bluuebunny/crossref_metadata_2025 huggingface dataset:
Age differentially mediates the relationship between plasma biomarkers and cognition detected by digital screening
Authors: Toniolo Sofia , Zhao Sijia , Scholcz Anna , Amein Benazir , Gallacher Anne , Ganse‐Dumrath Akke , Bukala Bernard R , Thompson Sian , Manohar Sanjay , Zetterberg Henrik , Husain Masud
Published: December 2023

Background

Plasma biomarkers are emerging as a useful tool to measure neurodegeneration, particularly in patients with Alzheimer’s Disease (AD). Digital cognitive testing is also increasingly used to detect cognitive changes in AD. Age is a major determinant of performance at cognitive testing and can affect the levels of different plasma biomarkers. However, little is known about how age mediates the relationship between plasma biomarkers and cognition.

Methods

38 AD and 48 age‐matched controls were recruited from the Oxford Centre for Cognitive Disorders. We used a fully remote digital visual short‐term memory (STM) task (Figure 1) and extracted eight cognitive metrics (Figure 1): Identification Accuracy (percentage of correctly identified items), Absolute Error (distance from the response location to the original item), Target detection (probability of correctly identifying the target), Misbinding (erroneously localizing an item to the remembered location of another item in memory), Guessing (random guessing), Identification and Localization Time (time to identify and drag the correct object to its remembered location), and memory Imprecision (width of the distribution around the target). Plasma p‐tau 181, GFAP, NFL, Aβ40 and Aβ42 were measured, and the Aβ42/40 ratio was calculated. In Model 1 (Figure 2) the correlation between digital cognitive metrics and plasma biomarkers is shown, while in Model 2 age was regressed out. A mediation analysis was then performed to look at the effect of age as a mediator.

Results

In Model 1, most cognitive metrics on the STM task were strongly associated with p‐tau 181, GFAP and NFL. Identification Accuracy was also negatively correlated with the Aβ42/40 ratio. No association with Aβ42 or Aβ40 was found. However, regressing out age had a profound impact on these correlations, particularly for GFAP and NFL, while p‐tau 181 was not significantly affected (Figure 2 and 3). The mediation analysis (Figure 3), shown for Identification Accuracy, confirmed that age had a more profound impact on GFAP and NFL compared to p‐tau 181.

Conclusions

These new digital metrics show a strong correlation with plasma biomarkers. Finally, age is an important mediator between plasma biomarkers and cognition, but that varies across different biomarkers.
Effect of Concomitant Aducanumab on AD Clinical Trial Outcomes
Authors: Kennedy Richard E
Published: December 2023

Background

Aducanumab was approved by the US FDA for treatment of mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD). Participants taking aducanumab or other anti‐amyloid antibodies are likely to become more common in clinical trials of novel therapies, but the effect of concomitant administration on trial outcomes is not known.

Method

We used a metadatabase of 18 ADCS studies and ADNI, containing 3480 participants with mild AD, to simulate current clinical trials methods. We randomly resampled the database for sample sizes of 400 to 1000 per group for hypothetical novel “drug” and “placebo” groups in 12‐, 18‐, and 24‐month duration trials. We simulated effects on the ADAS‐cog for both the experimental treatment and aducanumab with effect sizes from 0 (no effect) to 0.25 (moderate effect), with differential dropout in the aducanumab group ranging from 0% to 20%. Mixed effects models were used to determine power to detect treatment response.

Result

Participants eligible for aducanumab were younger, more likely to be male, more highly educated, and had higher MMSE scores at baseline and lower ADAS‐cog scores over time. The approximate decrease in power was up to 20% with a moderate effect of aducanumab and a dropout rate of 20% in the aducanumab group, increasing up to 30% if differential dropout also occurred in the experimental treatment group. (Figure: Simulated power for rates of progression on an experimental AD therapy by aducanumab status, with N = 800 per group, dropout rates of 0% to 20% among participants eligible and ineligible for aducanumab) Effects on power were greater when the effect size of aducanumab was greater than the effect size of the experimental treatment.

Conclusion

While randomization can ensure approximately equal effects of an anti‐amyloid antibody in both treatment and placebo groups in clinical trials of new experimental therapies, differential dropout among aducanumab users during the trial (as seen initial studies for aducanumab) can disturb this balance, with corresponding decreases in power to detect a treatment effect. Clinical trials should assess use of anti‐amyloid antibodies at baseline to ensure balance, and incorporate ongoing monitoring of potential dropouts could negatively impact trial outcomes.
The association between menopause and dementia risk
Authors: Peterson Amalia Jo , Miller Eliza C. , De Jager Philip L , Barnes Lisa L. , Arvanitakis Zoe , Bennett David A. A , Tom Sarah E.
Published: December 2023

Background

Women have a higher prevalence of Alzheimer’s disease compared to men. Studies are conflicting as to whether an earlier age of menopause or hysterectomy prior to natural menopause, are associated with an increased risk of cognitive impairment. The goal of this study was to determine whether age of menopause and hysterectomy are associated with incident dementia in a group of older, community‐dwelling women.

