bluuebunny/crossref_metadata_2025 huggingface dataset:
Mediterranean diet protects against neuroinflammation and degeneration in female nonhuman primates
Authors: Shively Carol A. , Negrey Jacob D. , Frye Brett M. , Johnson Corbin S.C. , Kim Jeongchul , Barcus Richard A. , Lockhart Samuel N. , Whitlow Christopher T. , Chiou Kenneth L. , Snyder‐Mackler Noah , Montine Thomas J. , Craft Suzanne , Register Thomas C.
Published: December 2023

Background

Mediterranean diets may reduce Alzheimer’s disease (AD) risk and preserve cognitive function relative to Western diets in part by protecting against neuroinflammation. In middle‐aged humans that subsequently develop AD, increased cortical thickness precedes atrophy. It is hypothesized that the initial increase in brain volumes may be due to early neuroinflammation that precedes neurodegeneration (Pegueroles et al. Alzheimers Dement 2017). Long term impacts of diet patterns on health are difficult to quantify in human beings. Thus, we addressed this hypothesis in cynomolgus macaques (Macaca fascicularis), a nonhuman primate that undergoes age‐related changes in brain structure and function, and responds to Western diets, like humans.

Methods

38 middle‐aged (mean = 12 years of age) female macaques were fed a Western or Mediterranean diet for 2.5 years in a randomized nonhuman primate trial. Changes from baseline in volumes of total brain, gray, cortical gray, and white matter, cerebrospinal fluid and (CSF), were determined by structural MRI. We also generated thickness‐based AD temporoparietal meta‐ROIs based on the AD clinical literature as previously described (Frye et al., 2021 Alzheimers Dement. 2021;17:733). Transcriptional profiles in the temporal cortex were determined at the end of the study by RNAseq.

Results

Western diet led to increases in temporoparietal cortical thicknesses, total brain and gray matter volumes, and diminished cerebrospinal fluid and white matter volumes. Diet significantly altered expression of seven genes (FDR<0.05). The Mediterranean group had lower expression of CDK14, a proinflammatory regulator, and higher expression of BTN2A1, KATNB1, LFNG, MRC2, SLCA32, and TMEM268, many of which have anti‐inflammatory associations. Several differentially expressed genes were correlated with AD‐relevant brain volumes. CDK14 was positively correlated with total brain, total gray, and cortical gray matter volumes and temporoparietal cortical thickness (Figure, Mediterranean = yellow), and negatively correlated with total white matter and CSF volumes. LFNG, MRC2, and SLCA32 were negatively correlated with total brain, total gray, and cortical gray matter volume, as well as temporoparietal cortical thickness, and positively correlated with CSF volume (all p’s<0.05).

Conclusion

These results suggest that the Mediterranean diet protects against, whereas the Western diet promotes, AD‐relevant neuroinflammation associated with early increases in gray matter volumes.
Flortaucipir tau PET in former American football players
Authors: Su Yi , Protas Hillary D. , Luo Ji , Chen Kewei , Alosco Michael L , Adler Charles , Balcer Laura , Bernick Charles B. , Au Rhoda , Banks Sarah J , Barr William , Coleman Michael J , Dodick David W. , Katz Douglas I , Marek Kenneth , Mariani Megan , McClean Michael D , McKee Ann C. , Mez Jesse B. , Daneshvar Daniel H , Palmisano Joseph N , Peskind Elaine R , II Robert W Turner , Wethe Jennifer , Rabinovici Gil D. , Johnson Keith A. , Tripodis Yorghos , Cummings Jeffrey L. , Shenton Martha E , Stern Robert A , Reiman Eric M. ,   DIAGNOSE CTE Research Project Investigators
Published: December 2023

Background

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET patterns and its relation to RHI exposure in former professional and college American football players.

Method

In this study, 218 DIAGNOSE CTE participants, ages 45‐74, with flortaucipir PET were included; 104 were former National Football League players (PRO), 58 were former college football players (COL), and 56 had no history of contact sports, other exposure to RHI, or traumatic brain injury (UE). Regional flortaucipir uptake was quantified using established procedures for three previously defined statistical regions (superior frontal, left parietal, and medial temporal) and compared across the three groups. Association analyses were also performed to examine the relationship between flortaucipir uptake and exposure to RHI using the cumulative head impact index for linear acceleration g‐force (CHII‐G). The potential clinical utility of flortaucipir PET for CTE was also investigated by examining its ability to differentiate participants meeting criteria for traumatic encephalopathy syndrome (TES) and probable or possible level of certainty for CTE pathology from those who do not meet those criteria.

Result

Significantly higher flortaucipir uptake was observed in former football players than in participants without RHI exposure, controlling for age and race for the superior frontal region (Fig. 1A), left parietal, and medial temporal regions. Association between regional flortaucipir uptake and CHII‐G was only observed in the superior frontal region in former players (PRO+COL) 60 years and older (Fig. 1B) and no association was observed in the full PRO+COL group. Flortaucipir PET was not able to differentiate TES groups in former football players (Fig. 1C).

