsara B , Sol Ketlyne , Bennett David A. A , Barnes Lisa L. , Vonk Jet MJ
Published: December 2023

Background

Cognitive reserve and brain maintenance may explain individual differences in trajectories of cognitive and brain aging due to various life exposures (e.g., education, cognitive enrichment). Cognitive reserve refers to the advantages that life exposures exert on cognitive abilities despite brain aging or disease; brain maintenance refers to the protective effects of life exposures on the brain itself (e.g., reduced rate of neuropathology accumulation). Previous findings showed that early‐life cognitive enrichment (ELCE) was associated with slower cognitive decline, which was partially mediated through global Alzheimer’s disease pathology. Building on this work, this study investigated mediation by β‐amyloid and tau pathology (reflecting brain maintenance) as well as moderation by early‐ and mid‐life cognitive enrichment (ELCE, MLCE; reflecting cognitive reserve) on cognitive functioning at last visit proximate to death.

Method

There were 1015 community‐based participants (M baseline age = 82.57±6.35) from the Rush Memory and Aging Project (MAP) and Minority Aging Research Study (MARS) cohorts, who completed annual cognitive and clinical assessments. ELCE and MLCE composite measures were derived from z‐scored self‐reported indicators obtained at baseline (Table 1). Summary measures of β‐amyloid and tau burden were derived from immunohistochemistry at autopsy. Late‐life cognition was measured using a global composite of 19 z‐scored neuropsychological tests obtained at last visit. To test for cognitive reserve, separate linear regression models examined whether ELCE and MLCE moderated relations between β‐amyloid or tau and cognition, adjusted for age at death and sex. To test for brain maintenance, a series of mediation analyses examined whether β‐amyloid and/or tau burden mediated the relationship of ELCE and MLCE with cognition.

Result

ELCE (p = .005) and MLCE (p = .005) moderated the relationship between tau—but not β‐amyloid—and late‐life cognition proximate to death (Figure 1). Mediation analyses revealed an indirect effect of β‐amyloid—but not tau—on the relation between ELCE (B = 0.058, p = .004) and MLCE (B = 0.040, p = .03) and late‐life cognition (Figure 2).

Conclusion

ELCE and MLCE improve late‐life cognition partially through reducing β‐amyloid, but not tau, accumulation (i.e., brain maintenance). In contrast, ELCE and MLCE are protective against late‐life cognitive impairment in the presence of tau pathology (i.e., cognitive reserve), but not β‐amyloid.
Associations between ASL‐derived cerebrovascular health and cognitive performance: results from the Insight 46 study
Authors: Dijsselhof Mathijs B.J. , Lu Kirsty , Lorenzini Luigi , Collij Lyduine E. , James Sarah‐Naomi , Thomas David L , Scott Catherine J , Manning Emily N , Cash David M ,   Insight 46 study Team, Hughes Alun D , Richards Marcus , Barkhof Frederik , Petr Jan , Mutsaerts Henk‐Jan
Published: December 2023

Background

Cardiovascular and cerebrovascular pathology may accelerate brain aging and cognitive decline. Structural cerebrovascular imaging biomarkers, such as white matter hyperintensities, reflect mostly irreversible accumulated damage. In contrast, cerebral blood flow (CBF), measured with arterial spin labelling (ASL) perfusion MRI, is a potential early haemodynamic biomarker of cognitive impairment. However, our understanding of physiological CBF variability and its relation with cognition is limited.

Method

We included 245 cognitively unimpaired participants from the Insight 46 birth cohort study, who underwent 3D T1‐weighted and pseudo‐continuous ASL‐MRI (labelling duration = 1800ms; post‐labelling delay = 1800ms) on a 3T Siemens Biograph mMR PET‐MRI scanner. Cognitive assessment included tests for logical memory (Wechsler Memory Scale‐Revised), associative memory (Face‐Name Associative Memory Exam), attention and processing speed (Digit‐symbol substitution and response inhibition test), non‐verbal reasoning (Matrix test), executive functioning (Choice Reaction Time), visuomotor integration (circle‐tracing task), and two composite scores (Mini‐Mental State Examination (MMSE) and the Preclinical Alzheimer Cognitive Composite).

