bluuebunny/crossref_metadata_2025 huggingface dataset:
Present mind in aging brain: Neural associations of dispositional mindfulness in cognitive decline
Authors: Sumec Rastislav , Filip Pavel , Vyhnalek Martin , Katina Stanislav , Hort Jakub , Sheardova Katerina
Published: December 2022

Background

Subjects at risk of dementia, such as subjective cognitive decline (SCD) and mild cognitive impairment (MCI), present with specific clinical symptoms, as well as functional and structural changes within the brain. Dispositional mindfulness (DM) has been linked to better cognitive performance and is associated with activation and grey matter volume of specific brain regions. It is yet unknown how DM is related to cognitive and neural parameters of those at risk of dementia.

Objective

To estimate the association of DM with cognitive functions, brain volumetry, functional connectivity and gray matter integrity in key regions relevant for cognition (hippocampus, anterior cingulate cortex) and self‐awareness (ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex) in SCD and MCI subjects.

Methods

79 non‐demented older adults with memory complaints ((SCD = 48, MCI = 31) were assessed by neuropsychological tests, MRI volumetry, resting‐state fMRI‐derived connectivity and DTI. Dispositional mindfulness was examined with Breath Counting Task (BCT).

Results

Participants with MCI showed significantly worse BCT performance in comparison to SCD (p˂0.001). In MCI, BCT performance was positively associated with connectivity (p˂0.001) and negatively related to mean gray matter diffusivity (p˂0.05) in vmPFC. No other significant associations were found between DM, MRI measures and neuropsychological variables in either group.

Conclusion

Worse cognition in subjects at risk of dementia may be reflected in changes in DM. Lower connectivity and worse gray matter integrity of vmPFC in MCI could play a role in the worsening of DM in this population. Longitudinal studies are needed to further clarify the relatedness of DM and neural changes elicited by neurodegeneration in people at higher risk of dementia.
Shorter disease duration in females with sporadic frontotemporal dementia
Authors: de Boer Sterre C.M. , Riedl Lina , Van der lee Sven J , Otto Markus , Anderl‐Straub Sarah , Landin‐Romero Ramon , Sorrentino Federica , Fieldhouse Jay L.P. , Reus Lianne M. , Halliday Glenda M , Galimberti Daniela , Diehl‐Schmid Janine , Ducharme Simon , Piguet Olivier , Pijnenburg Yolande A.L.
Published: December 2022

Background

Previous reported sex differences on disease duration (DD) of frontotemporal dementia (FTD) have been inconsistent and lack the comparison between genetic and sporadic FTD. Our aim was to study the difference in disease duration between males and females in genetic and sporadic FTD.

Method

Mortality data was obtained from 61 deceased patients with genetic FTD (52% male) and 117 deceased patients with sporadic FTD (64% male) from the international FTD cohort previously reported by de Boer et al., 2021. The age at symptom onset (AAO), age at death (AAD) and the DD (defined as the time between age at symptom onset and age at death) were compared between males and females in the genetic and sporadic FTD group using Mann Whitney U tests.

Result

Genetic FTD did not show significant sex differences in AAO, AAD and DD (p = 0.3, p = 0.3, p = 0.8 respectively, Figure 1). In sporadic FTD, the AAO and AAD did not significantly differ between males and females (p = 0.8 and p = 0.2 respectively). The DD in the sporadic FTD group was significantly shorter in females (median DD 7.0 years) in comparison to males (median DD 8.0 years, p = 0.01, Figure 2).

Conclusion

In this study we show that females with sporadic FTD have a shorter disease duration than males whereas in genetic FTD the disease duration does not differ between sex. These findings suggest the existence of sex‐related differences in the disease course of sporadic FTD. We urge the need for international epidemiological FTD studies to further explore the role of sex in both genetic and sporadic FTD.
Cortical diffusivity associates with early neuronal damage
Authors: Nowell Joseph , Debatisse Justine , Femminella Grazia Daniela , Raza Sanara , Edison Paul
Published: December 2022

Background

Diffusion weighted imaging can provide a marker a microstructural damage which cannot be detected by conventional structural MRI. Changes in cortical diffusivity may be a value marker of neuronal breakdown, which predates macrostructural damage. We aimed to evaluate the efficacy of cortical diffusivity in predicting the extent of metabolic changes in different stages of Alzheimer’s disease progression.

Method

90 participants diagnosed with mild to moderate Alzheimer’s disease were recruited at Imperial College London. A median split was conducted to categorise participants into ‘Early’ (MMSE ≥ 25, n = 42) and ‘Late’ stage of AD groups (MMSE < 25, n = 48) to reflect different stages of disease progression. All participants underwent [18F]fluorodeoxyglucose imaging with arterial input, t1‐weighted MRI images and diffusion weighted images were also acquired. Spectral analysis was conducted to calculate the cerebral metabolic rate of glucose (CMRglc). CMRglc and mean diffusivity maps were spatially normalised to MNI space and individualised grey matter object maps were created for all participants. Linear regression was conducted between CMRglc and mean diffusivity maps. Mean diffusivity and CMRglc values within the temporal lobe were extracted to confirm voxelwise results.

