bluuebunny/crossref_metadata_2025 huggingface dataset:
Brainstem Volume and White Matter Characteristics Associated with Cognitive Performance in Healthy Middle‐aged Adults
Authors: Li Yanrong , Caillaud Marie , Gallagher Isabelle , Youn Cherry , Park Jessica , Haley Andreana
Published: January 2025

Background

Traditionally linked to essential physiological functions, the brainstem is now acknowledged for its role in cognition and dementia. Abnormal tau protein accumulation starts in the brainstem. Late life brainstem volume at baseline also predicts later Alzheimer's Disease conversion. Yet, brainstem's association with cognitive function in healthy middle‐aged adults has been insufficiently studied. This research investigates the brainstem’s structure, focusing on volume and white matter integrity, and their correlation with cognitive performance in this healthy middle‐aged adults.

Method

A total of 202 middle‐aged adults aged 40 to 60, free of clinical conditions were enrolled. They underwent a comprehensive neuropsychological assessment evaluating their executive function, attention, and memory performance. T1 and diffusion tensor images (DTI) were collected on a 3T scanner. Brainstem and total intracranial volumes (TIV) were extracted from the T1 images. Fractional anisotropy (FA) values of superior and middle cerebellar puncle were extracted from the DTI images.

Result

After controlling for age, sex, education, and total intracranial volume, larger brainstem volume is significantly associated with better memory performance (F(5, 196) = 6.185, R2 = 0.1363, P < .001; βbrainstem vol = .069, P = .025) but not attention or executive function. Additionally, APOE4 carrier status significantly moderates the correlation between brainstem volume and attention (F(7, 85) = 2.902, R2 = 0.193, P < .01; βbrainstem vol:APOE4 status = .131, P = .034). After controlling for age, sex, and education, higher superior cerebellum peduncle FA value is significantly associated with better memory (F(4, 128) = 6.58, R2 = 0.1706, P < .001; βSCP FA= 5.098, P = .0018), attention (F(4, 128) = 4.706, R2 = 0.13, P = .001; βSCP FA= 3.983, P = .009), and executive function (F(4, 128) = 2.963, R2 = 0.085, P = .022; βSCP FA= 3.945, P = .018).

Conclusion

The study highlights the brainstem's significant association with memory performance and attention in middle‐aged adults, particularly among APOE4 carriers. This emphasizes the brainstem's potential as an early indicator of cognitive decline. The significant correlation between brainstem FA values and cognitions suggests that further exploration of other brainstem's measures should be included in future studies.
Protective mechanism of APOE3‐Christchurch in Alzheimer’s disease
Authors: Raulin Ana‐Caroline , Linares Cynthia , Alnobani Alla , Roy Bhaskar , Crow Ailsa , Doss Sydney V. , Kuchenbecker Lindsey A , Dacquel Maxwell V , Karch Celeste M. , Martens Yuka A , Liu Chia‐Chen , Bu Guojun , Kanekiyo Takahisa
Published: January 2025

Background

Homozygosity for the rare APOE3‐Christchurch (APOE3Ch) variant, encoding for apoE3‐R136S (apoE3‐Ch), was linked to resistance against an aggressive form of familial Alzheimer’s disease (AD). Carrying two copies of APOE3Ch was sufficient to delay autosomal AD onset by 30 years. This remarkable protective effect makes it a strong candidate for uncovering new therapies against AD. Thus, we aim to explore the protective mechanisms of APOE3Ch against AD onset, to inform therapy.

Methods

We used both amyloid mouse models and human induced‐pluripotent stem cells (iPSC) models to address this aim. We examined whether astrocytic expression of apoE3‐Ch through an AAV‐mediated approach can mitigate AD‐related pathology and toxicity in early (3.5 months old) and late (8 months old) amyloid pathology in 5xFAD mice. We also used isogenic iPSC lines carrying the APOE3Ch variant that were generated from APOE3 parental lines using CRISPR/Cas9 technology. Biochemical and biophysical properties of both recombinant and native apoE3‐Ch lipoprotein particles secreted by iPSC‐derived astrocytes have been investigated using different techniques including heparin affinity chromatography and size‐exclusion chromatography.

Results

We investigated the impact of astrocytic apoE3‐Ch on amyloid pathology and toxicity in 3.5‐month‐old and 8‐month‐old 5xFAD mice. We confirmed successful AAV‐mediated overexpression of apoE3 and apoE3‐Ch in astrocytes. We found apoE3‐Ch specific changes in protein levels and solubility. Astrocytic expression of apoE3‐Ch reduced soluble Aβ oligomer levels and ameliorated ER stress response compared to apoE3 in the 8‐month‐old 5xFAD mice. Furthermore, our findings showed altered biochemical properties of HEK cell‐derived apoE3‐Ch protein, including decreased heparin binding, altered receptor binding, and enhanced lipid accepting capacity. We also characterized APOE3Ch iPSC‐derived cell models, including iPSC‐derived astrocytes, neurons, and cerebral organoids, and found differences between APOE3 and APOE3Ch at the functional level in these iPSC models.