Conclusion

Elevated flortaucipir uptake was observed in former American football players to a group of unexposed men. The association between flortaucipir uptake and exposure to RHI may require a long latent period to manifest. Further investigation of more sensitive tau PET tracers and quantification techniques is warranted to better characterize CTE related tau pathology.
White matter hyperintensities: A long‐term consequence of repetitive head impacts?
Authors: Alosco Michael L , Ly Monica T. , Tuz‐Zahra Fatima , Tripodis Yorghos , Adler Charles , Balcer Laura , Bernick Charles B. , Peskind Elaine R , Mariani Megan , Au Rhoda , Banks Sarah J , Barr William , Wethe Jennifer , Bondi Mark W. , Delano‐Wood Lisa , Cantu Robert , Coleman Michael J , Dodick David W. , McClean Michael D , Mez Jesse B. , Palmisano Joseph N , Martin Brett M , Lin Alexander P , Koerte Inga , Cummings Jeffrey L. , Reiman Eric M. , Shenton Martha E , Stern Robert A , Bouix Sylvain
Published: December 2023

Background

Repetitive head impacts (RHI) from American football can lead to tau and non‐tau pathologies that might present as white matter hyperintensities (WMH) on FLAIR MRI. In 2022, we published a study in Alzheimer’s & Dementia that examined WMH and their association with risk factors and clinical function in former elite football players. That study will be presented during this symposium along with new unpublished data that used imaging and fluid biomarkers to examine etiological correlates (tau, amyloid, neurodegeneration, axonal injury, neuroinflammation) of WMH in the same cohort.

Methods

The multi‐site DIAGNOSE CTE Research Project recruited 180 football players and 60 asymptomatic males without RHI (“controls”), all 45‐74 years (Table 1). Participants completed MRI, lumbar puncture, and neuropsychological testing. Lesion Segmentation Toolbox estimated FLAIR WMH, FreeSurfer derived total cortical thickness, and a diffusion pipeline derived average global FA. CSF was analyzed for p‐tau181, Aβ1‐42, NfL, and sTREM2. Tobit regressions compared football players (n = 149) and controls (n = 53) on total and regional log‐WMH and estimated the effects of years of football and age of first exposure (AFE) to football on log‐WMH. Linear regressions evaluated log‐WMH and clinical associations in football players. Structural equation modeling (SEM) examined effects between log‐WMH and cortical thickness, FA, and the CSF biomarkers. Analyses accounted for age, race, revised Framingham Stroke Risk Profile (rFSRP), body mass index, APOE ε4, and evaluation site.

Results

Alosco et al. (2022) found older (i.e., 60+) but not younger football players had greater total, frontal, temporal and parietal log‐WMH compared to controls (FDR‐adjusted p‐values<0.05; Table 2). Among older football players, younger AFE was associated with greater log‐WMH (beta = ‐0.13, 95% CI = ‐0.23,‐0.02). Greater log‐WMH corresponded to worse Trails A‐B (beta = ‐4.32, 95% CI = ‐8.59,‐0.05) and List Learning Long Delay scores (beta = ‐0.56, 95% CI = ‐0.93,‐0.19). Subsequent unpublished SEM analyses in football players (Figure 1) showed the following direct effects on log‐WMH: higher rFSRP, higher CSF p‐tau181, lower FA, and reduced cortical thickness. There were no indirect effects. Compared to controls, SEM associations were stronger in football players exception for cortical thickness.

Conclusions

FLAIR WMH might have unique imaging characteristics, risk factors, and pathological underpinnings in people exposed to RHI.
Dysfunctional cerebral glucose transport in Alzheimer’s Disease
Authors: Nowell Joseph , Femminella Grazia Daniela , Ritchie Craig W , Holmes Clive , Walker Zuzana , Ridha Basil H , Lawrence Robert M , McFarlane Brady , Archer Hilary , Coulthard Elizabeth , Underwood Benjamin , Koranteng Paul , Karim Salman , Prasanna Aparna , Junaid Kehinde , McGuinness Bernadette , Nilforooshan Ramin , Thacker Simon , Russell Gregor , Malik Naghma , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Holscher Christian , Harrison John E , Hinz Rainer , Tadros George , Passmore Anthony Peter , Ballard Clive G , Edison Paul
Published: December 2023

Background

Glucose is the primary energy source required for the homeostatic function of the brain. Glucose transporter 1 (GLUT1) present at the blood‐brain barrier is a key regulator of glucose transport into the brain. Reduced GLUT1 expression is shown to exacerbate Alzheimer’s pathology in rodent models. Here we aimed to establish whether there are regional differences in ineffective glucose transport amongst people living with Alzheimer’s disease.

Method

125 participants diagnosed with Alzheimer’s dementia, with an [18F]FDG scan with atrial input were enrolled. All participants underwent 3‐tesla magnetic resonance imaging and [18F]FDG scan with continuous and discrete arterial sampling. Spectral analysis was performed to create 1‐minute input‐response function parametric maps. To produce glucose transfer maps we applied the following equation; K1 ⁎ Ca / τ (K1 = 1‐minute IRF map, Ca = Plasma glucose concentration, τ = 1.48 a lumped constant). Glucose transfer maps were then coregistered to the participants’ structural MRI and normalised to MNI space. Regional mean glucose transfer was then calculated for the anterior cingulate cortex, frontal lobe, hippocampus, parahippocampus, occipital lobe, parietal lobe, posterior cingulate cortex, striatum, temporal lobe, and thalamus. A within‐subject ANOVA was then performed to evaluate the regional differences in cerebral glucose transport.