Result

Sample characteristics are reported in Table 1. Associations were found between GM sCoV and MMSE (Male/Female ß = 0.74/‐0.75, p = 0.028, Figure 1), and GM sCoV and Logical Memory (Male/Female ß = 1.05/‐0.25, p = 0.005, Figure 2), but not between CBF and any cognitive scores (p>0.05).

Conclusion

In a cognitively unimpaired population, cognitive performance was associated with GM sCoV but not with other CBF parameters. However, in males, the relationship was opposite to what we expected. Further work should investigate to what extent this indicates macrovascular change occurs before perfusion alterations and could relate to future cognitive decline, and how they differ between sex.
Impact of Stress, Loneliness and Sociodemographic Factors on Psychological Well‐Being During the COVID‐19 Pandemic
Authors: Udeogu Onyinye , Mimmack Kayden J. , Gagliardi Geoffroy Pierre , Burling Jessa , Gatchel Jennifer , Quiroz Yakeel T. , Donovan Nancy J , Amariglio Rebecca E. , Sperling Reisa A. , Marshall Gad A , Vannini Patrizia
Published: December 2023

Background

Personal and social factors have had a varied effect on older adults during the COVID‐19 pandemic. Psychosocial factors and underlying pathological changes may have influenced the mental health of these older adults. Understanding the drivers behind the mental health of older adults during the pandemic may help identify treatment targets. We aimed to understand this phenomenon by exploring the relationships between the psychosocial factors iand self‐reported experiences of psychological well‐being.

Method

We included 149 participants (mean age: 75.6) from the Harvard Aging Brain Study and Instrumental Activities of Daily Living Study who took a survey conducted during the Summer of 2021, to assess stress (Perceived Stress Scale), loneliness (UCLA Loneliness Scale. 3‐item version), resilience (Connor Davidson Resilience Scale) and psychological well‐being (PROMIS‐Global Mental), encompassing self‐reported quality of life, mood and thinking, satisfaction with social relationships and anxiety and depressive symptoms. Pre‐assessed measures of cortical amyloid (PiB; mean time difference = 1.8 years) and medial temporal tau (Flortaucipir; mean time difference = 1.7 years) were also included. We performed a hierarchal regression analysis to understand the relationships among the psychosocial factors, controlling for demographics, amyloid, and tau as predictors of well‐being.

Result

Demographic and survey responses are presented in Table 1. Significant negative associations were found among perceived well‐being and pathology (amyloid and tau), stress and loneliness, such that increased pathology, increased stress and increased feelings of loneliness were related to worse mental health (Figure 1). A positive association was found between resilience and well‐being, such that increased resilience was related to higher well‐being. (Figure 1). The hierarchical regression analysis results revealed that loneliness (β = −0.32, t = −5.81, p<.001), stress (β = −0.38, t = −5.48, p<.001), and resilience (β = 0.28, t = 4.34, p<.001) uniquely accounted for a significant proportion of variance in well‐being even after controlling for demographic characteristics (age, sex, education, race) and psychosocial characteristics (marital status, living alone) (Table 2).

Conclusion

Our findings suggest that measuring and quantifying loneliness, stress, and resilience can help clinicians and researchers understand the potential detrimental effects of the COVID‐19 pandemic among older adults. These findings may extend to other prolonged exposures to stressful situations and uncover much needed targets for intervention.
Integration of cerebrospinal fluid pQTL and GWAS prioritizes novel causal proteins for Alzheimer’s disease
Authors: Western Daniel , Timsina Jigyasha , Wang Lihua , Wang Ciyang , Ruiz Agustin , Marquié Marta , Boada Mercè , Rojas Itziar , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Sung Yun Ju , Cruchaga Carlos
Published: December 2023

Background

Quantitative trait loci (QTL) are successful at identifying the functional gene for many loci identified through GWAS. While expression QTL (eQTL) studies robustly examine tissue‐specificity, most protein QTL (pQTL) studies have been limited to plasma. We have previously demonstrated that pQTL associations are highly tissue‐specific. Given the relevance of cerebrospinal fluid (CSF) to Alzheimer’s disease (AD) and other forms of neurodegeneration, we developed a CSF‐specific pQTL atlas and integrated it with AD GWAS to identify novel causal proteins for AD.