Conclusions

The proposed work and the developed methods to study apoE3‐Ch promises to provide new insights into the possible roles of this rare, mutated protein in protecting against AD, offering new therapeutic avenues for AD treatment.
Lower brain‐derived neurotrophic factor levels and hippocampal subfield volumes are associated with high diabetes risk in later life
Authors: Al‐Shaikh Jennifer Hanna , Ghosh‐Swaby Olivia R , Khan Ali R. , Thornton Jane , Bussey Timothy J , Saksida Lisa M , Liu‐Ambrose Teresa , Nagamatsu Lindsay S
Published: January 2025

Background

Older adults with type 2 diabetes (T2D) are more likely to develop Alzheimer’s disease (AD) due to impaired brain metabolism. Although the underlying mechanisms of this relationship are largely unknown, lower levels of brain‐derived neurotrophic factor (BDNF) –which promotes hippocampal neurogenesis in adulthood– and atrophy of the hippocampus are evident in patients with T2D and dementia, possibly linking the two conditions. The hippocampus is comprised of multiple subfields, each with their respective functions, cellular composition, and age‐related sensitivity. In particular, the dentate gyrus, known for its key role in memory processing, is one of the only regions in the brain capable of producing new neurons through BDNF. At the onset of dementia, the rapid loss of hippocampal tissue results in functional disconnection with other areas of the brain involved in cognition, making hippocampal atrophy a biomarker for cognitive decline. Understanding region‐specific hippocampal atrophy during the early stages of diabetes may provide insight into the link between T2D and brain atrophy that is characteristic of AD. Therefore, our study investigates the relationship between BDNF levels and hippocampal subfield volumes in older adults at risk for T2D.

Method

Sixty older adults (aged 60‐80 years, mean = 68.64, 72.34% female) at risk for diabetes completed demographic and medical history questionnaires. Diabetes risk was assessed using HbA1c, BMI, and a diabetes questionnaire. BDNF serum levels were analyzed from blood samples using an enzyme‐linked immunoassay test (ELISA). Anatomical T1 and T2 weighted brain images were collected via 3T MRI and analyzed using HippUnfold – a novel segmentation tool that accounts for individual variability in the folding patterns of hippocampal subregions.

Result

Preliminary results show that higher diabetes risk was associated with lower BDNF levels and reduced hippocampal subfield volumes. In addition, BDNF serum levels were predictive of hippocampal subfield volumes, specifically in the dentate gyrus.

Conclusion

Findings demonstrate a relationship between diabetes risk factors, BDNF, and hippocampal subfield volumes (i.e., dentate gyrus) in regions where neurogenesis continues throughout adulthood. As life expectancy and diabetes incidence increases, our study urges the development and application of interventions aimed at preventing the progression of diabetes‐related neurodegeneration.
Implementation analysis of community‐based centers for people with dementia and their family caregivers in Chile
Authors: Gajardo Jean , Aubert Josefina , Moreno Ximena , Aravena Jose M , Carcamo Felipe , Abusleme Maria T , Barrientos Carolina , Mascayano Franco
Published: January 2025

Background

Community‐based centers for people living with dementia (PLWD) have been implemented as part of the National Plan of dementia in Chile, delivering a multicomponent intervention to support PLWD and their families. There is limited knowledge on their implementation, and we had previously informed with respect to the implementation outcomes of the first center, called Kintun. This work offers an update on findings describing implementation outcomes of three more centers, with different implementation times and geographic locations in Chile.

Method

We conducted a realistic evaluation using multiple qualitative data collection strategies and diverse informants to analyze complex interventions considering 4 centers. For every center, key informants were identified at different levels (macro‐level of centralized policy, meso‐level of center coordinators and health service supervisors, and micro‐level of intervention deliverers and family caregivers) who participated in individual interviews or focus groups. Table 1 summarizes informants, data collection strategies, and implementation outcomes. Rapid qualitative analysis was used with predetermined codes describing implementation outcomes according to the Active Implementation Frameworks (Blanchard et al, 2017) and implementation outcomes by Proctor et al (2011).

Result

At a macro‐level of implementation, the centers have not experienced relevant transformations, but the lack of updated centralized technical orientations menace fidelity. At a meso and micro level, the centers have been adapted to improve sustainability and appropriateness, supporting their scalability. Differences in core components characterize a transition from adult day services to a multicomponent intervention, following a progressive interprofessional approach. Examples of implementation drivers were engagement with the local health network and and tailoring the intervention according to geographical and cultural context. Relevant implementation aspects of agreement and disagreement among actors were the appropriateness of the program and the program components, respectively.

Conclusion

Most relevant implementation drivers and adaptations to community centers for PLWD in Chile are identified at micro and meso levels, which stresses the need to define intervention components for standardization and monitoring, providing an implementation frame for new centers. Points of agreement and disagreement among the three levels are key for understanding priorities for improvement
Association of pulsatility of lenticulostriate arteries with cognitive decline in elderly adults: a 7T dual‐VENC PC‐MRI study
Authors: Tang Jianing , Zhao Tianrui , Joe Elizabeth B , Chui Helena C , Yan Lirong
Published: January 2025

Background

Cerebral small vessel disease (cSVD) is a major cause of vascular dementia. Mounting evidence suggests that cSVD pathology is closely linked to vascular dysfunction of lenticulostriate arteries (LSAs). Arterial pulsatility, quantified by pulsatility index (PI), has been used as an indicator of vascular dysfunction. With the advent of ultra‐high field 7T, the velocity and pulsatility of LSAs can be reliably measured. Directly assessing pulsatility of LSAs may offer valuable insight into pathophysiology of cSVD and cognitive impairment. This study aims to investigate relationship between LSA pulsatility and cognitive performance within an aged cohort.