Result

The parahippocampus exhibited the lowest rate of glucose transfer in comparison to all other regions (p < 0.001), followed by the hippocampus. The striatum and occipital lobe demonstrated the regions of the highest mean glucose transportation from blood to the brain. In terms of brain lobes, the temporal lobe showed the lowest rates of glucose transfer, followed by the parietal lobe, then frontal and occipital (p < 0.001).

Conclusion

We demonstrate dysfunctional BBB glucose transport in Alzheimer’s disease, with prominent glucose transport abnormalities localised in the parahippocampus. Impaired glucose transport was most apparent within temporal lobe structures. Targeting glucose transfer may be an effective way of treating Alzheimer’s disease.
The relationships between hippocampal cerebrovascular reactivity, hippocampal volume, and episodic memory in healthy ageing
Authors: Wang Congxiyu , Jobbins Lucy , Reid Graham , Hobden Georgina , Mackay Clare , Ebmeier Klaus P , Rieger Sebastian , Patel Raihaan , Kivimäki Mika , Singh‐Manoux Archana , Bulte Daniel , Suri Sana
Published: December 2023

Background

Cerebrovascular biomarkers such as cerebrovascular reactivity (CVR) have previously been associated with episodic memory. However, the relationship between memory and regional CVR within the hippocampus is not well studied. Moreover, whether this association is affected by hippocampal volume remains to be investigated. This study investigated the associations between hippocampal physiology, structure, and memory in ageing.

Method

Data from 104 participants (Age: Mean = 77±4.9 years) of the ongoing Oxford Heart and Brain Study was analysed for this study. CVR was assessed by a compensatory change in the blood oxygenation level dependent magnetic resonance imaging (MRI) signal in response to a 5% CO2 challenge, hippocampus volume was measured by structural MRI, and episodic memory was assessed with the Hopkins Verbal Learning Test Revised (HVLT‐R).

Result

Mean hippocampal CVR decreased with age (β = ‐0.004, p = 0.006). Mean hippocampal CVR was positively associated with mean hippocampal volume (β = 0.11, p = 0.010), and this association was driven by the left hippocampus after correcting for age and sex. Higher hippocampal CVR was also associated with better performance on the HVLT (β = 13.8, p = 0.035). This association was fully mediated by hippocampal volume, suggesting a path from cerebrovascular reactivity to episodic memory (Sobel’s z = 2.16, p = 0.030, see Figure 1).

Conclusion

This study presents novel findings showing that hippocampal CVR was associated with episodic memory, and this association was mediated by hippocampal volume. This suggests a pathway by which impairments in hippocampal CVR are associated with worse episodic memory via smaller hippocampal volumes.
Cognitive Assessment of Monolingual and Bilingual US Older Latino Populations
Authors: Velez‐Uribe Idaly
Published: December 2023

Commonly used neuropsychological tests may not be sensitive to cognitive changes in Native Spanish‐speaking Latinos living in the United States. Cognitive abilities are culturally bound, and therefore cultural and educational factors can influence an individual’s cognitive test performance. Cognitive tests have been most often developed for middle‐class English speakers, and therefore, they may present bias when the same tests are used within the Spanish‐speaking Latino community. Thus, cultural and linguistic factors, as well as other sociodemographic factors, need to be considered to assure validity and fairness in neuropsychological assessments. Culturally appropriate cognitive assessment is a critical issue when working with socio‐economically diverse Latino populations in the US.

Many Latino adults in the US are bilingual, with 59% of those speaking English also speaking Spanish. As language experience powerfully shapes the brain and cognitive function, bilingualism may play an important role in decreasing the risk of developing dementia later in life. Studies examining the role of sociocultural factors, including acculturation and quality of education, are needed, as well as research that helps develop more appropriate cognitive tests and normative data for different Latino heritages. In this session, the US Consortium of Aging, Dementia & Latino Studies (CADLAS) Cognition and Assessment Special Interest Group (SIG) will discuss recent developments, current challenges, and opportunities, as well as future research directions in this area. The SIG aims to promote collaborations among investigators from different States in the US to harmonize cognitive measures and assessment across cohorts and advance clinical research with US Latino populations.
Integration of Alzheimer’s Disease GWAS with Molecular QTLs Reveals Prioritized Risk Genes and Disease‐associated Molecular Alterations
Authors: Kucukali Fahri , Sleegers Kristel ,   EADB
Published: December 2023

Background

Despite the success of genome‐wide association studies (GWAS) to identify genetic variants associated with complex diseases, as the majority of these variants reside in non‐coding genome, one important task is to link these variants to disease‐associated molecular alterations in risk genes. To this end, we developed a systematic gene prioritization methodology that integrated our recent Alzheimer’s disease (AD) GWAS meta‐analysis with molecular quantitative trait loci (QTL) in disease‐relevant tissues and identified highly likely candidate risk genes and molecular alterations within the majority of 42 novel loci identified. In this subsequent study, we updated our pipeline with new molecular QTL catalogues and analyzed the complete landscape of AD risk.

Method

We performed GWAS‐QTL integration in AD‐relevant tissues and cells by querying the lead variants in each locus in the molecular QTL catalogues, (ii) investigating genetic colocalization between GWAS and molecular QTL signals using coloc, and (iii) conducting transcriptome, methylome, and proteome‐wide association studies (TWAS/MWAS/PWAS) using the EADB stage I meta‐analysis GWAS on 85,934 cases and 401,577 controls. The updated gene prioritization pipeline included new analyses based on new brain protein expression QTL (pQTL), cell‐type‐specific expression QTL (ct‐eQTL), expression QTL (eQTL), histone acetylation QTL (haQTL), and methylation QTL (mQTL) catalogues. Moreover, we used Nanopore RNA sequencing to further investigate risk‐associated splicing events revealed by splicing QTL (sQTL) integration.