Method

Female participants from three ongoing Rush cohorts, the Rush Memory and Aging Project, the Religious Orders Study, and the Minority Aging Research Study were included (total n = 3122, mean age = 77 years at baseline, SD = 7.8). Annual clinical assessments allowed for dementia status categorization, based on detailed neuropsychological testing and clinical judgment, using the NINDS‐ADRDA criteria. Age at menopause and hysterectomy status was based on self‐report at baseline. Data on ovarian preservation or removal at time of surgery was not available. Age of menopause was categorized into tertiles (<45, 45‐50, >50). Risk of dementia, with age at dementia diagnosis as the outcome, was evaluated using Cox proportional regression models adjusting for race, early‐life socioeconomic status, education, diabetes, and smoking status.

Result

At the time of these analyses, women were followed for an average of 8.3 years (SD = 5.6). Women in the earliest tertile of menopause age were less likely to be white, more likely to report having diabetes, and have longer hormone therapy use (p<0.01). In fully adjusted models, women with menopause at age 45‐50 (HR 0.80, 95% CI 0.67‐0.96) and age >50 (HR 0.74, 95% CI 0.62‐0.90) had a lower risk of dementia compared to women with menopause at age <45. Hysterectomy prior to natural menopause was not associated with an elevated risk of dementia (HR = 1.01, 95% CI 0.87‐1.19).

Conclusion

In a group of older women, earlier age at menopause but not hysterectomy was associated with an elevated risk of dementia. Future research will determine whether these associations differ by race or ethnicity and the factors that may contribute to such differences.

Funding: P30‐AG072975, R01‐AG17917, R01‐AG22081
Co‐Developing Awareness Video Campaign for People Living with Dementia with Lewy Bodies
Authors: Green Kit , Booi Laura
Published: December 2023

Background

Although Dementia with Lewy Bodies (DLB) is the second most common form of neurodegenerative dementia, information about DLB is often scarce and fragmented. Corresponding with this, the lived experience of DLB involves high rates of misinformation, social isolation, loneliness, and stigma. There is a need to develop outputs in which the expertise of those living with DLB, care‐partners and clinicians focused on DLB is shared.

Methods

Funded by a UKRI Catalyst Award, and after receiving ethical approval from Leeds Beckett University, this project implemented consulting workshops with key informants including: (i) people living with DLB; (ii) care‐partners of those living with DLB; (iii) Third Sector organizations and; (iv) clinicians focused on supporting those with DLB. The consulting workshops discussed the key issues surrounding DLB, from the perspective of the attendees. The outcome of these workshops highlighted the most salient topics for individuals who have recently come into the DLB community (either as a newly diagnosed person or care‐partner).

Results

Findings from the consulting workshops highlight the importance of peer‐support in DLB, including the topics of: hallucinations, sleep and peer‐support. Clinically, the subjects of early diagnoses, Capgras Syndrome and specific care needs were identified as key topics. Six short films are currently being developed based on the findings from the consulting workshops. The Creative Team, Research Team and lived‐experience experts will co‐develop the script for these videos. Each video will be one minute long in duration. The videos will offer a gentle, general introduction to the topic from an expert (mostly with lived experience), with the aim of removing fear and stigma.

Conclusion

These videos will offer guidance for shared experiential learning so that the person living with DLB and their CP will be better educated and equipped to support themselves and each other through the care pathway. The solution offered via the Lewy Video Campaign will contributes to improving access to information in an affordable, personable venue, supporting individuals into becoming integrated into the wider DLB community of both clinical and peer‐support.
Synaptic Marker NPTX2 Predicts Risk of MCI Clinical Symptom Onset
Authors: Pettigrew Corinne , Na Chan‐Hyun , Oh Sungtaek , Soldan Anja , Zhu Yuxin , Moghekar Abhay , Albert Marilyn S. , Worley Paul F
Published: December 2023

Background

Neuronal pentraxin 2 (NPTX2) is a synaptic protein involved in the homeostatic regulation of cortical network dynamics and synaptic plasticity. Prior cross‐sectional studies suggest that NPTX2 levels decline across the spectrum of Alzheimer’s disease (AD), and that NPTX2 levels can distinguish individuals with normal cognition vs. mild cognitive impairment (MCI) and AD dementia. Less is known about how levels of NPTX2 among individuals with normal cognition relate to future clinical outcomes. To address this, we examined whether baseline levels of NPTX2 predicted time to onset of clinical symptoms of MCI, both alone and in combination with AD biomarkers, among individuals who were cognitively normal at baseline and have undergone 16.3y of follow‐up, on average.

Method

Cerebrospinal fluid (CSF) was collected at baseline from 269 cognitively normal BIOCARD Study participants (M baseline age = 57.7y), including 77 (29%) who subsequently progressed to MCI or dementia (Table 1). Baseline NPTX2 levels were measured from three highly correlated peptides using quantitative parallel reaction monitoring mass spectrometry. NPTX2 peptide levels were standardized and averaged to create an NPTX2 composite score. Baseline levels of Aβ42/Aβ40, p‐tau181, and t‐tau were measured using Lumipulse automated electrochemiluminescence assays.

Result

In Cox regression models, lower NPTX2 levels were significantly associated with earlier time to MCI clinical symptom onset (HR = 0.76, 95% CI (0.601, 0.962), p = 0.02; Figure 1a). After accounting for CSF AD biomarkers (i.e., Aβ42/Aβ40 and tau), the association between NPTX2 levels and MCI symptom onset appeared stronger (Table 2; Figure 1b). Importantly, NPTX2 did not interact with AD biomarker levels (all p > 0.11) or APOE‐ε4 genetic status (p = 0.71) in relation to MCI symptom onset.