Method

Twenty‐five elderly participants (13 female: 71 ± 9.2 years) were enrolled in the study with written informed consent. Cognitive assessments were conducted including 19 participants undergoing the Mini‐Mental State Exam (MMSE) and 23 taking Montreal Cognitive Assessment (MoCA). High‐resolution phase‐contrast MRI (PC‐MRI) with dual‐VENC (Venc=20cm/s and 40cm/s) was performed on a Siemens 7T MRI scanner to image velocities of LSAs. PI was calculated by the difference between the peak systolic flow velocity and minimum diastolic flow velocity divided by the mean velocity throughout a cardiac cycle. Pearson correlation was used to evaluate the associations between LSA PI and age, education level, and cognitive measurements. A linear mixed‐effects model was used to test the association between LSA PI and cognitive measurements while correcting for the effects of age, gender, and education.

Result

Flow velocity curves and PI values of LSAs were successfully extracted and calculated from all 25 participants. Figure 1 shows an example of LSA imaging using PC‐MRI and the acquired velocity curve of LSAs. LSA PI significantly increased with age and lower education levels (p=0.002, 0.03, respectively) (Figure 2). Increased PI was strongly associated with lower MMSE scores with and without corrections for age, gender, and educational level (p=0.048, 0.028) (Figure 3). A similar trend was observed between PI and MOCA scores, although there was no significance (p=0.31).

Conclusion

This study has demonstrated that LSA pulsatility assessed by 7T high‐resolution PC‐MRI is strongly associated with aging, education, and cognitive performance. These findings suggest the dysfunction of LSA could contribute to the cSVD pathology and result in cognitive impairment.
Occipital amyloid‐β burden and clinical correlates in Lewy body disease
Authors: Vossler Hillary , Abdelnour Carla , Young Christina B. , Winer Joseph R. , Smith Alena , Smith Viktorija , Shahid Marian , Wilson Edward N. , Davidzon Guido A. , Mormino Elizabeth , Poston Kathleen L.
Published: January 2025

Background

Accurate assessment of amyloid‐β burden in Lewy body disease (LBD) is crucial due to the frequent co‐occurrence of amyloidosis. Current amyloid‐β PET imaging protocols often overlook the occipital lobe, a relevant area in Lewy body disease (LBD). We aimed to determine whether regional amyloid‐β in LBD is associated with global cognition, daily functioning, and neuropsychological performance.

Method

We included 193 Stanford research participants: 78 Cognitively Normal (CN), 42 Alzheimer’s disease (AD), 38 LBD‐Cognitively Normal (LBD‐CN), and 35 LBD‐Cognitively Impaired (LBD‐CI) who underwent 18F‐Florbetaben PET imaging (Table). We calculated SUVRs for the frontal, cingulate, parietal, temporal, and occipital regions using the cerebellum as the reference region. We then used linear regression models adjusted for age, sex, and education to examine the association between regional amyloid‐β burden and global cognition (measured with MoCA), daily functioning (measured with CDR‐SB), and performance in memory, executive function, visuospatial function, and attention/working memory/processing speed (measured with composite scores).

Result

In the LBD‐CI group, amyloid‐β burden in all regions, except the cingulate, was associated with worse MoCA (β = ‐14.31 (SE = 3.59), p < 0.0001) (Figure) and CDR‐SB scores (β = 5.05 (SE = 1.71), p < 0.004). Similarly, amyloid‐β burden in the frontal (β = ‐1.27 (SE = 0.60), p < 0.05), cingulate (β = ‐1.24 (SE = 0.59), p < 0.05), parietal (β = ‐1.42 (SE = 0.62), p < 0.05), and temporal (β = ‐1.68 (SE = 0.70), p < 0.05) regions was associated with worse memory performance, whereas amyloid‐β burden in the occipital region (β = ‐1.76 (SE = 0.88), p < 0.05) was associated with worse executive function. However, only the association between occipital amyloid‐β burden and MoCA scores survived multiple comparison correction. In the LBD‐CN group, regional amyloid‐β burden showed no associations with clinical outcomes.

Conclusion

Our study suggests the potential significance of the occipital region in assessing amyloid‐β burden among individuals with cognitive impairment due to LBD, as it is associated with worse global cognition. Further validation studies should include the occipital region when calculating SUVRs should be considered in people with LBD.
Autoradiographic comparison of [11C]PiB and [18F]NAV4694 in post‐mortem human brain tissue
Authors: Aliaga Antonio , Therriault Joseph , Aliaga Arturo Aliaga , Socualaya Kely Monica Quispialaya , Soucy Jean‐Paul , Macedo Arthur C. , Carello‐Collar Giovanna , Bastiani Marco De , Rahmouni Nesrine , Pascoal Tharick A. , Zimmer Eduardo R. , Rosa‐Neto Pedro
Published: January 2025

Background

To evaluate the in vitro binding properties of [11C]PiB and [18F]NAV4694 head‐to‐head in post‐mortem human brain tissue.

Method

Autoradiography was used to assess uptake of [11C]PiB and [18F]NAV4694 in control (CN) and Alzheimer’s disease (AD) autopsy‐confirmed brain tissues. The study focuses on the analysis of the prefrontal cortex, inferior parietal cortex, posterior cingulate cortex and hippocampus sections in 11 CN and 11 AD cases. The binding values of [11C]PIB and [18F]NAV4694 were calculated from regions of interest (ROIs) drawn manually in the mentioned sections. In addition, a histopathology study (CERAD) was performed in the posterior cingulate cortex section of 10 CN and 10 AD cases.