Result

Our brain ct‐eQTL coloc results showed that while the most risk‐associated gene expression alterations are specific to microglia, the proportion of astrocyte‐specific eQTL colocalizations were doubled compared to the previous studies. These included EGFR, a previously prioritized gene due to bulk brain eQTL coloc hits, whose downregulation was regulated by the protective signal specifically in astrocytes. Importantly, in a previously unresolved locus we could prioritize HS3ST5 through astrocyte‐specific eQTLs as well. Furthermore, pQTL coloc and PWAS prioritized SNX1, a previously prioritized gene at a lower confidence together with neighboring FAM96A gene, by implicating its genetic downregulation with increased AD risk.

Conclusion

Our updated pipeline systematically prioritized AD risk genes and disease‐associated molecular alterations in the majority of risk loci, and contributed to better interpretation of AD GWAS and understanding of genetically‐associated molecular mechanisms underlying AD risk.
T‐PEP Related Presentation: Alzheimer’s disease pathogenic protein SORLA forms homodimer potentially required for its function
Authors: Kitago Yu
Published: December 2023

Background

So far, many genetic and molecular studies have indicated that the single‐pass transmembrane receptor SORLA can cause Alzheimer’s disease (AD) when mutated, but the detailed mechanism of how SORLA is involved in the pathogenesis of AD is still unknown. SORLA has a unique domain architecture including a huge, multidomain extracellular region with a Vps10p domain and 6 tandem repeats of fibronectin‐type‐III (3Fn) domains plus a short cytoplasmic tail. Although this unique composition must be essential for its potential function as a guiding molecule for protein sorting inside cells, there has been limited information about its overall molecular architecture. We are focusing on the function of SORLA in guiding trafficking along with the retromer complex, and recently found SORLA seems to form homodimers on the cell surface, which correlates with its function.

Method

We employed a highly efficient recombinant expression system for extracellular proteins using mammalian cells that enables detailed biochemical analysis. Using this technique, we produced recombinant secreted protein samples of the whole ectodomain and some fragments derived from human SORLA, and investigated its dimerization property by pull‐down assay followed by SDS PAGE and native PAGE. To investigate the three‐dimensional architecture, we ran a structural prediction using the amino acid sequence of SORLA’s ectodomain only without its signal sequence, propeptide, transmembrane region, and cytoplasmic region, using the program AlphaFold2.

Result

Our biochemical experiments showed that human SORLA has homodimer forming property through its Vps10p domain and 3Fn domains. For theVps10p domain especially, it is indicated that the major fraction forms a homodimer in solution. Based on current structural information, we successfully created a mutant that forms covalent bound homodimer with an artificially introduced intermolecular disulfide bond. Interestingly, the predicted model of the ectodomain shows a folded compact structure, indicating that SORLA’s ectodomain forms a large globular shape on the surface of cells.

Conclusion

Our biochemical experiments showed that SORLA has two putative, opposite‐facing dimeric interfaces. Along with the computational molecular prediction, we propose that SORLA forms polymeric fibril‐like high dimensional structure inside the tubular endosomal membrane, supported by the retromer oligomer from the cytoplasmic side.
Effect of Diet on Cognitive Function and Gut Microbiota in Aged Rats.
Authors: Solch‐Ottaiano Rebecca J , Harper Colin , Engler‐Chiurazzi Elizabeth , Wang Hanyun , Ouvrier Blake , McDonald Katherine , Bix Gregory J , Biose Ifechukwude Joachim , Maraganore Demetrius M
Published: December 2023

Background

Many patients with mild cognitive impairment and Alzheimer’s disease have alterations in the gut microbiota. Dietary consumption directly modulates gut microbiota; therefore, the quality of a diet may impact cognitive function and susceptibility to memory impairments. We hypothesized that consumption of the Mediterranean diet (MeDi) versus the Western diet (WD) will improve cognitive function through beneficial changes to the gut microbiota.

Method

Twelve‐month‐old male Fischer 344 rats (n = 14/group) were randomly assigned to a MeDi, WD, or Chow diet (positive control to MeDi) for three months. Animals then underwent neurobehavioral assessments (n = 10/group) including the Morris water maze and radial arm water maze to assess aspects of short‐ and long‐term memory. Data were analyzed via One‐ or Two‐Way Repeated Measures ANOVA where appropriate. Fecal samples were collected prior to the behavior. Microbial composition was determined by 16S rRNA sequencing.

Result

The MeDi and WD groups consumed more kcals (p<0.05) at various weeks and weighed more compared to the chow group (p<0.05). There was no difference in time to reach the platform between the MeDi and WD or Chow groups in the Morris water maze, however, animals consuming the chow diet were quicker to reach the platform compared to the WD (p = 0.046). There were no differences in total errors measured by the radial arm water maze (p = 0.50) between diets. Gut microbiota composition (β‐diversity) was distinct between diets (Weighted and Unweighted UniFrac, p<0.001).