Result

In this cohort, voxel‐wise statistics revealed a significant relationship between cortical diffusivity and reduced CMRglc, particularly in our ‘early’ stage AD group. Most notable correlations were located within temporal lobe regions. Regional analysis revealed that increased temporal lobe mean diffusivity was strongly correlated with decreased CMRglc in ‘early’ AD participants (r=‐0.525, p<0.001, 95% CI: ‐0.263 to ‐0.715). We found evidence of a weaker correlation in the ‘late’ AD group between increased diffusivity and CMRglc reductions within the temporal lobe (r=‐0.322, p=0.026, 95% CI: ‐0.042 to ‐0.555).

Conclusion

Cortical mean diffusivity is a valuable predictor of early neuronal damage measured by cerebral glucose metabolism in Alzheimer’s disease. This association was strongest in earlier stages of the disease trajectory, as such, we establish that cortical mean diffusivity as an early biomarker in Alzheimer’s disease which reflects early changes in tissue integrity and cell/organelle breakdown.
TSPO gene polymorphism in Korean population
Authors: Shin Dong Jin , Noh Young
Published: December 2022

Background

18‐kDA translocator protein (TSPO protein) expression increases in neuroinflammation. Specific ligands that binds to TSPO protein can be used to visualize neuroinflammation. Due to the reported dependency of binding properties of the second‐generation TSPO ligands on a genetic polymorphism of the TSPO gene, all individuals were genotyped and classified as low‐, medium‐, or high‐affinity binder (LAB, MAB, and HAB). The objective of this study is to investigate the rs6971 gene polymorphism in Korean population.

Method

We performed genetic testing in 109 subjects including Alzheimer’s disease, mild cognitive decline, Lewy body disease, subcortical vascular dementia, and cognitively unimpaired participants. All of them performed MRI and detailed neuropsychological test. 29 participants also took 18F‐DPA714 PET. Exon 4 of the TSPO gene containing the polymorphism rs6971 (Ala or Thr at position 147) as well as exon/intron junctions were PCR amplified and sequenced using Sanger method. The identified rs6971 genotypes (C/C, C/T, or T/T) code for the amino acids Ala/ Ala, Ala/Thr, or Thr/Thr at position 147 of the TSPO protein and were considered to generate a high‐, medium‐, or low‐affinity binding phenotype, respectively.

Result

We found 96.3% of the study subjects were HAB (105 out of 109 subjects), and 3.7% of the subjects were MAB (4 out of 109 subjects). There was no participant who was LAB. From HapMap data allele frequency, American group had 69.2%of HABs, 28% of MABs, and 2.8% of LABs. In African group, 67.4% was HABs, 29.4% was MABs, and 3.2% was LABs. In Asian group, 96.9% was HABs, 6.1% was MABs, and 0.1% was LABs. In Europe group, 45.7% was HABs, 43.8% was MABs, and 10.5% was LABs.

Conclusion

Korean population had lesser frequency of MABs and LABs like other Asian population. Therefore, availability of second‐generation TSPO PET related to rs6971 gene polymorphism would be lesser affected.
Accessibility of Mixed Reality Technologies for people living with dementia
Authors: Desai Shital , Abendschein Robin , Astell Arlene J.
Published: December 2022

Background

Mixed reality technologies (MRTs) are increasingly being explored for use in dementia but there is a lack of information about the accessibility of different types of MRT hardware and software to develop new applications. We examine the accessibility of four MRTs for people living with dementia.

Method

Phase 1: Step‐by step analysis of all set‐up, initiation and game play actions was undertaken by one of the research team. Phase 2: Twenty‐two people with dementia (mean MoCA 14, aged 63 to 88 years), tested four MRT technologies and applications: Hololens: Young Conker; Xbox Kinect: Bowling; Osmo: Tangram and iPhone‐X: Stack‐AR. Interaction and game play actions were coded to identify accessibility promoting and inhibiting features from video recordings of their play sessions.

Result

Accessibility of the four hardware and software pairings varied considerably, including the cognitive demands to successfully interact with both the technology and the games. People with dementia attempted to use all of the technologies and games and found them more or less accessible in line with the step‐by‐step analysis of the hardware/software pairings.

Conclusion

The functionality in MRTs that can successfully prompt people with dementia through games could be extended to completing other daily activities, such as cooking. However, successful use requires careful consideration of the cognitive demands and other accessibility factors made by the hardware and software. The findings can support development of bespoke MRT applications for people living with dementia.
DNA methylation profiling across brain regions in Huntington’s disease.
Authors: Wheildon Greg , Weymouth Luke Stephen , Smith Adam R. , Smith Rebecca G. , Troakes Claire , Al‐Sarraj Safa , Lunnon Katie
Published: December 2022

Background

Huntington’s disease (HD) is an autosomal dominant condition that occurs due to the expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene. The translated HTT protein has an expanded polyglutamine sequence thought to cause deleterious effects. These effects cause severe neurodegeneration in the striatum. In HD there is also clear atrophy in the cerebellum and a reduction in cortical thickness, including in the entorhinal cortex (EC). Epigenome wide association studies (EWAS) of DNA methylation differences in HD have thus far been limited to the cerebral cortex and use older technologies such as the Illumina 450K array. In this study, we performed an EWAS of HD in the striatum, EC and cerebellum, using the Illumina EPIC methylation array to profile 850, 000 sites across the genome.