Result

For both radiotracers investigated, we observed significant differences between CN and AD tissues uptakes in the prefrontal cortex, inferior parietal cortex, posterior cingulate cortex and hippocampus. Higher binding was detected for [18]NAV4694 compared to [11C]PIB in AD prefrontal, inferior parietal, and posterior cingulate cortices, while binding in the hippocampus was comparable for both radioligands. A strong correlation between [18]NAV4694 and [11C]PIB was found in the prefrontal cortex (R=0.934, p<0.0001) and inferior parietal cortex (R=0.833, p<0.0001), and lower values were obtained in the posterior cingulate cortex (R=0.699, p=0.0003) and hippocampus (R=0.72, p=0.0002). The analysis of correlation between the binding of [11C]PIB and [18F]NAV4694 in the posterior cingulate cortex section and the CERAD histopathology scores revealed a higher concordance for [18F]NAV4694 (R=0.796) compared to [11C]PIB (R=0.485).

Conclusion

This study reports the first head‐to‐head comparison of [11C]PIB and [18F]NAV4694 in postmortem human brain tissue. [11C]PIB and [18F]NAV4694 showed high binding to amyloid beta aggregates in post‐mortem human brain tissues by autoradiography. Our results suggest that NAV4694 may have a higher effect size when differentiating between individuals with and without AD.
Association of Epigenetic Aging with Plasma Biomarkers of Amyloid, Tau, Neurodegeneration and Neuroinflammation in Diverse Hispanic/Latino Adults
Authors: González Hector , Tarraf Wassim , Gonzalez Kevin A , Kuwayama Sayaka , Parada Humberto , Ramos Alberto R , Rundek Tatjana , Perreira Krista M , Levin Bonnie , Decarli Charles , Fornage Myriam
Published: January 2025

Background

Epigenetic clocks are biomarkers of biological age based on DNA methylation (DNAm) patterns and are widely used as predictors of health and aging outcomes. Multiple epigenetic clocks have been developed and reflect different aspects of the multidimensional aging process, above and beyond chronological age. To date, no study has examined the relationship of epigenetic aging with circulating biomarkers of Alzheimer’s Disease (AD). We investigated the association of 6 epigenetic clocks with plasma glial fibrillary acidic protein (GFAP), amyloid beta 40 and 42, phosphorylated tau 181 (p‐tau181), and neurofilament light chain (NfL) in diverse Hispanic/Latino adults.

Method

We estimated PC‐based epigenetic age acceleration from 6 epigenetic clocks in 2662 Hispanic and Latino adults (mean age 64.1 years; 56% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) who had available blood DNAm and plasma biomarker data at visit 2. These included first generation clocks, Horvath1, Horvath2 (“skin‐blood”) and Hannum clocks; second generation PhenoAge and GrimAge; and third generation DunedinPACE. We used survey linear regression weighted least squares to estimate the association of each of these measures with each of the plasma biomarkers.

Result

There were varying strengths of association between the clocks and the plasma biomarkers. There were significant associations of faster acceleration in all epigenetic clocks with higher plasma levels of NfL. There were significant associations of faster acceleration in all epigenetic clocks except DunedinPACE with higher plasma levels of Abeta40 and Abeta42. Faster PhenoAge acceleration was associated with higher levels of all circulating biomarkers (Table).

Conclusion

Epigenetic age acceleration is associated with circulating biomarkers of amyloid, tau, neurodegeneration and neuroinflammation in diverse Hispanics/Latinos. The second‐generation clock PhenoAge, trained on nine clinical biomarkers and chronological age, showed consistent and strongest associations across all biomarkers, suggesting that it may be particularly relevant to predicting AD.
Serum Alpha‐Synuclein and Inflammatory Markers profile in an Egyptian Alzheimer’s and Parkinson’s Diseases patients: A Pilot Study
Authors: Heikal Shimaa Adel
Published: January 2025

Background

Alzheimer’s and Parkinson's disease are the most common neurodegenerative diseases. In the current study, we explored the potential of blood‐based markers to differentiate Alzheimer's disease (AD) and Parkinson's disease (PD) from healthy controls using ELISA assays via measuring the serum level of α‐Syn and panels of inflammatory cytokines in the small pilot cohort of Egyptian volunteers. With the ongoing genetic studies, upcoming data suggest that it is not trivial to revisit the findings reported in specific populations to be tested in each ancestor of different genetic and environmental backgrounds.

Method

A total of 42 participants were recruited from the Neurology department, Suhag University Hospital, including 18 AD cases, 9 PD cases, and 15 healthy controls. Clinical and demographic characteristics were well‐matched among the three groups.

Result

The current data is the first to provide evidence in an Egyptian cohort that aligns with earlier reports that serum level of α‐synuclein can be a specific marker for distinguishing PD patients from healthy individuals but not AD patients. Both AD and PD, however, exhibited shared neuroinflammatory profiles with elevated IL‐6 and decreased IL‐10, hinting at a common inflammatory component despite their distinct etiologies. While trends toward increased IL‐1β and TNF‐α were observed in AD, the lack of statistical significance suggests a more limited role in its pathogenesis or the need to expand the sample size.