Conclusion

CSF levels of the synaptic marker NPTX2 predict time to progress to MCI among individuals with normal cognition, suggesting that NPTX2 may be an early prognostic biomarker of synaptic dysfunction. Moreover, this association appears to be additive and independent of AD biomarker levels. Future work is underway to determine if NPTX2 provides resilience to cognitive impairment in the presence of AD pathology, and if there is a differential relationship with markers of amyloid vs. tau.
An Epigenome‐wide association study of psychosis in Alzheimer’s disease dorsolateral prefrontal cortex
Authors: Kouhsar Morteza P , Weymouth Luke Stephen , Creese Byron , Bergh Sverre , Wedatilake Yehani , Torkamani Ali , Smith Adam R. , Selbæk Geir , Sweet Robert , Ballard Clive G , Mill Jonathan , Kofler Julia , Pishva Ehsan , Lunnon Katie
Published: December 2023

Background

Psychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving aetiology. In this study, we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of post‐mortem brain samples.

Method

Brain samples were obtained from the University of Pittsburgh Alzheimer’s disease Research Centre (PITT‐ADRC). AD pathology was assessed and classified using CERAD neurotic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. We used the presence or absence of delusions and hallucinations, Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) to categorise our samples into AD with Psychosis (AD+P) and AD without Psychosis (AD‐P) groups. DNA was extracted, bisulfite‐treated and profiled on the Illumina Methylation EPIC Array and genotyping was carried out on the Illumina Global Screening Array (GSA).

Result

After data quality control, 153 samples (40 AD‐P, 113 AD+P) remained for further analysis. The normalized beta values and the effect estimate values were used to extract Differentially Methylated positions (DMP) and differentially methylated regions (DMRs), respectively. To identify methylation quantitative trait loci (mQTLs) in both cis and trans, SNP‐CpG pairs with a p‐value threshold of <1e‐5 were calculated. We performed a colocalization analysis for the most significant DMPs and mQTLs, using publicly available summary statistics of relevant genome‐wide association studies (GWAS).

Conclusion

The development of effective therapies for AD+P is an urgent priority and requires a better understanding of the molecular mechanisms underlying this syndrome. To address this, we have collated a well‐powered study cohort to interrogate the epigenetic basis of AD+P in the brain and have identified several loci of interest that require further study.
Tau‐PET signal in Alzheimer’s disease is related to immune activation and synaptic signaling measured with CSF proteomics
Authors: Rikken Roos M. , Vromen Eleonora M. , Coomans Emma M. , Visser Denise , Barkhof Frederik , Boellaard Ronald , Golla Sandeep S.V. , van Berckel Bart N.M. , Ossenkoppele Rik , den Braber Anouk , Vijverberg Everard G.B. , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Teunissen Charlotte E. , Visser Pieter Jelle , van de Giessen Elsmarieke , Tijms Betty M.
Published: December 2023

Background

Tau tangles are one of the pathological hallmarks of Alzheimer’s disease (AD) and can be quantified using PET. It remains unclear which molecular processes are related to tau aggregation. Protein levels in CSF can be used to study such underlying processes. This study aims to identify biological processes related to tau‐PET using unbiased CSF proteomics in participants along the AD continuum.

Method

We included 89 participants with CSF proteomic and [18F]flortaucipir (tau)‐PET data available from the Amsterdam Dementia Cohort and the EMIF‐preclin AD study (N = 68 with abnormal CSF Aβ42 [64.7% cognitively impaired, 67.6% tau‐PET visual read positive] and N = 21 controls [normal cognition and normal CSF AD biomarkers]) (table 1). [18F]flortaucipir BPND was quantified in the temporal meta‐ROI (Braak I, Braak III, Braak IV). CSF proteomics was measured using untargeted LC‐MS/MS based on TMT labelling. We included proteins available in the whole sample (n = 1421 proteins). Protein concentrations were normalized to the control group. We determined the relationship between tau‐PET BPND (outcome) with protein levels (determinant) using linear regressions with sex and age as covariates, stratified for group. GO database was used for biological pathway enrichment analyses within the AD group for proteins thresholded at p<0.05 for positive and negative associations separately.

Result

Higher CSF tau levels were associated with higher tau‐PET BPND (β = 0.092, p = 0.002). In total, 458 proteins were associated with tau‐PET BPND in AD. A higher tau‐PET BPND was related to higher levels of 140 proteins and lower levels of 318 proteins. Proteins that showed higher levels with increasing tau‐PET BPND were mainly involved in immune system processes (figure 1), while the proteins with lower levels were predominantly related to synaptic processes and cell signaling (figure 2). No significant associations were found within controls.