Conclusion

There were no differences in short‐ or long‐term memory in aged animals consuming a MeDi or WD for three months. Diet‐modulated the gut microbiota as exhibited by differences in β‐diversity between the MeDi, WD, and Chow. As animals consumed a chow diet throughout their lifespan, the MeDi or WD may need to be started earlier in life to exhibit differences.

Funding: NIH Mentoring Research Excellence in Aging and Regenerative Medicine5P20GM103629‐10
Expositions of children’s drawings to reduce stigma regarding the elderly and dementia
Authors: Bormans Kasper , Zwakhalen Sandra ,   Health Sciences Research
Published: December 2023

Background

Dementia and old age are overloaded with stigma and harmful connotations. The elderly are predominantly portrayed and perceived as depressed, lonely and dependent. This negative perspective encourages mutual avoidance behavior and confronts the elderly with a social death. Looking through the eyes of children at the challenges of the future in elderly care can benefit the public health sector.

Method

In this study, we collected 796 children’s drawings from 98 children of 10 years old from 4 elementary schools. Every child completed a 16‐week educational trajectory with positive interventions to connect generations. Pre‐ and post‐intervention, the children made portraits of elderly people and grandparents who are neutral, happy or unhappy. The drawings are implicit instruments for accessing and visualizing children’s hidden perceptions of old age and dementia. The evolutions in the pre‐ and post‐measurements demonstrate the mental landscape of children, and of society as a whole, is malleable and open to change.

Result

The artistic exhibition reached over 3000 visitors in 3 weeks and received a lot of national media attention. The novelty is in the simplicity. The unprejudiced viewpoint of children can deliver society a more constructive approach of the elderly, and people with dementia in particular. Children can teach us to focus more on dignity, positivity and humanity.

Conclusion

This research indicates that the perspective of children can help the general public to nuance the negative view of old age and dementia. Positive qualities of children can be used to lighten the burden of dementia for society.
Microstructural integrity and structural connectivity of medial temporal lobe subregions is related to Alzheimer’s pathology
Authors: Adams Jenna N. , Granger Steven J. , Taylor Lisa M. , Kim Soyun , Harrison Theresa M. , Harris Alyssa L. , McMillan Liv , Colon‐Perez Luis , Keator David B. , Yassa Michael A.
Published: December 2023

Background

The earliest effects of Alzheimer’s disease pathology on medial temporal lobe (MTL) gray matter microstructure and white matter connectivity are still unknown. Here, we applied ultra‐high‐resolution diffusion MRI to characterize microstructural integrity and structural connectivity of the MTL, and tested associations with Alzheimer’s pathology and memory performance in cognitively normal older adults.

Method

83 participants (M = 71.7yrs, 66% female) received structural and ultra‐high‐resolution diffusion MRI (0.67×0.67×3mm). Subsamples received [18F]‐florbetapir (FBP) to measure Aβ (n = 77; global summary SUVR), [18F]‐MK6240 to measure tau (n = 23; entorhinal SUVR), and performed an object mnemonic discrimination task (n = 74). Structural MRI was processed with ASHS to obtain MTL ROIs (Fig1). Diffusion MRI was processed with FSL DTIfit to calculate mean diffusivity (MD), an index of cellular integrity. Tractography was performed with DSI Studio. ROI‐to‐ROI streamlines were calculated (Fig3A) and used for structural connectivity graph analyses of the MTL network. Analyses controlled for age and sex, with scan interval and education in relevant models.

Result

Entorhinal MK6240 SUVR was associated with increased MD in transentorhinal cortex (BA35; r = 0.72, p<0.001), entorhinal cortex (EC; r = 0.61, p = 0.004), and dentate gyrus (DG; r = 0.46, p = 0.04; Fig2A), while global FBP SUVR was associated with higher MD in EC (r = 0.25, p = 0.03). Worse mnemonic discrimination performance was associated with increased MD in DG (r = ‐0.29, p = 0.01), with trends in EC (r = ‐0.23, p = 0.06) and CA3 (r = ‐0.20, p = 0.09; Fig2B). The number of streamlines between EC and DG was not significantly associated with entorhinal MK6240 SUVR (r = ‐0.32, p = 0.17), FBP SUVR, or mnemonic discrimination (ps>0.37). Lower global efficiency of the MTL network was associated with increased entorhinal MK6240 SUVR (r = ‐0.50, p = 0.025) yet better mnemonic discrimination performance (r = ‐0.28, p = 0.02; Fig3B).

Conclusion

Entorhinal tau pathology and memory performance are closely related to microstructural integrity and structural connectivity of the MTL, suggesting tau‐related MTL neurodegeneration may drive early memory decline.
Dietary patterns, cardiometabolic and brain health in the PREVENT Dementia Cohort
Authors: Gregory Sarah , Dounavi Maria‐Eleni , Low Audrey , Ntailianis Georgios , O'Brien John T , Parra‐Rodriguez Mario A , Shannon Oliver M , Stevenson Emma , Ritchie Craig W , Ritchie Karen , Wells Katie , Muniz‐Terrera Graciela
Published: December 2023

Background

The Mediterranean diet (MedDiet) has been associated with better cardiometabolic and brain health. Research has suggested differences in these associations between men and women, with men typically reported to benefit more from higher MedDiet adherence. However there remains a lack of research in this area in non‐Mediterranean countries. This study aimed to explore cross‐sectional associations between MedDiet adherence in the PREVENT Dementia cohort (UK and Ireland), stratified by sex.