Conclusion

These findings, although promising and the first of a kind to be conducted in Egyptian patients, necessitate further investigation with larger sample sizes to solidify these markers' potential for diagnosis and fully unravel the specific roles of individual cytokines in each disease.
“I Find that the Music Really Do Help Them Calm Down”: Qualitative Interviews to Support the Development of a Music‐based Application to Improve Sleep Disturbances in Persons Living with Dementia
Authors: Petrovsky Darina , Sefcik Justine S. , Mobarki Abeer , Kolte Sharvari , Amponsah Abigail , Hodgson Nancy A , Wu Bei
Published: January 2025

Background

Most persons living with dementia (PLWD) experience sleep disturbances at some point during their disease. Music interventions are promising to address sleep disturbances because long‐term memory for music remains relatively preserved in PLWD. The purpose of this study was to identify the prototype features of the mobile application, entitled, “Calming Music Personalized for Sleep Enhancement in PeRsons living with Dementia” (CoMPoSER) for use among PLWD and their caregivers by conducting the first round of qualitative interviews to co‐design the content, features, and layout of the application prototype.

Method

In the first step of the study (out of two), we conducted 13 virtual interviews with 20 stakeholders (seven PLWD and thirteen caregivers). Five interviews included dyads (n = 3) or triads (n = 2) of PLWD and their caregivers. We used the mHealth Usability framework for mobile applications (Tajudeen et al. 2022) to guide our directed content analysis. Based on this analysis approach, we present the findings under the framework’s constructs.

Result

The average participant age was 66.7 years old (SD: 17.2). Most were women (n = 14). Twelve identified themselves as White/Caucasian, six as Black/African American, and two as Asian. The participants shared with us that it was important to design a mobile application that is simplistic and easy to navigate. For example, too many song options may confuse PLWD. Participants also talked about what their preferences for soothing colors. We captured preferred styles of music that PLWD and caregivers enjoy listening to and the high potential usefulness of the mobile application. Moreover, individuals conveyed their varying levels of comfort with technology. Some expressed high comfort levels, while others outlined the specific assistance and help information needed to feel at ease using the application.

Conclusion

We used information gathered in the first step of the study to inform the second‐round interview questions. PLWD and caregivers in this study were committed to the process of developing a music‐based application to improve sleep. Their insights on simplistic features, navigation, and colors of the potential application will inform the next round of interviews, after which the prototype of the mobile application will be developed.
Selective sex‐based differences in the association between angiogenic and Alzheimer’s Disease biomarkers in a preliminary cohort of rrAD participants
Authors: Lutshumba Jenny , Wilcock Donna M. , Lee Tiffany , Zhu David C , Scheel Norman , German Dwight C , Zhang Rong , Trout Amanda , Stowe Ann M
Published: January 2025

Background

Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD) are the two most common forms of dementia, with overlapping risk factors including cardiovascular risk factors such as hypertension and dyslipidemia. The etiology of both VCID and AD shows sex‐based differences, as well as sex‐based differences in cardiovascular risk factors. However, how sex differences influence AD and angiogenic biomarkers in older adults who have high cardiovascular risk factors is not known.

Method

AD and angiogenic biomarkers for VCID were measured from the plasma of a subgroup (n=96) of participants from the ‘risk reduction for Alzheimer’s disease’ (rrAD) two‐year clinical trial (NCT02913664; completed Jan. 2022; n=513 total participants). rrAD participants had a family history of dementia or subjective memory complaints, hypertension, and dyslipidemia. The subgroup in the study included 31 males and 65 females (aged: 71‐85). Baseline values for AD biomarkers: Total tau, pTau181, Aβ40, and Aβ42, angiogenic biomarkers: Tie‐2, VEGF‐A, VEGF‐C, VEGFR1, and VCID biomarkers: bFGF, VEGF‐D, PlGF were analyzed using Meso Scale Discovery (MSD). Nonparametric analysis evaluated the sex differences in biomarkers, linear regression evaluated the relationship between AD biomarkers and angiogenic biomarkers in both sexes.

Result

We found sex‐based differences in AD biomarkers such that females had a higher expression in Total tau and Total tau/Aβ42 (p=0.0021, p=0.0003, respectively) while pTau181 was higher in males (p=0.0216). pTau181/ Aβ42 and Aβ42/40 ratios showed no sex differences, nor did baseline angiogenic biomarkers. There was, however, a selective sex difference in the association between angiogenic and AD biomarkers. In females, Total tau is associated with VEGF‐D (R2= 0.0746, p=0.0277), and Tau/Aβ42 is associated with VEGF‐A and VEGFR‐1(R2= 0.0747, p=0.0275; R2= 0.0973, p=0.0114, respectively). In males, pTau181 and pTau181/Aβ42 are associated with VEGF‐D (R2= 0.2637, p=0.0031; R2= 0.1799, p=0.0174, respectively), Aβ42/Aβ40 is associated with VEGF‐C (R2= 0.1491, p=0.0319), and Tau/Aβ42 is associated with bFGF (R2= 0.1458, p=0.0340).

Conclusion

There is a selective sex‐based difference in plasma AD biomarkers and their association with angiogenic biomarkers in this preliminary cohort of older adults with high risks of developing Alzheimer’s disease and related dementias.
“Inhibition of mitochondrial carbonic anhydrases prevents endothelial cell death and blood brain barrier dysfunction in models of amyloidosis.”
Authors: Lemon Nicole L , Vazquez‐Torres Rafael , Canepa Elisa , Rullan Rebecca M Parodi , Ilies Marc A , Fossati Silvia
Published: January 2025

Background

The Neurovascular Unit is a multicellular structure of the CNS known to become dysfunctional in Alzheimer’s Disease (AD) and cerebral amyloid angiopathy. Amyloidosis disrupts the function of cerebrovascular endothelial cells (cECs) via extrinsic and intrinsic apoptosis, and induction of blood brain barrier (BBB) permeability. Findings in our lab demonstrated that pan‐Carbonic Anhydrase inhibitors (CAi’s) prevent mitochondria‐mediated apoptotic mechanisms in cECs. Therefore, we hypothesized that the mitochondrial CA isoforms, CA‐VA and ‐VB mediate Aβ‐induced cell death and other deleterious mechanisms in cECs. Importantly, mitochondrial isoform CA‐VB is increased in models of amyloidosis. Thus, we anticipate using a pharmacological selective CA‐Vi will reduce cerebrovascular EC apoptosis and prevent EC activation. We also hypothesize that CA‐VB KO in human cerebral cECs will rescue mitochondrial‐mediated apoptosis and protect from BBB dysfunction. Finally, we anticipated that CA‐Vi prevents cognitive decline/AD pathology in the 3xTG mouse model.