Method

We generated CSF proteomics (Somalogic, 7,584 analytes) data for 3,107 individuals. pQTL mapping was performed using a three‐stage approach: discovery, replication, and meta‐analysis. We analyzed the tissue‐ and molecule‐specificity of our associations by comparing to plasma & brain pQTLs and various eQTLs. We performed a proteome‐wide association study (PWAS) and Mendelian randomization (MR) to prioritize proteins affecting AD. We determined shared protein‐disease genetic regulation using colocalization. Using AD‐associated proteins, we built risk models of disease status.

Result

We identified 2,316 significant pQTL (1,247 in cis and 1,069 in trans) for 1,960 proteins, of which 1,720 were novel and not reported in the largest currently available pQTL studies in plasma or brain. Through PWAS, we identified 440 proteins associated with AD risk, which show enrichment in neurons (with APOE region) or microglia/macrophages (without APOE). MR prioritized 37 proteins as causal and colocalization identified 153 proteins that share genetic etiology with AD. Seventeen of these proteins overlap between all three methods and multiple (including PILRA, PRSS8, and SIRPA) represent novel causal proteins for AD. A protein risk score using PWAS‐identified proteins outperformed a polygenic risk score (PRS) at predicting amyloid/tau positivity across ages (AUC: 0.852‐0.906 vs. 0.724‐0.806, P<0.002) and across APOE genotypes (AUC: 0.809‐0.893 vs. 0.70‐0.80, P<0.027).

Conclusion

We reported the largest CSF pQTL analysis to date and confirmed that CSF pQTLs are largely tissue‐specific. We identified proteins involved in AD that confirm reported candidate genes and prioritize new ones at GWAS loci. We developed accurate prediction models using prioritized proteins. Our findings offer insights into AD biology undetected with plasma pQTL analyses, supporting proteogenomic databases in neurologically‐relevant tissues.
Biomarkers of microvascular dysfunction and cerebral white matter connectivity: The Maastricht Study
Authors: Beran Magdalena , van Gennip April C.E. , Stehouwer Coen D.A. , Jansen Jacobus F.A. , Gupta Monideepa D. , Houben Alfons J.H.M. , Berendschot Tos T.J.M. , Webers Carroll A.B. , Wesselius Anke , Schalkwijk Casper , Backes Walter H. , de Jong Joost J. , van der Kallen Carla J.H. , van Greevenbroek Marleen M.J. , Köhler Sebastian , Vonk Jet M.J. , Geerlings Mirjam I. , Schram Miranda T. , van Sloten Thomas T.
Published: December 2023

Background

Microvascular dysfunction may contribute to the development of various cerebral disorders, including cognitive dysfunction, dementia, and certain forms of depression. The suggested mechanism through which microvascular dysfunction contributes to these disorders is by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and cerebral white matter connectivity.

Method

We used cross‐sectional data from The Maastricht Study, a Dutch population‐based cohort (n = 4,326, mean±SD age 59.4±8.6 years, 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers (CRAE and CRVE), a composite score of flicker light‐induced retinal arteriolar and venular dilation response, and a composite score of plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble E‐selectin (sE‐selectin) and von Willebrand factor (vWF)). White matter connectivity was calculated from 3T diffusion MRI to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient and local efficiency) of cerebral white matter connections.

Result

A higher endothelial dysfunction composite score was associated with a longer characteristic path length (beta per SD: 0.066 (95% confidence interval: 0.017; 0.114)) after adjustment for sociodemographic, lifestyle and cardiovascular factors, but not with any of the other white matter connectivity measures. All other measures of microvascular dysfunction were not associated with any of the connectivity measures after adjustments.