Method

120 striatum, EC and cerebellum DNA samples from 22 control and 20 HD subjects were selected and matched for sex, age and post‐mortem interval. The samples were chosen to be as free from co‐existing pathologies as possible. The majority of subjects were represented in each brain region. The DNA was bisulfite converted, randomized and profiled using the EPIC array. The methylation intensities for each sample were subjected to quality control (QC). Following QC, the samples were analyzed in R for differences in methylation between HD and control samples within each brain region, before being subjected to cross‐regional analysis.

Result

We have used linear regression models to identify differentially methylated positions (DMPs) in specific brain regions in HD. We have used regional analyses to identify differentially methylated regions (DMRs) consisting of multiple adjacent DMPs. Finally, downstream analyses have highlighted epigenetically altered pathways in disease.

Conclusion

This study builds a clearer picture of DNA methylation profiles in HD in disease relevant brain regions. Future studies should integrate this with other levels of genomic regulation.
Biological, physiological, neurobiological, neurophysiological pathogenesis of Alzheimer’s, dementia, neurodegenerative diseases:
Authors: Mayer Gabriele
Published: December 2022

Background

Human beings use all sensory organs in biological/physiological, neurological/functional ways to feed the brain/brain cells with necessary input/impulses of all environment information for the brain. Practical review: Our lifestyle, ‐losing anymore in life emotional our reactions are: fear, stress, panic, aggressive, depressive, affected person withdraws him/herself: forgets daily life structures/real‐world, loses relationships of any kind , falls backwards in development stages.

Method

a)physiological system: In body/brain are changes of pathological biochemical/neuobiochemical milieu. The brain cells will not work through less neurotransmitters, the brain cells go down.‐The pathological milieu in brain is through less input functions of sensory organs, without/less consciousness.

Result

a)Factual review results are:‐cognitive/perceptions skills dysfunctions,‐abilities wakefulness is less,‐deficiencies/shortcomings disorders, ‐reality misconceptions, ‐daily life relationship loss,‐brain related disorders: ‐"vascular earlier microcirculatory failure in brain, Damage of Brain Cells”, ‐neurodegenerative diseases,‐and metabolisms disorders through: ‐ our lifestyle, ‐unhealthy nutrition, ‐not enough fluid intake,‐occupying all sensory organs. b)physiological system: It’s ‐too little fluid, too little blood speed, ‐oxygen lack, ‐nutrients distribution, detoxification, exchanges in cells are too slow. This leads to slower metabolism. ‐And delay processing of motor output with, –movement/balance disorders, ‐brain cells metabolic disturbances,‐circulatory disorders, ‐focus/concentration difficulties.‐perceptions disorders,‐ incorrectly feelings/movements. Through poor flow blood properties: ‐blood speed reduction, ‐brain circulatory disorders,‐body/brain oxygen lack, ‐harmful toxins and medication reactions can not be controlled in combination mix with alcohol. All calling up:‐pathological/neurobiochemical reactions in the brain and this leads to neurodegenerative diseases. ‐c)practical system

results

‐abilities wakefulness/perceptions of all sensory organs are less.‐ deficiencies/shortcomings disorders, ‐reality misconceptions, ‐relationship loss to daily‐life. System: Molecular in brain: a)‐through neurobiochemical changes, neurotransmitters building themselves are low, leads to brain cells death. b)‐synapses transmissions glutamate failures, molecular reactions are misfolded proteins productions, with pathological neurobiochemical reactions: growth of fibrils, amyloids, blockades other brain cells. Cells death : power of weight, press, speed of brain cell death. Human being is dead. It's a normal wrongful process.

Conclusion

In practical work:‐prevent, stop this, ‐follow biological, physiological function to feed your human brain/brain cells. Therapy is “Rediscover Recovery Practical Reference Training”, multidisciplinary work fields. The goal is: affected person status rebuilding, person’s reintegration in family (not as patient),
The AppNL‐F mouse model of Alzheimer’s Disease demonstrates reduced serum Aß42 levels and Aß42/Aß40 ratio, changes that correlate with CSF Aß levels and cerebral Aß42 plaque load
Authors: Andersson Emelie , Schultz Nina , Blennow Kaj , Zetterberg Henrik , Hansson Oskar
Published: December 2022

Background

Recent development of novel assays has made it possible to reliably measure proteins for diagnosis of Alzheimer’s disease (AD) in blood in addition to cerebrospinal fluid (CSF). Previous studies have shown that blood and CSF Aß40 and Aß42 levels correlate in AD patients, and other studies have demonstrated that a reduced plasma Aß42/Aß40 ratio inversely correlates with amyloid burden in the brain (determined by PET). However, more studies are needed to fully understand how these Aß changes in blood correlate with CSF Aß as well as the cerebral Aß plaque load. In this current study, we aim to investigate these associations by the use of a novel knock‐in mouse model, AppNL‐F.

Method

Serum, CSF and brain tissue was collected from 3‐18 months old App NL‐F knock‐in mice. Levels of serum and CSF Aß40 and Aß42 were analyzed using Simoa Technology (Quantrix). Mouse brain sections were immunostained against Aß42 to determine the cerebral Aß42 plaque load.

Result

In serum from our AppNL‐F mouse model, we found increased levels of Aß40, decreased levels of Aß42 as well as a decreased Aß42/Aß40 ratio with increasing age, particularly after 12 months of age, which was similar in time to the changes observed in CSF. These alterations in serum Aß42 levels and Aß42/Aß40 ratio were associated with the increase of cerebral Aß42 plaque load (Rs ‐0.50 and ‐0.51, respectively), which were lower compared to the associations between CSF Aß42 and Aß42/Aß40 ratio with Aß42 plaque load (‐0.71 and ‐0.70, respectively).