Method

Human cerebral microvascular ECs (hCMECs) were treated with Aβ40‐Q22 Dutch mutant alone, and in combination with CA‐Vi, and we measured outcomes of mitochondria‐mediated apoptosis and BBB function. In parallel to pharmacological inhibition, we employed CA‐VB KO hCMECs to understand the contribution of CA‐VB to mechanisms of EC apoptosis and BBB function. To confirm the findings in vivo, we treated 3xTG AD mice with CA‐Vi from 6 to16 months of age. Mice went through behavior paradigms, and tissue was harvested. We then measured BBB and cell death outcomes, in addition to Aβ and tau levels.

Result

Inhibition of CA‐V prevented Aβ40‐Q22‐induced mitochondria‐mediated EC death and activation. CA‐VB KO in hCMECs also protected against Aβ‐induced cell death and BBB permeability. Importantly, CA‐Vi prevented cognitive decline, Aβ and tau accumulation, and EC activation in 3xTG mice.

Conclusion

Inhibition of mitochondrial CA‐V is protective in models of amyloidosis and AD in vitro and in vivo through the prevention of mitochondria‐mediated cell death and loss of BBB function. Future studies will aim to understand the cell‐specific mechanisms of CA‐V inhibition.
Unraveling Alzheimer's Disease Heterogeneity: A Comparative Analysis Using HYDRA and CHIMERA
Authors: An Gordon , Benzinger Tammie L.S. , Sotiras Aristeidis , Gordon Brian A.
Published: January 2025

Background

Alzheimer's Disease can present with heterogenous neurodegenerative patterns. In order to optimize clinical trials and personalized medicine, the identification and characterization of diverse pathological brain patterns associated with AD have become paramount. Optimal approaches to identify such heterogeneity are unknown. The present study employed two distinct clustering approaches, namely HYDRA and CHIMERA, to delineate the spatial pattern of brain atrophy attributable to AD. Methods were applied to MRI scans from the Open Access Series of Imaging Studies (OASIS‐4) project.

Methods

HYDRA uses a convex polytope formed by multiple linear hyperplanes that correspond to various pathological patterns, capturing disease subtypes. CHIMERA assesses the pathological transition by transforming NC distribution to separate transformations matching the disease distribution. While both identify spatial patterns, the distinction lies in HYDRA's discriminative analysis of disease subtypes and CHIMERA's generative nature on disease progression through distribution matching.

Results

Both approaches identified two patterns, or subtypes (Figure 1) with similar CDR results (Figure 2). All subtypes demonstrate marked atrophy within the medial temporal areas, notably the hippocampus. Disparities are evident when assessing subtypes: Subtype‐2 across both methods shows pronounced variations in regions such as superior frontal, middle temporal, parietal cortex, and precuneus, areas paramount in AD pathology. Conversely, HYDRA's Subtype‐1 highlights subtle differences in temporal cortex relative to its Subtype‐2. CHIMERA's Subtype‐1, while mirroring its Subtype‐2 pattern, is less intensified, suggesting an earlier AD stage. Collectively, these patterns concur with recognized AD neuropathological trajectories, pinpointing regions initially impacted in progression. In addition, an in‐depth exploration of subsequent analysis including a longitudinal data evaluation to observe the progression of these patterns over time is slated for later investigation.

Conclusion

Our findings demonstrate data‐driven approaches to derive clinically meaningful patterns of neurodegeneration. A parallel evaluation of both approaches accentuates the robustness of clustering techniques, revealing consistent and overlapping insights into the intricate pathological landscapes of AD. This convergence in findings bolsters confidence in the reliability of such analytical tools in AD research.
Association of Blood Pressure Mean and Variability with Hippocampal Subfield Volumes in Cerebral Amyloid Angiopathy with Mild Cognitive Symptoms
Authors: SVEIKATA Lukas , Zotin Maria Clara Zanon , Schoemaker Dorothee , Perosa Valentina , Assal Frederic , Greenberg Steven M. , Viswanathan Anand
Published: January 2025

Background

The interaction between Alzheimer's pathology and cerebral amyloid angiopathy (CAA), a common cerebral small vessel disease, plays a crucial role in cognitive impairment development in older adults. Recent studies suggest that increased blood pressure (BP) variability may affect subclinical vascular disease and cognitive decline. However, it is currently unknown whether a particular BP profile is linked to hippocampal subfield volumes, which are a significant feature of cognitive decline in neurodegenerative diseases. Therefore, we conducted a study to investigate the relationship between BP profile and hippocampal subfields in nondemented subjects with CAA.