Conclusion

Using CSF proteomics, we identified 458 proteins associated with tau‐PET in AD. Higher tau burden was associated with increased levels of proteins involved in immune activation suggesting a role of the immune system in tau accumulation. Furthermore, higher tau burden was associated with lower levels of proteins related to synaptic process hinting at a role for tau in synaptic degeneration.
Investigating enhancement of TIE2 activation as a means of preserving blood‐brain barrier integrity and preventing cerebral amyloid angiopathy in Alzheimer’s Disease
Authors: Marola Olivia J , Onos Kristen D , Maclean Michael , Keezer Kelly J , Howell Gareth R
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA) co‐occurs with cognitive impairment and neurodegeneration in Alzheimer’s disease (AD). We have shown wild‐derived WSB/EiJ (WSB) mice transgenic for APP/PS1 robustly developed CAA and are thus a useful tool to investigate the mechanisms driving CAA. It has been hypothesized that loss of blood brain barrier (BBB) integrity causes improper amyloid clearance and vascular deposition. One mechanism by which this is possible is the deactivation (loss of phosphorylation) of endothelial cell TIE2. TIE2 phosphorylation is negatively regulated by endogenous antagonists ANGPT2 and VE‐PTP, which can be manipulated to potentially bolster BBB integrity and prevent CAA. Here, we fully characterize CAA pathogenesis in WSB.APP/PS1 mice and explore the efficacy of enhancing TIE2 phosphorylation to protect from BBB dysfunction and CAA.

Method

Male and female WSB mice harboring the APP/PS1 transgene were aged to 4, 6, 8, 14, and 18 months. Brains were histologically assessed for parenchymal plaque deposition and CAA. To investigate the importance of TIE2 inactivation in driving BBB dysfunction in WSB mice, adult WSB and B6 mice were treated with 5mg/kg lipopolysaccharide (LPS; known to induce BBB leakage) or vehicle control. Brains were harvested 16 hours later and bulk RNA‐seq was performed to investigate modulation of Angpt2 expression.

Result

Male and female WSB.APP/PS1 mice exhibited significant parenchymal plaque deposition and CAA by 8 months, which was further increased by 14 and 18 months. Furthermore, while expression of Angpt2 was significantly upregulated after LPS treatment in both B6 and WSB compared to vehicle‐treated counterparts, WSB showed a significantly greater increase compared to B6.

Conclusion

WSB.APP/PS1 mice develop progressively severe CAA, which may be driven by unique susceptibility to BBB dysfunction. The enhanced elevation of WSB Angpt2 upon LPS treatment may reflect susceptibility of WSB vasculature to BBB degradation and therefore CAA development. Thus, TIE2 phosphorylation will be experimentally elevated in WSB.APP/PS1 mice through Angpt2 heterozygosity and VE‐PTP pharmacological inhibition with AKB‐9778 to determine whether protecting the BBB is a viable strategy to prevent CAA. Furthermore, B6 and WSB.APP/PS1 F2 gene mapping studies will be utilized to identify WSB‐associated alleles driving CAA pathogenesis.
Resting state brain networks activity and association with transfer of cognitive training gains
Authors: Faraza Sofia , Dyrba Martin , Wolf Dominik , Fischer Florian U , Knaepen Kristel , Kollmann Bianca , Binder Harald , Mierau Andreas , Riedel David , Tüscher Oliver , Fellgiebel Andreas , Teipel Stefan ,   German AgeGain study group
Published: December 2023

Background

Age‐related cognitive decline increases the need for cognitive interventions to maintain cognitive function. Cognitive training is considered an effective non‐pharmacological intervention. Transfer of training gains to untrained tasks is a key indicator for the effectiveness of cognitive training. However, the underlying brain mechanisms need to be further investigated. We implemented a cognitive training study to assess functional connectivity determinants of transfer of training gains.

Method

A sample of 181 healthy older adults (mean age: 68 years) underwent a 4‐week cognitive training across three sites. The control group consisted of 54 older adults. To evaluate transfer and training effects, participants underwent a neuropsychological assessment before and after the training. A second follow‐up assessment was applied 12 weeks after the training. The training group was divided in subjects who had and who did not have successful transfer, which was defined as higher improvement in cognitive tasks than the control group. We used composite scores representing working memory, memory and executive functions to assess transfer and training effects. Baseline resting‐state functional magnetic resonance imaging was used to investigate the functional connectivity of brain networks associated with cognitive functions. We extracted brain resting state networks using the Independent Component Analysis (ICA) approach.

Result

We observed successful transfer of cognitive training gains in most of the participants. Our results demonstrated spatially restricted effects (p<.01 uncorrected) for the association of transfer of gains with the resting‐state connectivity of brain networks, such as the Default Mode Network and Central Executive Network.

Conclusion

Transfer of training gains in aging is possible. A strong association between transfer of gains and resting‐state functional connectivity was not identified.
Relationship of structural and functional visual biomarkers with measures of amyloid, tau, and neurodegeneration across the AD continuum
Authors: Mathew Sunu , WuDunn Darrell , Mackay Devin , Vosmeier Aaron , Tallman Eileen F. , Deardorff Rachael , Dage Jeff L. , Clark David G. , Farlow Martin R. , Brosch Jared R. , Gao Sujuan , Apostolova Liana G. , Saykin Andrew J. , Risacher Shannon L
Published: December 2023

Background

The eye often reflects changes seen in the brain in neurodegenerative diseases. This study sought to examine the relationship of contrast sensitivity measured using frequency doubling technology (FDT) and retinal thickness measured using optical coherence tomography (OCT) with temporal lobe neurodegeneration, cerebral tau deposition, and mean plasma ptau181 in older adults along the Alzheimer’s disease (AD) continuum.