Conclusion

Our results from the AppNL‐F knock‐in model, show that decreased serum Aß42 and Aß42/Aß40 ratio are mirroring both the decreased Aß42 and Aß42/Aß40 ratio in CSF as well as correlate with increasing cerebral Aß plaque load. These findings indicate that Aß changes in serum and CSF in the AppNL‐F mouse model mirror Aß alterations seen in preclinical AD. Furthermore, these results suggest that changes in Aß42 and Aß42/Aß40 ratio occur simultaneously in serum and CSF and well in concurrent with the deposition of Aß in the brain.
The association of multimorbidity and neuropsychological test scores in Canadian cohorts recruited in 1991 and 2015
Authors: Vargas‐González Juan‐Camilo , Hachinski Vladimir , Speechley Mark R. , Daley Mark J. , Were Jason , Sharma Ishor , Stranges Saverio
Published: December 2022

Background

Multimorbidity is associated with cognitive decline. Little information exists regarding whether the relationship between multimorbidity and cognitive decline has changed over the last few decades.

Objective

To compare estimates of the association between multimorbidity (MM) and performance on cognitive tests in two prospective cohorts of Canadian community‐dwelling older adults recruited 24 years apart.

Method

We analyzed the two datasets separately, including participants ≥65 years from both baseline and first follow‐up of the Canadian Study of Health and Aging (CSHA, 1991 – 2001; first follow up in 1996) and the Canadian Longitudinal Study on Aging (CLSA, 2015 – ongoing; first follow up in 2018). We excluded participants with baseline dementia. In both cohorts, we defined MM as two or more conditions from a list of 14. The neuropsychological tests were Animal Naming Test (ANT) and the Rey Auditory Verbal Learning Test (RAVL) for both cohorts. Tests of frontal function were the Digit Symbol Substitution Test (DSST) in the CSHA and the Mental Alternation Task (MAT) in the CLSA. We performed multilevel linear modelling. We controlled for confounders, which were detected using a Directed Acyclic Graph.

Result

We included 497 participants from the CSHA and 9308 from the CLSA. The mean age was 78.0 in the CSHA and 72.0 in the CLSA, and male accounted for 36.4% in the CSHA and 50.2 in the CLSA. Mean MM was 2.1 in both cohorts, with a higher prevalence of MM in women (CSHA 63.9%; CLSA 64.2%) than in men (CSHA 55.8%; CLSA 59.5%). When comparing both cohorts, we found that baseline MM was not associated with changes in the Z‐scores for the ANT (CSHA: 0.16, CI95: ‐0.014 to 0.34; CLSA: ‐0.002, CI95: ‐0.044 to 0.04), RAVL delayed recall (CSHA ‐0.033, CI95: ‐0.23 to 0.16; CLSA: 0.031, IC95: ‐0.013 to 0.074), or DSST in CSHA (0.1, CI95: ‐0.084 to 0.29) / MAT in CLSA (0.008, CI95: ‐0.035 to 0.052).

Conclusion

We did not find differences in Z‐scores changes over 5 years follow up in the CSHA and 3 years follow up in the CLSA, for three neuropsychological tests among Canadians ≥65 years recruited over two decades apart.
Augmenting cognitive training in older adults with transcranial direct current stimulation: Initial results from the Phase III ACT trial and new directions
Authors: Woods Adam J. , Alexander Gene , Cohen Ronald , Marsiske Michael , DeKosky Steven T , Hishaw Georg A. , Wu Samuel S. , Indahlastari Aprinda , Albizu Alejandro , Fang Ruogu
Published: December 2022

Background

Effective non‐pharmacological interventions to remediate age‐related cognitive decline and alter trajectories toward dementia are limited. The Augmenting Cognitive Training in Older Adults trial (ACT) was the first phase III randomized clinical trial initiated for transcranial direct current stimulation.

Method

This NIA funded trial sought to evaluate whether 3 months of cognitive training paired with bilateral 2mA tDCS to the frontal lobes could produce clinically meaningful improvement in a composite measure of cognitive function in healthy older adults: the NIH Toolbox Fluid Cognition Composite score. The ACT trial will be unblinded April 30, 2022. Further still, over the past 5 years, it has become increasingly evident that fixed dosing approaches to tDCS, like those used in the ACT and every other trial to date, are insufficient for addressing individual differences and maximizing clinical outcomes.

Results

We will present, for the first time, the primary outcome results from the ACT trial. In addition, we will present initial findings from related secondary neuroimaging and cognitive indices. In this talk, we will also present preliminary findings from our ongoing work to refine dosing technology for tDCS in older adults using computational modeling, artificial intelligence and multimodal imaging, paired with tDCS outcomes from the ACT trial.