Method

We investigated the relation between BP mean and variability and hippocampal neurodegeneration in a memory clinic cohort of non‐demented participants with possible and probable cerebral amyloid angiopathy (CAA), diagnosed using the modified Boston criteria v1.5. Linear regression models were used to assess the associations between BP profile and hippocampal volumes. The subfield volumes were measured using an automated method on T‐1 weighted sequence using FreeSurfer v6.0. The BP profile was defined using serial outpatient BP measurements five years prior to 3T research MRI. The BP variability was calculated using the coefficient of variation (standard deviation/mean).

Result

We have included 59 participants (74.3 ± 6.8 y, 9/50 F/M) who underwent a median of 12 (IQR 26) outpatient BP measurements five years prior to index MRI. We found a significant association between mean BP and all measured hippocampal subfields, notably the CA1: b=‐032, p=0.008, CA3: b = ‐0.24, p=0.049, CA4: b=‐0.34, p=0.003, and the subiculum: b=‐0.29, p=0.006), adjusted for age and brain volume normalized for total intracranial volume. However, we found no significant association with long‐term BP variability

Conclusion

We found significant associations between mean BP and hippocampal subfields volumes. Our results suggest that elevated BP, but not its variability, is a modifiable risk factor for preventing hippocampal degeneration in the context of CAA‐related cognitive impairment. Further pre‐planned analyses will evaluate the associationa in a subgroup of participants with mild dementia and non‐CAA participants.
Body Mass Index and Brain Aging: Microstructural Effects Mapped with Advanced Diffusion MRI
Authors: Benavidez Sebastian M , Lawrence Katherine E , Nabulsi Leila , Laltoo Emily , Abaryan Zvart , Villalon‐Reina Julio E , Nir Talia M , Gari Iyad Ba , Zhu Alyssa H , Haddad Elizabeth , Jahanshad Neda , Thompson Paul M.
Published: January 2025

Background

High body mass index (BMI) is a risk factor for dementia, and prior diffusion‐weighted magnetic resonance (dMRI) work has shown that higher BMI is associated with lower white matter (WM) integrity. The tensor distribution function (TDF) is an advanced dMRI model that is sensitive to the effects of both healthy aging and Alzheimer’s disease (Nir et al., 2017; Lawrence et al., 2021). Here we use TDF – together with the conventional dMRI model diffusion tensor imaging (DTI) and the advanced dMRI model neurite orientation dispersion and density imaging (NODDI) (Zhang et al., 2012) – to characterize BMI effects on WM microstructure aging in later adulthood in the large‐scale UK Biobank dataset.

Method

Cross‐sectional dMRI data from 34,763 participants were analyzed (64.7 ± 19.5 years old, 48.4% male) from the UK Biobank dataset. WM metrics were extracted for 20 WM regions of interest (ROI) using the ENIGMA‐DTI protocol and FSL’s tract‐based spatial statistics (TBSS) (Jahanshad et al., 2013; Smith et al., 2006). We examined the interaction between BMI and age (demeaned linear and quadratic age terms) while including standard nuisance covariates. Results were corrected for multiple comparisons across ROIs using the false discovery rate method.

Result

Significant interactions were observed between BMI and age across the deep WM for every dMRI model examined (all corrected p<0.05). When averaging across the full WM, higher BMI was significantly associated with lower fractional anisotropy (DTI‐FA) among older participants (corrected p=0.04). Orientation dispersion (NODDI‐OD) was relatively higher in those with higher BMI in midlife coupled with less pronounced higher values in older adults (corrected p=0.03). Higher BMI was also associated with higher isotropic volume fraction (NODDI‐ISOVF) in middle‐age (corrected p=0.02).

Conclusion

These results in a cross‐sectional sample reveal that BMI is significantly associated with age trajectories in older individuals’ brain WM microstructure. This may help elucidate the biological mechanisms of BMI as a risk factor for dementia. Future research should consider longitudinal cohorts that include individuals who convert to dementia, to better understand how BMI affects WM aging.
Dried blood spots as a matrix for measuring AD biomarkers: optimizing parameters of analysis and evaluating technical stability
Authors: Hammerschlag Bruno L. , Fatima Hadia A , Celedon Johanna , Ragas Trevor L , Webster Hannah A , Arnold Steven E , Kivisäkk Pia
Published: January 2025

Background

An advantage of blood‐based biomarkers of Alzheimer’s disease (AD) is that collection is easily repeatable and minimally invasive. Repeated biomarker measurements provide greater sensitivity for detecting within‐person change, which in clinical trials can allow for reductions in sample sizes required to detect treatment effects and shorten trial periods. We validated Dried Blood Spots (DBS) as a novel matrix for measuring blood biomarkers of AD, as collection is easily repeatable, less burdensome for participants, and more economical than phlebotomy, and shipment and storage are simplified. Our goal was optimizing collection methods and parameters of measurement, and evaluating the technical stability of repeat measurements and day‐to‐day variability in individual study participants.

Methods

We measured levels of phosphorylated tau 217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using commercially available electrochemiluminescent immunoassays in DBS and paired plasma samples. Venous blood was obtained from participants in the Massachusetts Alzheimer’s Disease Research Center’s longitudinal cohort study and patients undergoing diagnostic lumbar punctures at Massachusetts General Hospital. DBS samples were prepared by applying whole blood immediately post‐collection to Whatman 903 filter cards and stored at room temperature. Before analysis, DBS samples were punched out of cards and eluted at room temperature overnight.