Conclusion

The present study suggests that microvascular dysfunction, as quantified by a set of various measures, is not consistently associated with cerebral white matter connectivity. Only a composite score of plasma biomarkers of endothelial dysfunction was associated with a longer characteristic path length, with a longer characteristic path length being indicative for a topographically less integrated and less efficient cerebral network. Future cross‐sectional and longitudinal studies are needed to further understand the role of microvascular dysfunction in the development of cerebral disorders.
[18F]PI2620 tau deposition increases along the Alzheimer’s disease continuum in Down Syndrome and in presence of amyloid
Authors: Pegueroles Jordi , Camacho Valle , Montal Victor , Bejanin Alexandre , Videla Laura , Aranha Mateus Rozalem , Benejam Bessy , Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Barroeta Isabel , Carmona‐Iragui Maria , Lleo Alberto , Flotats Albert , Fortea Juan
Published: December 2023

Background

Down’s syndrome (DS) is currently considered a genetic form of Alzheimer’s disease (AD). People with DS develop early‐onset AD due to an extra copy of the amyloid precursor protein gene, present on chromosome 21. Thus, DS is a unique model to study AD pathophysiology. We aimed to study the neurofibrillary tau burden in adults with DS using the second‐generation Tau PET tracer [18F]PI‐2620 and assess its relationship with amyloid PET.

Method

Cross‐sectional study. We included 46 subjects: 18 euploid subjects without cognitive impairment and 16 asymptomatic DS, 4 DS with prodromal AD and 8 DS with AD dementia. All subjects underwent dynamic [18F]PI‐2620 PET/CT, [18F]Flutemetamol amyloid PET/CT and T1w‐MRI scans. PET images were co‐registered to the corresponding T1w‐MRI and intensity normalized by the mean value in the reference region (whole cerebellum for [18F]Flutemetamol and inferior cerebellar cortex for [18F]PI‐2620). For amyloid PET, the mean of the composite region (frontal, temporal, parietal, and cingulate) was calculated and transformed into Centiloid units. [18F]PI‐2620 tracer retention was quantified in region of interest (ROIs) corresponding to individual anatomical definitions of Braak stages I‐II, III‐IV and V‐VI. ANOVA was used to test differences between clinical diagnoses. To assess the relationship between amyloid and tau, vertex‐wise analysis was performed using the PETSurfer toolbox of Freesurfer.

Result

The pattern of tau deposition in symptomatic DS included typical AD areas (i.e., temporal and parietal lobe, precuneus; Fig1). Differences in [18F]‐PI2620 uptake along the AD continuum in DS were statistically significant in the three Braak staging ROIs only between asymptomatic DS and demented DS, although a trend was observed between controls and demented DS (Fig2). The vertex‐wise regression showed a relationship between local tau burden and global amyloid deposition in widespread areas, but especially in typical AD ones (Fig3; FWE‐corrected p<0.05).

Conclusion

[18F]PI‐2620 PET presented high affinity to tau aggregates in symptomatic DS subjects, and presented similar deposition as in sporadic AD. Tau PET deposition measured by [18F]PI‐2620 increased along the AD continuum in DS and was mainly present in subjects with high amyloid burden.
Genomic editing of APOE4/4 to APOE3/3 in iPSCs bearing African or European local ancestry surrounding APOE
Authors: Oron Oded , DeRosa Brooke A. , Rajabli Farid , Celis Katrina , Feliciano‐Astacio Briseida E. , Silva‐Vergara Concepcion , Beecham Gary W. , Adams Larry D. , Tejada Sergio J. , Mena Pedro R. , Whitehead Patrice , Hamilton‐Nelson Kara L. , Starks Takiyah D. , Byrd Goldie S. , Cuccaro Michael L. , Young Juan I. , Pericak‐Vance Margaret A. , Vance Jeffery M. , Dykxhoorn Derek M.
Published: December 2023

Background

The APOE4 genotype is the main contributor to the risk of developing Late Onset Alzheimer’s Disease (LOAD), while the APOE3 genotype has no effect on LOAD risk. Previously our group has shown that Local Ancestry (LA) surrounding APOE4 regulates APOE expression in adult individuals. As LOAD pathology has been shown to develop decades before the onset of symptoms, we sought to explore if LA has similar or different effect in mitotic cells, and whether the APOE3 genotype modulates the effect of the LA. To answer this question, we generated APOEε3/3 and APOEε4/4 isogenic induced Pluripotent Stem Cells (iPSCs) lines from individuals with either European LA or African LA.