Conclusion

We will present new analyses, available only upon unblinding of ACT. These data use person‐specific computational models of tDCS current flow paired with machine learning and clinical outcomes to identify critical characteristics of tDCS current in the brain (e.g., intensity, direction of current flow) most strongly associated with response vs. non‐response. These data will provide initial insight into which regions of the brain and what characteristics of current were strongly associated with treatment response in the ACT trial. In addition, these data also provide critical insight into how stimulation dosing (electrode positioning, stimulation intensity) can be modified at a person‐specific level to potentially enhance clinical outcomes. Thus, the proposed talk will provide state of the art trial findings from the first completed tDCS Phase III clinical trial paired with next generation approaches to remediated age‐related cognitive decline using tDCS technology.
At‐Home Data Collection with an App‐Based Cognitive Assessment for Detecting Memory and Executive Functioning Changes in Aging and Pre‐Clinical AD
Authors: Mechanic‐Hamilton Dawn , Halberstadter Kimberly , Lydon Sean , Liebenberg Erin , Wolk David A.
Published: December 2022

Background

Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility of at‐home, app‐based memory and executive functioning tasks included in the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical AD.

Method

The mCAPP includes three gamified tasks (Figure 1): (1) a “concentration” memory task that includes learning and matching hidden card pairs with increasing memory load, pattern separation features (lure vs. non‐lure), and spatial memory (2) a stroop‐like task (“brick drop”) with speeded word and color identification and response inhibition components and (3) a digit‐symbol coding‐like task (“space imposters”) with increasing pairs and incidental learning components. Participants also completed the NACC UDS3, additional paper and pencil tests, and NIH Toolbox measures. Participants used the mCAPP at home for two weeks. Participants included sixteen older adults (56% female; age=71.4±5.0, education=16.4±3.1; 63% White, 31% Black, 6% Multiracial) without cognitive impairment enrolled in the Penn ADRC cohort.

Results

Participants played 12.1±4 times over two weeks, with 15/16 playing more than the assigned sessions. Almost all participants (88%) used a smartphone, but few (31%) played games on their phone. Usability rating was 6.2±0.7 (1‐7 scale) and most participants reported task difficulty was just right (75%‐81%). All tasks showed lower performance with increasing age and brick drop inhibition and space imposters also correlated with education (p’s<0.05). Concentration performance correlated with UDS3 memory measures (p’s<0.05, Figure 2). Brick drop performance correlated with measures of attention and executive functioning (p’s<0.05, Figure 3). Space imposters correlated with the Digit Symbol Substitution Test (p<0.001, Figure 4). Some participants performed similarly across AM and PM sessions, while others showed differential performance. Initial change scores from the first to second session and from the 2nd to the last sessions did not show significant change.

Conclusion

This pilot study shows acceptability and usability of the app for at‐home use. Performance across measures indicate initial reliability and validity of mCAPP with continued data collection with a larger sample needed.
Amyloid and tau pathologies associate with distinct aspects of the inflammatory cascade
Authors: Bellaver Bruna , Leffa Douglas Teixeira , Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , De Bastiani Marco Antônio , Tissot Cécile , Lussier Firoza Z , Therriault Joseph , Benedet Andréa Lessa , Servaes Stijn , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Gauthier Serge , Schöll Michael , Ashton Nicholas J. , Zimmer Eduardo R , Zetterberg Henrik , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A
Published: December 2022

Background

Inflammation has long been pointed out as a key feature in Alzheimer’s disease (AD). However, the heterogeneity of AD pathology might trigger different aspects of the immune response. Here, we aimed to study the association of the newly proposed concept of inflammatory composite indexes with Aβ and tau pathologies across the aging and AD spectra. We hypothesize that distinct inflammatory pathways are associated with the different hallmarks of AD.

Method

A panel of 92 inflammation‐related markers was measured in the CSF of 60 individuals (35 cognitively unimpaired and 25 cognitively impaired) from the McGill TRIAD cohort. These 92 proteins were clustered by ontogenetic similarity and physical interaction using STRING. A z‐scored composite value representing each cluster was created for each individual. Individuals were classified as Aβ‐ and tau‐positive using global [18F]AZD4694 and temporal meta‐ROI [18F]MK6240 PET, respectively. Linear regressions (corrected by diagnosis, age, sex, and APOEɛ4 status) and receiver operating characteristic (ROC) analyses evaluated clusters’ performance.

Result

Of the six clusters identified in our protein network analysis, three positively correlated with global Aβ‐PET (C4,C5, and C6) and three with meta‐ROI tau PET (C2,C4, and C5;Fig.1). However, controlling for Aβ PET, tau PET was only associated with C2, indicating that the association with the other two clusters (C4 and C5) was dependent of Aβ pathology. The cluster exclusively associated with tau (C2), represents tumor necrosis factor‐mediated signaling pathways. On the other hand, C6, related to the stimulation of interferon‐gamma production, and C5, related to glial cell‐derived neurotrophic receptor binding, are exclusively associated with Aβ. ROC analysis showed that all clusters presented a better performance predicting Aβ‐PET positivity than tau‐PET positivity (Fig.2A,B). Additionally, overall the clusters showed a better performance than sTREM2, a classical inflammatory biomarker.