Method

Participants included 28 individuals with subjective cognitive decline (SCD), 18 mild cognitive impairment (MCI), 4 with AD, and 30 age‐matched cognitive normal (CN) from the Indiana Memory and Aging Study at the Indiana ADRC. Participants were excluded from the study if they had significant eye disease determined to interfere with OCT, FDT, non‐AD dementia, or exclusion for MRI or PET. Mean deviation (MD) and pattern standard deviation (PSD) from FDT were used as measures of contrast sensitivity. OCT scans from each eye to measure retinal thickness in the retinal nerve fiber layer (RNFL) and macula. MRI scans were processed using Freesurfer v6 to measure medial (MTL) and lateral temporal lobe (LTL) volumes. LTL SUVR values were extracted from [18F]flortaucipir PET scans. Plasma ptau 181 was measured using a SIMOA assay. Finally, the association between contrast sensitivity, average RNFL thickness, macular volumes with temporal lobe volumes, LTL tau, and mean plasma ptau181 was assessed using a partial Pearson correlation, covaried for age, sex, and diagnosis. p<0.05 was considered significant.

Result

RNFL thickness was decreased in patients with AD. Hippocampal volume correlated with RNFL thickness and macular volume in both eyes and with PSD in the left eye. The inferior temporal volume correlated with MD in both eyes, while mean plasma ptau181 with PSD in both eyes. Finally, lateral temporal lobe tau was correlated with the inner retinal layers of ganglion cell layer plus inner plexiform layer thickness.

Conclusion

Contrast sensitivity correlates with temporal lobe volumes and mean plasma ptau181. RNFL thinning and macular volumes are associated with hippocampal atrophy, and inner retinal nuclear layers correlate with lateral temporal tau. Imaging of the eye may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.
Evaluation of locus coeruleus changes during aging by post‐mortem brain MRI contrast
Authors: Marinho Pedro Burlacchini , Rodriguez Roberta Diehl , Carreira Luzia Lima , Heinsen Helmut , Chaim Khallil Taverna , Grinberg Lea T. , Leite Claudia da Costa , Otaduy Maria Concepción Gracía
Published: December 2023

Background

Neuropathological studies have pointed to the importance of neurodegeneration in the locus coeruleus (LC) as a possible early biomarker of Alzheimer’s Disease (AD). The aim of this study is to explore a non‐invasive MRI technique to evaluate normal and pathological changes in the LC during aging.

Methods

Subjects were recruited from our Capital’s Death Verification Service. After obtaining written consent from family members, 24 individuals (55‐94 yrs) were submitted for post‐mortem brain in situ MRI with a 7T scanner. Post‐mortem interval ranged from 7 to 20 hours and body temperature varied from 14.8°C to 26°C. MRI protocol included acquisition of multi‐echo gradient‐echo axial images with 2 mm thickness and 0.4 mm in‐plane resolution. LC signal intensity was evaluated from a single gradient‐echo image presenting the brightest signal for the LC. In the same slice normalized values for the left and right LC were quantified (LNV and RNV) by selecting a ROI on the brightest spot of the LC (one‐pixel sized) and dividing it by the signal intensity measured in the left and right pons, respectively (ROI of approx. 50mm2) (Figure1). Subject’s Clinical Dementia Rating (CDR) was obtained by interviewing a close family member. A two‐tailed paired t‐test was performed between the RNV and the LNV, and dependence with age was analyzed by Pearson correlation.

Results

CDR was 0 (n = 17); 0,5 (n = 2); 1 (n = 1), 2 (n = 1), and 3 (n = 3). LNV was higher than RNV (t(23) = 3.9; p< 0.001 (Figure2). The mean of LNV and RNV (MNV) was higher in individuals with CDR = 0 than in subjects with CDR >0, but subjects with CDR>0 were also significantly elder, and there was a significant effect of age on the MNV (r = ‐ 0,49, p = 0,015), Figure 3.

Conclusion

MRI LC contrast was able to depict LC changes as a function of age, whereby subjects with symptons seemed to present lower LC intensity. The left LC was consistently brighter than the right LC endorsing results observed in other studies (Betts et al.2019 https://doi.org/10.1016/j.dadm.2019.02.001). Future histopathological analysis will help to elucidate the origin for this signal difference.
Distinct effects of cholesterol profile components on amyloid and vascular burdens
Authors: Kim Jun Pyo , Yoo Heejin , Cheon Bo Kyoung , Park Yu Hyun , Kim Soo‐Jong , Ham Hongki , Jang Hyemin , Kim Hee Jin , Koh Seong‐Beom , Na Duk L , Seo Sang Won
Published: December 2023

Background

Cholesterol plays important roles in β‐amyloid (Aβ) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aβ and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aβ and CSVD burdens in a large, non‐demented Korean cohort.

Method

We enrolled 1,175 non‐demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aβ PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low‐density lipoprotein cholesterol [LDL‐c], high‐density lipoprotein cholesterol [HDL‐c], and triglyceride) level as a predictor and each image marker (Aβ uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders.

Result

Increased LDL‐c levels (β = 0.014 to 0.115, p = 0.013) were associated with greater Aβ uptake, independent of the APOE e4 allele genotype and lipid‐lowering medication. Decreased HDL‐c levels (β = −0.133 to −0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL‐c levels were also associated with decreased hippocampal volume (direct effect β = −0.053, p = 0.040), which was partially mediated by Aβ uptake (indirect effect β = −0.018, p = 0.006).