Method

PBMCs were derived from APOEε4/4 carrying individuals with either African or European APOE LA. To generate APOE isogenic lines, we formed a ribonucleoprotein (RNP) complex using a previously published APOE sgRNA (Lin et al. 2018) and performed nucleofection using the 4D‐Nucleofector system (Lonza). Homozygous APOEε3/3 edited and APOEε4/4 unedited isogenic clones were selected, and confirmed to lack unwanted off‐target editing. Isogenic clone pluripotency was confirmed by immunocytochemistry (SOX2, NANOG and OCT4a staining). APOE expression in the isogenic clones was tested by quantitative Real‐Time PCR and significance was calculated by Student’s T‐test.

Result

Isogenic clones were similar in their pluripotency and growth characteristics. Preliminary APOE expression in the iPSC line carrying the African LA was higher (p = 0.0002) in each of the individual APOEε3/3 KI clones (n = 3) compared to each of the individual unedited APOEε4/4 clones (n = 2), showing consistency within each isogenic group. In contrast, the APOE expression in the iPSC line carrying the European LA was not significant in the APOEε3/3 KI clones (n = 2) compared to the parental line.

Conclusion

Our data suggests that differences in local ancestry has a direct effect on the expression of APOE isoforms in iPSCs. This finding supports previous reports in frontal cortex suggesting that the regulation of APOE expression differs depending on ancestry.
Solving the pervasive problem of protocol non‐compliance in neuroimaging using an open‐source tool mrQA
Authors: Sinha Harsh , Raamana Pradeep Reddy
Published: December 2023

Background

Large‐scale datasets are becoming the norm in estimating the brain‐behavior relationships, which are acquired via engagement with participants over several years often across multiple sites and scanners. However, maintenance of imaging protocols in MRI centers is still an ad‐hoc process. Acquisition parameters, including but not limited to flip angle (FA), repetition time (TR), and echo time (TE), are routinely improvised at individual sites to accommodate changes in software/hardware and to suit the needs of the patient. Non‐compliance in acquisition protocol can lead incompatible MR images hindering downstream analysis. For example, co‐registration with the structural counterpart becomes difficult if EPI is non‐compliant with the field map.

Method

We present an open‐source tool mrQA to automatically identify variations in acquisition parameters. A dataset is parsed to extract the parameters for each run. and compared against a reference protocol. If unavailable, reference protocol is inferred based on the most frequent value for each parameter. We recommend using mrQA for datasets in DICOM format (even though mrQA supports NIfTI) to prevent any non‐compliant parameters at the MRI scanner itself because other formats such as JSON sidecar (for NIfTI) lack standardization and hence, are often incongruous with across datasets.

Result

To assess the prevalence of protocol compliance, we evaluate over 20 public datasets on OpenNeuro (BIDS) and the ABCD dataset (FastTrack ‐ DICOM). The exploration is not meant to be a finger‐pointing exercise but to discover common pitfalls in MR acquisition that can confound the research we do. Table 1 and Table 2 summarize the results for OpenNeuro and ABCD datasets, respectively. The results are reported separately for each vendor as even the same parameters differ in the unit of measurement across vendors.

Conclusion

We demonstrate the pervasive problem of protocol non‐compliance based on the analyses of many open datasets from OpenNeuro and the ABCD dataset. Our tool, mrQA can summarize acquisition parameters from a MR dataset, in order to discover any issues of non‐compliance. Even though, the effect of non‐compliance on signal intensity will depend on the specific tissue in context, explicit characterization should precede any analyses in case there is considerable non‐compliance in acquisition parameters.