Conclusion

Our novel clustering approach supports that Aβ and tau proteinopathies are associated with distinct aspects of the inflammatory cascade. Our results suggest that a composite of inflammatory proteins better identifies AD pathology than a single marker. Finally, this suggested cluster approach helps to understand the inflammatory response to Aβ and tau and can uncover inflammation‐related AD pathways.
Cognitive‐behavioral associations of amygdala subregional tau pathology in cognitively unimpaired Presenilin‐1 E280A mutation carriers
Authors: Langella Stephanie , Sanchez Justin S , Martinez Jairo E. , Rubinstein Zoe B. , Baena Ana Y. , Vila‐Castelar Clara , Ramirez‐Gomez Liliana A. , Aduen Paula , Jacobs Heidi I.L. , Sperling Reisa A. , Johnson Keith A. , Lopera Francisco , Gatchel Jennifer R , Quiroz Yakeel T.
Published: December 2022

Background

Carriers of the Presenilin‐1 (PSEN1) E280A mutation are virtually determined to develop Alzheimer’s disease (AD) dementia by midlife. Tau pathology accumulates in the amygdala of PSEN1 carriers prior to clinical onset. Amygdala dysfunction, particularly in basolateral regions, may contribute to early neuropsychiatric symptoms in sporadic AD and other dementias. We aimed to examine the cognitive‐behavioral associations of subregional amygdala tau pathology in preclinical PSEN1 carriers, focusing on episodic memory and neuropsychiatric symptoms.

Methods

Participants included 25 unimpaired PSEN1 carriers and 37 non‐carriers from the Colombia‐Boston (COLBOS) Biomarker Study, matched in age, sex, and education (Table 1). In vivo regional tau pathology was measured using PET (Flortaucipir), with lateral and basal (aggregate region comprised of basal and accessory basal nuclei) amygdala as primary regions of interest (automatic segmentation using FreeSurfer v7). Memory was measured using the CERAD Word List Delayed Recall. Neuropsychiatric symptoms were measured using the Geriatric Anxiety Scale (GAI) and Geriatric Depression Scale (GDS). Associations with tau were tested using Spearman correlation. Group differences on cognitive‐behavioral measures were tested using independent samples t‐tests.

Results

Carriers and non‐carriers did not differ in overall depression or anxiety symptoms, but carriers had lower memory recall scores (Table 1). In carriers, lower recall was associated with greater tau accumulation in lateral (r = ‐.422, p = .036) but not basal (r = ‐.291, p = .158) amygdala. Higher depressive symptoms in carriers were associated with greater tau in both lateral (r = .530, p = .007) and basal (r = .467, p = .019) amygdala. Anxiety symptoms were not associated with amygdala tau in carriers (ps > .309). No significant associations were observed in non‐carriers.

Conclusions

Amygdala tau pathology is associated with depressive symptoms and lower memory recall in cognitively unimpaired PSEN1 carriers, particularly in lateral amygdala. These results suggest that lateral amygdala tauopathy may be an early indicator of disease progression and may underlie cognitive and neuropsychiatric changes associated with early AD. Future longitudinal studies with larger samples and additional regional tau measures are needed to clarify the effects of subregional amygdala tau pathology on clinical onset and progression of AD.
Negative Correlation of Corpora Amylacea with pTau in the Hippocampus of People with AD
Authors: Dallmeier Julian , Vontell Regina T , Davis David A. , Gober Ryan , Barreda Ayled , Garamszergi Susanna , Sun Xiaoyan , Wander Connor , Cohen Todd J , Scott William K.
Published: December 2022

Background

Recent studies suggest corpora amylacea (CA) activity may be involved in modulating AD pathology. Normally, CA function in the clearance of brain waste products by amassing cellular debris and extruding it into the cerebrospinal fluid. Disruption of this process may play a role in AD pathogenesis, and its effect might be influenced by degree of tau pathology and genetic risk. In this study, we determined if the abundance of CA was correlated with paired helical filament tau pathology in the CA1 region of the hippocampus in AD postmortem tissue samples. Tau pathology was assessed using both total pTau and total NFTs. Additionally, we investigated whether that correlation was influenced by APOE genotype.

Method

Postmortem brain hippocampal tissue sections from 11 brain donors with pre‐mortem cognitive impairment and neuropathologically confirmed AD were double‐stained with Periodic‐acid Schiff (PAS) stain to identify CA and AT8 antibody to identify hyperphosphorylated Tau protein (pTau). Using the Motic slide scanner, stained sections were digitized at 40x. QuPath 0.3.2 was used to extract the CA1 hippocampal region and export to ImageJ for analysis. ImageJ 1.8 color thresholding was used to quantify the number and area of CA and pTau. Neurofibrillary tangle (NFT) pathology was classified by pTau aggregations larger than 150μm2. The percent area occupied (%AO) was calculated by dividing the sum of all positively stained objects by the area of the image, then multiplying by 100. Pearson correlations between CA %AO, pTau %AO, and NFT %AO were calculated in Python 3.7.

Result

While not statistically significant, we found negative correlations of CA %AO with pTau %AO (‐0.14), and NFT %AO (‐0.28) in the CA1 of the hippocampus. These correlations (‐0.68 and ‐0.54 respectively) were stronger in the 4 individuals who did not carry the AD risk‐increasing APOE‐4 allele.

Conclusion

These results suggest that as CA decline, pTau accumulates, which is consistent with prior studies that described a decline in CA from intermediate to advanced Braak Stages (III‐VI) in the dentate gyrus. These changes are consistent with our
Brain TSPO expression is associated with plasma pTau181 & pTau231 across the AD spectrum
Authors: Rahmouni Nesrine , Therriault Joseph , Tissot Cécile , Lussier Firoza Z , Stevenson Jenna , Stevenson Alyssa , Servaes Stijn , Ashton Nicholas J. , Arias Jaime Fernandez , Wang Yi‐Ting , Kang Min Su , Karikari Thomas K , Gauthier Serge , Pascoal Tharick A , Zetterberg Henrik , Blennow Kaj , Benedet Andréa Lessa , Rosa‐Neto Pedro
Published: December 2022

Background

Microglial activation is an important component of the immune response in the brain of AD patients and has been shown to follow a similar propagation pattern to tau tangle accumulation. However, it is unclear to what extent cerebral microglial activation is associated with biofluid concentrations of phosphorylated tau (pTau). The objective was to investigate whether concentrations of pTau181 and pTau231 are correlated with microglial activation indexed by [11C]PBR28 PET across the AD spectrum.