Conclusion

Our findings highlight that increased LDL‐c and decreased HDL‐c levels are important risk factors for Aβ and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL‐c and HDL‐c levels is a potential strategy to prevent dementia.
Automated quality control of structural brain MRI scans from aging and dementia datasets
Authors: Griffanti Ludovica , Bhalerao Gaurav V , Gillis Grace , Dembele Mohamed , Suri Sana , Ebmeier Klaus P , Klein Johannes C , Hu Michele , Mackay Clare
Published: December 2023

Background

Dementias platform UK (DPUK) currently hosts over 40 dementia cohorts and provides a remote analysis environment for multimodal cross‐cohort data analysis. Nineteen cohorts include brain MRI data, hence automated quality control (QC) becomes crucial for the reliability of image analyses. This work aims to provide a framework for quality prediction of T1‐weighted (T1w) scans from aging and dementia datasets: we compared manual quality ratings with the output of two existing automated QC pipelines and propose a new QC classifier.

Method

We used 2438 T1w scans (including patients and controls, 1.5T and 3T scanners, 3 manufacturers, 11 sites) from 4 different aging and dementia datasets (ADNI, Whitehall II, Oxford Parkinson’s Disease Centre, Oxford Brain Health Clinic). Manual quality ratings for all images were performed by the dataset owners. Each image was processed in MRIQC (Esteban et al. 2017, PLoS ONE) and CAT12 (Computational Anatomy Toolbox, Gaser et al. 2022, bioRxiv). We compared the quality agreement for MRIQC predictions and CAT12’s weighted image quality ratings (IQR) with manual QC using inter‐rater reliability. Further, we explored the effect of changing the accept‐reject threshold from automated QC tools on the reliability measure. Finally, we designed a custom QC classifier (manual QC as target) by combining MRIQC and CAT12’s quality metrics as features and training linear support vector machines in a nested cross‐validation framework.

Result

We found overall agreement between automated QC methods and manual QC when applied to dementia datasets (MRIQC: Kappa = 0.30, p = 0.001; CAT12: Kappa = 0.28, p = 0.001). Adjusting the acceptance thresholds of the automated tools within dataset improved the agreement. On the combined data (training N = 1951; test N = 487), the proposed classifier showed 94.2% accuracy (sensitivity 94.3%, specificity 85.7%) on the test data. Leaving one site out (training with 10 sites, N = 2055), we found 86.4% accuracy (sensitivity 86.2%, specificity 100%) on the test site (N = 383).

Conclusion

The performance of the proposed classifier appears promising on these heterogeneous datasets from different scanners. In the future, we aim to utilise this framework for improving generalisability of prediction and release the classifier on the DPUK data portal to robustly QC T1w scans for other aging and dementia cohorts.
Neuronal lipid metabolism genetics and Early‐Onset Alzheimer’s Disease: A systematic review and meta‐analysis of observational studies
Authors: Badell Camila S , Apuy Anthony R , Ponce Oscar J , Palomino Luis E , Benites Vicente A
Published: December 2023

Background

Early Onset Alzheimer’s disease (EOAD) is associated with mutations in APP, PSEN1 and PSEN 2 genes but few studies have assessed its relationship with mutations involved in lipid metabolism and the amyloid cascade. Therefore, this study seeks to determine the association of ABCA7, SORL1 and APOE mutations with EOAD.

Method

The protocol was registered in PROSPERO(CRD42022328366). We included comparative observational studies assessing the association of ABCA7, SORL1 and APOE mutations with the development of EOAD in patients younger than 65 years old. The search strategy was performed in five databases (MEDLINE, Scopus, Web of Science, EMBASE, Opengray) from their inception to May 7th,2022. Abstract and full‐text screening, data extraction and risk of bias (RoB) assessment were performed in duplicates. RoB was assessed with Newcastle‐Ottawa Scale. We performed a random effects meta‐analysis for dichotomous outcomes by using the DerSimoniain Laird method. Effect sizes were reported as odds ratio (OR) with their corresponding 95% confidence intervals (95%CI).

Result

A total of 2191 studies were screened and seven studies (n = 8992) were included; one was a retrospective cohort and six were case‐control studies. Three studies had high RoB and four had low RoB. Overall, 60% were female and the mean age ranged from 33.9(SD±17.1) to 57.4(SD±5.6). Three case‐control studies (n = 5098) found a significant association of ABCA7 mutation with EOAD (OR:2.51 95%CI[1.33‐4.73]; tau‐squared = 0.20, I‐squared = 66%). Two case‐control studies (n = 3107) found that SORL1 mutation was not associated with EOAD (OR:3.65 95%CI[0.76‐17.49]; tau‐squared = 1.15, I‐squared = 89%). Two case‐control studies and one cohort study (n = 787) found that APOE4 allelic variant mutation of the APOE gene had significant association with EOAD (OR:13.21; 95%CI[3.81‐45.85]; tau‐squared = 0.90, I‐squared = 75%) and that the APOE2 allelic variant mutation was not associated with EOAD.