Method

After deriving scores to quantify adherence to the MedDiet (MEDAS, MEDAS continuous and Pyramid), we used linear regression and linear mixed effects models to test for associations between the MedDiet scores, cardiometabolic health (blood pressure, BMI, glycemia, cholesterol, triglycerides) and brain health (white matter hyperintensity volume (WMHV), cortical thickness, hippocampal subfield volumes, cognition). Propensity scores were calculated to strengthen causality inferences from the data, and used as covariates along with total energy intake and Western diet scores.

Result

We included 533 participants, mean age 51.25 (±5.40) years, majority women (60.0%). Higher MedDiet scores (MEDAS data presented) were associated with lower blood pressure (systolic ß: ‐1.16, p:0.009; diastolic ß: ‐1.00, p<0.001) and BMI (ß: ‐0.53, p<0.001). There were significant interactions between MedDiet and sex for diastolic blood pressure and hip‐to‐waist ratio. When stratified by sex, women had significant positive associations between MedDiet scores and blood pressure (systolic ß: ‐1.45, p: 0.006; diastolic ß: ‐1.29, p<0.001), BMI (ß: ‐0.51, p: 0.02) and glycemia (Pyramid only: ß: ‐0.11, p: 0.02), whereas men only had a significant association with BMI (ß: ‐0.45, p: 0.02) (Figure 1). There were no significant associations between dietary scores and any markers of brain health. An exploratory path analysis found a significant mediation between the Pyramid MedDiet score, pulse pressure and WMHV (Figure 2), which was only seen in women.

Conclusion

There were significant associations between higher MedDiet scores and better cardiometabolic health, particularly for women. There were no direct associations with brain health outcomes, however a path analysis suggested a mediating effect of pulse pressure between the MedDiet and WMHV. Sex‐stratified nutritional guidelines to support better cardiometabolic health, may lead to better brain health and warrant further investigation.
Brain glutathione may be associated with white matter hyperintensities in patients with cardiovascular disease
Authors: Chen Jinghan Jenny , Herrmann Nathan , Survilla Kate , Black Sandra E. , Ramirez Joel , Andreazza Ana C. , Oh Paul I. , Gallagher Damien , Graham Simon J. , Lanctôt Krista L.
Published: December 2023

Background

White matter hyperintensity (WMH) is a marker of age‐related cerebrovascular damage and is correlated with cognitive impairment; ischemia and inflammatory mechanisms have been proposed to be involved in its pathogenesis. These processes are associated with oxidative stress (OS), which may impair cellular function and affect antioxidant balance; however, the role of central antioxidant responses is still unclear.

Method

Patients (age 55‐85) with ≥2 vascular risk factors or a previous vascular event were assessed at baseline for an exercise rehabilitation program. All participants completed the Montreal Cognitive Assessment (MoCA). Baseline WHM severity was determined using the standardized Canadian Dementia Imaging Protocol and semiautomatic protocols. Brain glutathione (GSH) at baseline was obtained in the anterior cingulate (AC) and occipital region (OC) using 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b).

Result

Of 30 participants (mean age: 66.2 ± 7.42 SD; 80% male) currently enrolled, brain volumetric measurements were completed for 25 participants. Lower MoCA score was associated with greater total WMH volume, controlling for age (b[SE] = ‐0.017 [0.005], t(22) = ‐3.24, p = 0.004); this relationship remained significant when controlling for years of education separately (b[SE] = ‐0.016 [0.006], t(22) = ‐2.86, p = 0.01). Correcting for cerebrospinal fluid volume, lower AC‐GSH level was associated with higher deep WMH volume in the medial middle frontal (MMF) region of interest (b[SE] = ‐0.056 [0.023], t(23) = ‐2.38, p = 0.026), but not with MMF paraventricular WMH volume. After controlling for age, the model was no longer significant (F (2, 22) = 2.87, p = 0.078). No significant associations were found between OC‐GSH and occipital lobe WMH.

Conclusion

As expected, total white matter hyperintensity volume was associated with poorer global cognition. In the medial middle frontal (MMF) region of interest, higher deep WMH was associated with lower GSH levels, suggesting altered brain antioxidant levels may be associated with the presence or formation of WMH. Recruitment is ongoing, and additional participants are needed to reinforce findings and to control for confounders in the analysis.
Loss of Progranulin Results in Increased Pan‐Cathepsin Expression
Authors: Anderson Abigail , Gillett Drew A , Boles Jake , Wallings Rebecca L , Tansey Malu Gámez
Published: December 2023

Background

Mutations in the progranulin (PGRN) encoding gene, GRN, cause familial frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis and is also implicated in Parkinson’s disease. These mutations result in decreased PGRN expression. PGRN is highly expressed in peripheral immune cells and microglia and regulates cell growth, survival, repair, and inflammation. As well, PGRN is implicated in regulating lysosome function, however, the exact role of PGRN in lysosomal function and how this contributes to inflammation and degeneration is not entirely understood. To better understand the role of PGRN in regulating lysosome function, I examined how loss of GRN impacts lysosomal and cathepsin activity.

Method

Using mouse embryonic fibroblasts (MEFs), I performed immunocytochemistry and immunoblotting assays to analyze fluorescent signal from LAMP1 (lysosomal marker) and BMV109 (marker for cathepsin activity).

Result

GRN‐/‐ MEFs exhibit increased expression of pan‐cathepsin activity relative to GRN+/+ MEFs, and significantly impacts expression of LAMP1.