Method

The present study was conducted in a population of 130 individuals from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort: 20 young cognitively unimpaired, 65 cognitively unimpaired elderlies, 31 with mild cognitive impairment and 14 with AD dementia. Participants were evaluated with blood biomarkers and [11C]PBR28 PET. Plasma pTau181 and pTau231 concentrations were quantified using a Simoa assay. Microglial activation was assessed via [11C]PBR28 PET, standardized uptake value ratios (SUVRs) were calculated between 0 and 90 minutes post‐injection, using cerebellum grey matter as the reference region. Voxel‐based regression models evaluated the relationship between plasma pTau181 and pTau231 with neuroinflammation as assessed by PET, correcting for age and sex.

Result

In the present study, positive correlations were found between concentrations of both pTau181 and pTau231 and neuroinflammation indexed by PET‐imaging. Voxel‐level analyses indicated that these associations prenominated in regions of the default mode network including the precuneus, posterior cingulate cortex and medial prefrontal cortex. These regional associations survived corrections for multiple comparisons.

Conclusion

Peripheral phosphorylated tau is associated with neuroinflammation in brain regions associated with AD. Our findings highlight the importance of neuroinflammation in the pathogenesis of AD.
Association of Mid‐life Discrimination Stress and Coping on Brain Volumes
Authors: Kulshreshtha Ambar , Misiura Maria , Hu William T. , Verble Danielle D , Likos Kelly D. S. , Wharton Whitney
Published: December 2022

Background

Chronic stress is related with poor health outcomes including changes in brain structure and function. Stress‐related glucocorticoid and adrenergic receptors are richly expressed in hippocampus, prefrontal cortex, and amygdala, but it is unclear if all forms of stress impact these brain regions. Perceived discrimination is a form of stress, and there is limited research in how perceived discrimination can impact brain volumetrics. Our goal is to assess the association of perceived discrimination in brain regions prone to stress‐related affect.

Methods

We examined data from 35 cognitively normal, racially diverse, middle‐aged adults with a parental history of Alzheimer’s disease (AD). Participants provided medical history, demographic and discrimination survey data. Discrimination scales included the Expanded Everyday Discrimination Scale (EED), Major Experiences of Discrimination Scale (MED), Heightened Vigilance Scale (HVIGIL), and Coping with Discriminating scale (COPE). Participants underwent structural MRI with high resolution anatomical images of regions including the hippocampal, prefrontal cortex and amygdala. Multivariate linear regression was used to model the association between stress scales and brain volumes controlling for age and race. Volumes are adjusted for intracranial volume.

Results

Participants were average 61.5 years, 60% women, 8.6% African American and 40% had a postgraduate education. 54.3% participants had hypertension, 74.3% had dyslipidemia. EED score was associated with an increase in left (p = 0.49) and right (p = 0.03) hippocampal volume. MED score was associated with an increase in left (p< 0.01) and right (p = 0.01) hippocampal volume. HVIGIL sum score was associated with an increase in left (p = 0.02) and right (p = 0.03) hippocampal volume. The COPE sum score was associated with increased in left p = 0.01) and right (p< 0.01) hippocampal volume. There was a positive association in the above stress scores with left and right amygdala and prefrontal cortex, but these were not statistically significant.

Conclusion

Contrary to our hypothesis we found that perceived discrimination is associated with larger brain volumes particularly in the hippocampus region. Mid‐life discrimination when accompanied with better coping skills is related to larger brain volumes suggesting mechanisms that warrant further exploration. Mid‐life maybe an important phase for intervention efforts to mitigate long‐term effects of stress.
Gender differences in cognitive performance among health volunteers of SANSCOG cohort
Authors: Lingegodwa Abhishek Mensegere , Giridhar Varsha , TEJA KARRU VENKATA RAVI , Sundarakumar Jonas S. , Ravindranath Vijayalakshmi , Collaborators SANSCOG
Published: December 2022

Background

Women are at higher risk of AD probably due to longer life span. However, differences in cognitive performance across gender among normal aging individuals is inconclusive. Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG) is a longitudinal study in healthy aging individuals in a town located near Bangalore, India.

Method

Our objective was to compare cognitive performances at baseline assessment measured by COGNITO battery and HMSE between men and women participants of SANSCOG cohort who did not have dementia.

Result

In a sample of 2354 individuals, 1141 (48.5%) were women. Men were older and had more years of education when compared to women. Generalized linear models were constructed which used age and education as confounding variables revealed that males performed better than females on global cognition (β = ‐0.62, p < 0.001). When we examined individual domains, men achieved better scores in visuospatial domain and attention domain, however, women achieved better scores in memory domain. In the language domain, females scored more than males in semantic association test but males scored more in semantic fluency. There was no difference found in executive function domain.