Conclusion

Despite the high heterogeneity in our results and limited number of studies, this study shows that ABCA7 and APOE mutations may be associated with an increased risk of EOAD. Larger high‐quality cohort studies are needed to address this research question.
The value of peer contributions and different forms of social support in rare dementia bereaved caregiver groups
Authors: Waddington Claire , McKee‐Jackson Roberta , Baou Celine El , Hayes Oliver S , Brotherhood Emilie V , Harding Emma , Stott Joshua , Crutch Sebastian J
Published: December 2023

Background

Peer support has a key role to play in national and local health services worldwide given growing need, pressure on resources, and strategic drives towards supporting people to manage their own health. Yet evaluation of peer‐only and multi‐component peer and professional group services is held back by research methodology gaps, including the absence of direct, within‐session evaluation tools. The current study evaluates the relationship between participation and conversational characteristics using linguistic analysis of a series of online bereaved support groups.

Method

Participants were bereaved family caregivers (N = 102) attending Rare Dementia Support bereaved support group meetings between March 2017 and March 2022. Attendance rates and (virtual) travel distance were compared for in person meetings (N = 9 sessions; 2017‐2019) and online meetings (N = 26 sessions; 2020‐2022). During each online session, notable phrases & contributions were recorded using a verbatim note‐making process and shared with participants post‐session as a reminder of the experiences shared by group members. These text files (660 phrases comprised of 9,600 words) were analysed using Linguistic Inquiry and Word Count (LIWC; Pennebaker et al., 2015) software, automatically classifying words into LIWC categories of analytical thinking, clout, authenticity and affect variables.

Result

The switch to online sessions increased accessibility to bereaved support in terms of attendance rates (Figure 1A), geographical proximity (Figure 1B) and group consistency (Figure 1C, e.g. higher proportion of online attendees returned for further sessions [in person 42%, online 69%; McNemar χ2 = 3.84, p = 0.0001]). Linear regression analyses with robust standard errors revealed that greater session attendance (mean number of sessions attended by participants present) was associated with conversations that were more authentic and less emotional and definitive (i.e. more reflective) over time (regression coefficients: Authentic: 0.111 [0.073, 0.149]; Affect: ‐0.637 [‐1.089, ‐0.185]; Clout: ‐0.066 [‐0.112, ‐0.020]; see Figures 2A‐C). The level of analytical thinking was maintained across sessions (Analytic: ‐0.012 [‐0.086, 0.061]; see Figure 2D).

Conclusion

Online peer groups offer a practical and effective medium for bereavement support. Shifting the focus of evaluation to the processes of social support – how it is delivered and received – rather than just the outcomes, offers insights into the mechanisms of peer support.
Predictors of subjective and objective cognitive performance examined in an online sample of adults with and without prior COVID‐19 infection.
Authors: Butler Joe , Lawson Rachael A , Ling Jonathon , Paddick Stella‐Maria , Parra‐Rodriguez Mario A , Hodgetts Sophie , Taylor John‐Paul , Watermeyer Tamlyn J
Published: December 2023

Background

COVID‐19 is still a major public health concern. COVID‐19 is known to affect the central nervous system (CNS), however, the extent of the cognitive effects of infection are unknown. We developed an online battery for community testing, to learn more about the cognitive effects of infection.

Method

Participants were recruited between October 2020 and December 2021 from social media, and completed objective cognitive‐tasks and online health questionnaires using Psytoolkit (Stoet, 2017). Subjective questionnaire measures included fatigue, sleepiness, mood, and cognitive complaints. Objective cognitive tests measured sustained attention; spatial span; and visual short‐term memory. Participants self‐reported their comorbidities. Prior COVID‐19 infection was identified by self‐reported positive PCR or lateral flow test. Data was split into age/infection status groups of i) 18‐34y positive infection (n = 69, mean‐age: 21.4 [3.6]); ii) 18‐34y negative infection (n = 189, mean‐age: 22.65 [4.3]); iii) positive infection (n = 26, mean‐age: 46.9 [7.1]); and iv) 35y+ negative infection (n = 68, mean‐age: 45.44 [7.56]).

Result

Of 359 participants recruited, 95 (26.4%) reported a prior positive COVID‐19 test. We found no differences in demographic variables and any variables of interest between Covid‐positive and Covid‐negative groups overall. However, within the age/infection status groups, we found:

The 35+ Covid positive group reported higher fatigue (d = 0.69) and performed poorer (d = 0.66) on a visual short‐memory task relative to the 35+ Covid‐negative individuals.

Within the overall Covid‐positive sample, younger age β = ‐0.18, p = 0.04); higher fatigue (β<0.001) and poorer mood (β = ‐0.18, p = 0.05), were associated with greater perceived cognitive complaints [R2 = 0.63 (adjusted R2 = 0.6), F(6,75) = 21.1, p <0.001]. Furthermore, a higher number of co‐morbidities (β = ‐0.31, p = 0.01) was associated with poorer spatial span [R2 = 0.25 (adjusted R2 = 0.19), F(6, 75) = 4.23, p = 0.001].

Within the overall Covid‐negative sample, sleepiness (β = 0.32, p<0.001) and higher fatigue (β = 0.54, p<0.001) were associated with greater perceived cognitive complaints [R2 = 0.66 (adjusted R2 = 0.63), F(6, 65) = 20.9, p<0.001]. There were no significant associations with objective cognitive performance within this sample.