Conclusion

The significant increase in pan‐cathepsin activity in the GRN‐/‐ MEFs confirms that PGRN loss does alter cathepsin expression, which may be a result of compensatory mechanisms happening within the cell. Further investigations will include assessing LAMP1 and BMV109 expression in microglia from from GRN‐/‐ mice, in the hopes to understand the role of PGRN in lysosomal function in immune cells of the central nervous system and the diseases in which it is implicated.
Changes in Brain Glutathione in patients with mild vascular cognitive impairment
Authors: Chen Jinghan Jenny , Herrmann Nathan , Survilla Kate , Black Sandra E. , Ramirez Joel , Andreazza Ana C. , Oh Paul I. , Gallagher Damien , Graham Simon J. , Lanctôt Krista L.
Published: December 2023

Background

Oxidative stress (OS) has been implicated in age‐related neurodegeneration and may be important in prodromal states such as mild vascular cognitive impairment (mVCI). Higher peripheral OS is reported in mVCI patients; however, the role of central antioxidant defenses in mVCI is unclear. Glutathione (GSH) is a major brain antioxidant, and so brain GSH in possible mVCI vs. controls was assessed.

Method

Possible mVCI patients (1 standard deviation (SD) below population norms in verbal memory, executive function (EF), processing speed, or working memory, age 55‐85, and currently enrolled in a cardiac rehabilitation program due to having 2 or more vascular risk factors or previous vascular event) and cognitively‐normal (CN) controls are recruited from a 6‐month exercise rehabilitation program. All participants received 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy) to quantify brain GSH at baseline in the anterior cingulate (AC) and occipital region (OC). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b), a cut‐off of 20% was used to reject spectra of poor quality.

Result

In 30 participants (mVCI n = 16, CN n = 14), anterior cingulate (AC) GSH (I.U. ± SD) was higher in mVCI (1.86 ± 0.45) compared to CN (1.63 ± 0.50) (F(1,18.8) = 4.6, P = 0.04), this difference became trending after correcting for cerebrospinal fluid volume ((F(1,18.2) = 3.9, P = 0.06). No difference was detected for OC‐GSH before or after correcting for cerebrospinal fluid volume. Higher AC‐GSH was correlated with lower Montreal Cognitive Assessment score (rho (26) = ‐0.42, p = 0.02).

Conclusion

Preliminary data suggest an upregulation in anterior cingulate glutathione in mVCI, which might reflect a compensatory increase in antioxidants as a response to increase peripheral oxidative stress previously reported in these patients. Recruitment is ongoing and additional participants are needed to reinforce findings.
Systemic vascular risk, white matter injury, and relative cerebral blood flow independently contribute to cognitive decline beyond amyloid and tau burden
Authors: Shirzadi Zahra , Yau Wai‐Ying Wendy , Boyle Rory , Properzi Michael J , Buckley Rachel F. , Yang Hyun‐Sik , Scanlon Catherine E , Hsieh Stephanie , Amariglio Rebecca E. , Papp Kathryn V. , Rentz Dorene M. , Price Julie C , Johnson Keith A. , Sperling Reisa A. , Chhatwal Jasmeer P. , Schultz Aaron P.
Published: December 2023

Background

Age, systemic vascular risk factors, white matter injury, cerebral blood flow, amyloid, and tau burden are well‐established contributors to late‐life cognitive decline. Given the strong relationship among these measures, we proposed a model to extract latent factors and isolate domain‐specific measures that underlie cognitive decline in preclinical AD.

Method

Data were available for 166 cognitively unimpaired older adults from Harvard Aging Brain Study (Table1). We used the following measures: 1) cortical amyloid burden from PiB‐PET; 2) inferior temporal cortex FTP‐PET; 3) relative cerebral blood flow (R1) from dynamically‐acquired PiB‐PET; 4) white matter hyperintensities (WMH) from FLAIR‐MRI; 5) Peak width of skeletonized mean diffusivity (PSMD) from DTI‐MRI; 6) gray matter volume (GMV) from MPRAGE‐MRI; 7) Framingham Heart Study cardiovascular disease risk (CVD); 8) Preclinical Alzheimer Cognitive Composite‐5 (PACC). We extracted slopes using linear mixed effect models for longitudinal PACC decline and GMV atrophy (follow‐up = 7.4±2.8 years). The remaining data were obtained from baseline. We used exploratory factor analysis (varimax rotations) to extract orthogonal factors. These factors were used in a regression model to explain PACC decline. We next examined whether GMV atrophy acts as a mediator of factors and PACC decline. Subsequently, we investigated whether factors interact to further explain PACC decline.

Results

Original variables were highly interrelated (Figure1A) and correlated with PACC decline (Figure1B). Scree test showed 6 factors were sufficient (cumulative variance:96%, Figure2A). All factors except Factor5 (age) independently explained PACC decline (Figure2B, r2 = 0.44). Including GMV atrophy removed effect of Factor1 (white matter injury, Figure2B, r2 = 0.51). Factor3 (amyloid) interacted with Factor1 and Factor4 (tau) in explaining PACC decline (Figure2C, r2 = 0.58).