Conclusion

We have demonstrated that healthy rural Indian women perform poorly in global cognition and attention suggesting that they are at greater risk of developing dementia.
A longitudinal analysis of depressive symptoms in relation to repeated measurements of regional tau
Authors: Munro Catherine E , Buckley Rachel F. , Vannini Patrizia , Hanseeuw Bernard , Quiroz Yakeel T. , Farrell Michelle E. , Rentz Dorene M. , Blacker Deborah , Sperling Reisa A. , Johnson Keith A. , Amariglio Rebecca E. , Marshall Gad A , Gatchel Jennifer R
Published: December 2022

Background

Depressive symptoms are commonly observed early in Alzheimer’s disease (AD), but their temporal association with progression along the AD continuum is less clear. We sought to determine if initial measurements of regional tau were predictive of increasing depressive symptoms, and if changes in depressive symptoms predicted later tau levels. We examined these relationships in a region of early tau accumulation (i.e., entorhinal cortex (EC)), and in regions of later neocortical tau spread commonly involved in affective regulation (amygdala and medial and lateral orbitofrontal cortex (mOFC, lOFC)).

Method

Participants (n = 257; mean age = 70.7; 61% female) came from the Harvard Aging Brain Study, a longitudinal observational cohort of cognitively unimpaired adults with no/low depression at baseline (mean years of follow‐up = 7.2). All participants completed the self‐reported 30‐item Geriatric Depression Scale (GDS) annually and tau PET imaging (Flortaucipir‐FTP) every 3 years. On average, initial tau PET scans occurred 2.3 years after enrollment and the latest available scan occurred 5.1 years after enrollment. Separate linear mixed effects models investigated relationships between longitudinal GDS and cross‐sectional regional tau (FTP PET SUVr), at initial scan and at the latest scan available, in the following regions of interest: EC, amygdala, mOFC, and lOFC. Covariates included age, sex, and education.

Result

Higher initial FTP levels were associated with significant increases in GDS score over time in temporal cortex (amygdala: b = 0.29,p = 0.0002; EC: b = 0.21,p = 0.0006) and mOFC (b = 0.30,p = 0.004), with marginal significance in lOFC (b = 0.21,p = 0.07). However, the reverse temporal sequence was only observed between GDS scores over all time points and later measurement of amygdala FTP, such that increasing depressive symptoms over time preceded higher final amygdala tau levels (b = 0.15,p = 0.02).

Conclusion

Higher tau in EC, amygdala and OFC regions predicted increasing depressive symptoms over time in older adults. Only for the amygdala did we also observe the converse relationship: increasing depressive symptoms predicting higher final tau. These results suggest early tau proliferation in affective regions is associated with increased depressive symptoms, though the question of causality is still unclear. Further work is needed to dissect possible temporal relationships across whole brain voxels to better understand depressive symptoms in AD progression.
Factors associated with the Big 5 personality traits in Alzheimer’s disease and related dementias (ADRD)
Authors: Rhodes Emma , Massimo Lauren , Mechanic‐Hamilton Dawn , McMillan Corey T , Phillips Jeffrey S , Burke Sarah E , Hlava Quinn , Cook Philip , Gee James C. , Grossman Murray
Published: December 2022

Background

Informant ratings of behavior and personality change are the gold standard of measurement in Alzheimer’s disease and related dementias (ADRD) where insight is often impaired, but informant report can be biased by psychosocial factors such as caregiver burden. This study assessed the impact of caregiver burden on informant ratings of patient Big 5 personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, Openness) and associations between degree of discrepancy between informant and patient ratings with cortical volume in regions implicated in loss of insight.

Method

A sample of 70 ADRD participants with heterogeneous neurodegenerative clinical phenotypes (Figure 1) and their informants completed the NEO Personality Inventory (NEO‐PI). Disease severity was measured using the Clinical Dementia Rating Scale (CDR). Caregiver burden was measured using the Zarit Burden Interview (ZBI). Discrepancy scores were computed for all NEO‐PI Big 5 scores and a global discrepancy score. Participants were classified as having high/low discrepancy using a median split for each NEO‐PI discrepancy score. T1‐weighted 3T MRI grey matter volumes were normalized to intracranial volume for all ROIs in the Schaefer100×17 parcellation, and linear regression analyses related global difference score to Bonferroni‐corrected atrophy regions.

Result

Higher levels of caregiver burden were associated with higher informant ratings of patient Neuroticism (ß = 0.02, p = .013) and lower informant ratings of patient Agreeableness (ß = ‐0.02, p = .0004), Conscientiousness (ß = ‐0.02, p = .005), and Openness (ß = ‐0.01, p = .014) independent of disease severity. Patients with high global discrepancy scores showed reduced cortical volumes in left ventral PFC, right medial PFC, and right superior temporal gyrus. Patients with low discrepancy scores showed relatively preserved cortical volumes in bilateral somatomotor cortex, right posterior cingulate, and left supplementary motor, superior parietal lobule, and postcentral gyrus (all p‐values<.05, Figure 2). Reduced volumes in the high discrepancy group were driven by patients with bvFTD (Figure 3).

Conclusion

Informant ratings of Big 5 personality factors may be confounded by caregiver burden, highlighting the need for more objective measures of personality and behavior in ADRD. Additionally, high levels of discrepancy between informant and patient ratings of personality may reflect loss of insight secondary to cortical atrophy in frontal and temporal structures.