Conclusion

COVID‐19 infection status was associated with subjective and objective cognitive complaints. Adults aged 35‐63 years with prior COVID‐19 infection appear to be differentially affected. These data add to the body of evidence indicating there are cognitive consequences from COVID‐19 infection.
Relationship between loss of awareness of cognitive decline and tau pathology in the Alzheimer’s disease spectrum: modulatory role of resting‐state functional connectivity
Authors: Cacciamani Federica , Gagliardi Geoffroy Pierre , Mimmack Kayden J. , Qiao Krystal , Bueichekú Elisenda , Marshall Gad A , Sepulcre Jorge , Diez Ibai Palacio , Vannini Patrizia
Published: December 2023

Background

Patients with Alzheimer’s disease (AD) often demonstrate anosognosia, which is reduced awareness of cognitive decline. Anosognosia has been associated with tau accumulation (d'Oleire Uquillas et al., 2020) and impaired resting‐state functional connectivity (FC) in self‐referential networks (Vannini et al., 2017, Valera‐Bermejo et al., 2022). The explicit links between AD pathological deposits and large‐scale functional networks associated with anosognosia have yet to be elucidated. Here, we sought to examine whether FC plays a modulatory role in the effect of tau on awareness in participants across the AD spectrum.

Method

We included 58 participants from two observational cohorts—44 asymptomatic (Clinical Dementia Rating (CDR) global score = 0) and 14 symptomatic (CDR≥0.5) individuals (Table1). Awareness was measured as the participant‐study partner discrepancy on the Cognitive Function Index. Flortaucipir‐PET was used to quantify tau accumulation, and segregation analysis was applied to resting‐state fMRI data to asses within‐network connectivity. For both modalities, the mean value in each of the Yeo 7 networks was used. First, a linear regression model was performed to assess the association between awareness and group (i.e., symptomatic/asymptomatic). Linear regression models were also used to assess the relationship between awareness and tau in the 7 networks, separately. Finally, we examined the effect of the FC×tau interaction on awareness. All models were adjusted for age, sex, and education.

Result

Holding age, sex, and education constant, mean awareness was 0.18 lower in symptomatic (vs. asymptomatic) participants (p<0.01). Lower awareness was associated with a higher tau burden in all 7 networks (Table2). Interaction effects between tau and FC were observed. Specifically, reduced awareness was associated with high tau burden when the salience network was less functionally connected (Figure1A; β = ‐0.23, p = 0.02) and when the dorsal attention network was more functionally connected (Figure1B; β = 0.70, p = 0.03). For all other networks, the relationship between awareness and tau was not modified by the FC of the same network (Table2).

Conclusion

These findings provide new insights into the neuropathological correlates of anosognosia in AD. It suggests that anosognosia is not only due to local pathology in single brain areas but also to altered connectivity between them, especially within self‐referential networks.
Childhood community advantage and late‐life brain health among a racially/ethnically diverse cohort
Authors: Peterson Rachel , George Kristen M , Maillard Pauline , Decarli Charles , Gilsanz Paola , Soh Yenee , Lor Yi , Kind Amy J. , Corrada María M. M. , Mungas Dan M. , Mayeda Elizabeth Rose , Glymour M. Maria , Barnes Lisa L. , Whitmer Rachel A.
Published: December 2023

Background

Many studies associate late‐life community disadvantage with worse late‐life brain health. It is unknown if childhood community disadvantage is associated with late‐life brain health in racially/ethnically diverse populations.

Method

KHANDLE and STAR are racially/ethnically diverse harmonized cohorts of older members of Kaiser Permanente Northern California. A random subset of participants (N = 411) underwent 3T MRI; regional brain volumes and white matter integrity were measured. Stabilized inverse probability weights were estimated to account for imaging selection based on study, race/ethnicity, baseline age, and sex/gender. Residence at birth was geocoded and linked to historical Area Deprivation Indices (ADI) from the Neighborhood Atlas. ADI is a nationally ranked percentile, where higher scores represent greater relative community disadvantage. Weighted general linear models investigated associations between continuous ADI (rescaled so 1 unit = a change of 10 percentile points of national ADI rankings) and imaging measures among participants age 65+. Separate weighted models examined associations between national ADI quintiles grouped for analysis as <20th percentile (the most advantaged quintile), 20th‐79th percentiles (middle 3 quintiles) and > = 80 (most disadvantaged quintile) and imaging measures.

Result

Compared with the complete KHANDLE/STAR cohorts, the imaging sample was younger with larger proportions of Latino adults and STAR participants (Table 1). Among the imaging sample, those with ADI> = 80 were older, had lower educational attainment, were more likely to be Black and less likely to be White or Asian when compared with those with ADI<20. Increases in continuous ADI were associated with worse brain health, including lower gray matter volume (β = ‐0.05, 95% CI = ‐0.08, ‐0.02), larger lateral ventricle (β = 0.06, 95% CI = 0.02, 0.10), and larger white matter hyperintensities (β = 0.06, 95% CI = 0.03, 0.08; Table 2, Model Set 1). In models examining categorical ADI, those with ADI> = 80 (least advantaged communities) had significantly worse brain health across all measures and those with ADI = 20‐79 had larger white matter hyperintensities when compared with those with ADI<20 (ref = most advantaged quintile; Table 2, Model Set 2).

Conclusion

Community disadvantage in childhood is associated with worse brain health in late life. Future work will explore the potential pathways (e.g., individual education attainment; midlife cardiovascular risks) that may explain these associations.