Conclusion

Latent factors of systemic vascular risk, white matter injury, and relative cerebral blood flow (but not age) independently explain cognitive decline beyond amyloid and tau burden in this preclinical AD cohort. GMV atrophy mediates these associations with the strongest effect on white matter injury suggesting a strong link between white matter injury and neurodegeneration. These results suggest that current markers of cerebrovascular injury contribute to cognitive decline beyond systemic vascular risk (CVD), amyloid, and tau burden. The mechanism by which systemic vascular risk impacts cognition requires further explication.
Plasma p‐tau181 and nfl as surrogates biomarkers in clinical trials targeting preclinical stage of Alzheimer’s disease
Authors: Ferreira Pamela C.L. , Ferrari‐Souza João Pedro , Tissot Cécile , Bellaver Bruna , Leffa Douglas Teixeira , Povala Guilherme , Lussier Firoza Z , Therriault Joseph , Benedet Andrea Lessa , Ashton Nicholas J. , Cohen Ann D. , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Soucy Jean‐Paul , Gauthier Serge , Villemagne Victor L , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R. , Karikari Thomas K , Pascoal Tharick A.
Published: December 2023

Background

The preclinical stage of Alzheimer’s disease (AD) is one of the main focuses of clinical trials. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants’ disease progression in clinical trials targeting cognitively unimpaired (CU) individuals. Although longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) and neurofilament light chain(NfL) correlate with AD progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Here, we aimed to evaluate the utility of using changes in plasma p‐tau181 and NfL as surrogate biomarkers for clinical trials targeting preclinical AD.

Method

We access 257 CU older individuals that had available Aβ‐PET at baseline, as well as the baseline, up to 24‐month plasma p‐tau181 and NfL measures from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We calculate the estimated sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers.

Result

We demonstrated that therapeutical clinical trials of 24‐month follow‐up using p‐tau181 and NfL would require 78% and 63% smaller sample sizes compared with a 12‐month follow‐up(Figure 1). The use of intermediate levels of Aβ(CL20‐40), rather than merely Aβ positivity, as an enrichment strategy reduced the sample size by 73% for p‐tau181 and 59% for NfL over 24 months. As demonstrated in Figure 2A the estimated cost of a clinical trial using only plasma biomarkers is lower than using neuroimaging biomarkers for surrogacy(Figure 2A). However, as showed by Figure 2B a trial including all Aβ positive individuals, the total estimated cost when considering surrogate biomarkers plus other related assessments are numerically higher using plasma than neuroimaging biomarkers; while trials including only individuals with intermediate Aβ levels, the cost was similar using plasma and neuroimaging biomarkers for surrogacy.

Conclusion

Our results suggest that to monitor large scale large‐scale population interventions in CU Aβ positive individuals’ plasma p‐tau181/ NfL could potentially be used. Furthermore, using a strategy that has been proposed in recent clinical trials, we demonstrated that the use of intermediate levels of Aβ is more cost‐effective than trials using Aβ‐positive individuals in clinical.
Gut microbial families associate with brain volume in cognitively unimpaired aging adults
Authors: Ibrahim Muhaison H , Heston Margo B. , Kang Jea Woo , Ennis Gilda E. , Harding Sandra , González Antonio , Johnson Sterling C , Asthana Sanjay , Knight Rob , Kaddurah‐Daouk Rima F. , Rey Federico E. , Bendlin Barbara B
Published: December 2023

Background

The gut microbiome may be a potential modifiable risk factor for Alzheimer’s disease (AD). Studies have identified gut microbial associations with amyloid and tau pathology, however the microbiome’s preclinical relationship with neurodegeneration measures including brain gray matter (GM), white matter (WM), and total brain (TBV) volumes require further examination. For this study, we hypothesized that higher relative abundances of Ruminococcaceae, Prevotellaceae, Pasteurellaceae, Enterobacteriaceae, and Bifidobacteriacea would be associated with higher GM, WM, and TBV given prior differences in a smaller AD cohort.

Method

157 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention provided fecal samples and underwent T1‐weighted neuroimaging. The sample was enriched for participants with preclinical AD and APOE e4 carriage. CAT12 (SPM12) was used to process images and quantify brain volumes. 16S rRNA V4 fecal bacteria sequencing was performed using published methods. Taxa were denoised, classified, and agglomerated at the family taxonomic rank. Multiple regressions tested the associations of each bacterial family with GM and WM individually, and with total volume (GM and WM volumes summed). Covariates included age and total intracranial volume.

Result

Analyses focused on relationships with the afore‐mentioned families even though several others were observed in the sample. Prevotellaceae showed significant positive associations with all three brain volume measures. Pasteurellaceae showed negative correlations with GM and TBV, and no significant association with WM. Enterobacteriaceae showed a significant negative association with TBV but no significant associations with other measures of brain volume. Ruminococcaceae and Bifidobacteriaceae had no significance with all measures of brain volume.

Conclusion

Greater abundance of Prevotellaceae was associated with larger volumes. Prevotellaceae are known to be diminished in Parkinson’s disease, and produce short chain fatty acids which maintain intestinal barrier integrity. Higher Enterobacteriaceae was associated with lower total volume, consistent with prior studies showing Enterobacteriaceaeare elevated in AD. Higher Pasteurellaceae was associated with smaller TBV; some bacteria in the family Pasteurellaceae are pathogenic and are associated with disease, possibly explaining this association. Ruminococcaceae and Bifidobacteriaceae were not liked with brain volume in this cognitively unimpaired cohort. Overall, these findings suggest specific microbial families associate with neurodegeneration.