Results

We optimized pre‐analytical factors of DBS analysis by investigating differences in elution times and temperatures, and matrix and diluent effects. Using our optimized protocol, GFAP [median (IQR): 4.1 (6.7‐2.2) pg/ml], NfL [29.2 (36.3‐15.2) pg/ml], and pTau217 [4.5 (5.6‐3.3) pg/ml] were detected over the lower limit of quantitation (LLOQ) in all samples. Excellent correlations between plasma and DBS concentrations were observed for GFAP (r=0.90; p<0.0001) and NfL (r=0.96; p<0.0001), while initial validation in a smaller sample size indicated acceptable correlation for pTau217 (r=0.78; p<0.01).

Conclusions

We found measurable levels of three key biomarkers of AD in DBS samples. Concentrations were significantly correlated to levels in paired plasma samples. We are currently evaluating technical repeatability and short‐term variability in capillary DBS levels of pTau217, GFAP, and NfL.
The neural substrate linking olfactory deficits to cognitive decline in MCI
Authors: Karunanayaka Prasanna , Elyan Rommy , Ahmed Biyar , Kanekar Sangam , Peiris Senal , Pang Ran , Eslinger Paul , Yang Qing
Published: January 2025

Background

A combination of impairments in odor threshold and discrimination, which are both predominantly sensory level functions, and olfactory cognition contribute to age‐related odor‐identification deficits. However, in Alzheimer’s disease (AD), odor identification is more impaired compared to sensory‐level olfactory functions. We, therefore, hypothesized that match and mismatch olfactory fMRI tasks could be used to isolate areas of odor‐identification and that these areas would include primary as well as secondary olfactory structures. We combined functional magnetic resonance imaging (fMRI) with an olfactory detection task to investigate the neural substrates underlying odor identification.

Method

Twenty‐five healthy controls and eighteen MCI subjects (Table 1) took part in an olfactory fMRI odor detection task. The task required subjects to press a button with their right index finger to identify an odorant (i.e., oddball) from a list of distractors. An out of magnet olfactory identification and threshold test was also conducted. This multiple‐choice test was used to measure a participants’ ability to identify twenty different odors.

Result

A contrast of HC>MCI, for all odor conditions, yielded activation in brain regions shown in Figure 1C. These regions were used in a subsequent correlation analysis. The left supramarginal gyrus was included based on a study where the TPJ area (which includes parts of the supramarginal and superior temporal gyrus) was highly active in the left hemisphere. A correlation analyses using both HC and MCI showed significant positive correlations between activity in the L supramarginal, L superior temporal, L TPJ and L inferior frontal orbital areas, and out‐of‐magnet olfactory identification scores (Figure 2).

Conclusion

Our novel fMRI task elicited robust activation in higher‐order olfactory structures. Since Lower activation in these regions correlated with lower ID scores across the entire cohort. HC shows greater activity in higher order brain regions, suggesting an impaired top‐down identification mechanism in MCI. There seems to be a separation between HC and MCI in Figure 2. This will be further investigated using a larger sample size.
Associations among Neurofilament light chain (NfL), Depressive Symptoms and Cognition in autosomal dominant Alzheimer´s disease
Authors: Aguillon David Fernando , Vasquez Daniel , Baena Ana Y , Vila‐Castelar Clara , Acosta‐Baena Natalia , Garcia Gloria , Giraldo‐Chica Margarita M. , Tirado Victoria , Muñoz Claudia , Guzman Claudia F , Martinez Jairo E. , Giudicessi Averi , Langella Stephanie , Lopera Francisco , Gatchel Jennifer R. , Quiroz Yakeel T.
Published: January 2025

Background

Depressive symptoms are associated with neurodegeneration in individuals at increased risk for late‐onset Alzheimer’s disease, but these relationships are less clear in younger individuals and those at risk for autosomal dominant Alzheimer’s Disease (ADAD). Neurofilament light chain (NfL) is a biomarker of axonal damage and neuronal degeneration that becomes abnormal several decades before clinical onset in ADAD. To address this gap, we investigated the associations among depressive symptoms, plasma NfL and cognition in a younger cohort affected by the PSEN1‐E280A genetic variant. Carriers of this variant usually develop dementia by their 50s.

Method

A total of 677 carriers (574 cognitively unimpaired and 103 cognitively impaired) and 620 non‐carriers (median age 32 [Interquartile range IQR 24‐42], 55% women, 8 median education years [IQR 4‐11] from the Colombian kindred with ADAD due to the PSEN1‐E280A mutation were included. Participants underwent a neuropsychological evaluation, which included the Mini‐Mental State Examination (MMSE), a Spanish version of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) word list learning test (WLL), the 15‐item Geriatric Depression Scale (GDS), and the Functional Assessment Staging Test (FAST) to assess functional independence. Mann‐Whitney‐Wilcoxon test was used to examine group differences, and Spearman’s correlations were used to investigate associations among depressive symptoms, NfL and cognition.

Result

Compared to non‐carriers, carriers had higher levels of NfL (carriers=10.98, IQR 5.34‐13.44; non‐carriers=7.41, IQR 4.68‐8.90, p<0.001). There were no group differences in depressive symptoms (carriers =3.44, IQR 1‐5; non‐carriers=2.73, IQR 1‐4, p=0.19). In carriers, higher NfL levels were associated with higher GDS scores (r=0.093; p<0.001). Higher GDS scores were associated with lower MMSE scores (r= ‐0.18; p<0.001) and poorer CERAD WLL performance (r=‐0.17; p<0.001).

Conclusion

Our study showed that higher NfL plasma levels are associated with higher levels of self‐reported depressive symptoms in individuals with ADAD. These findings support neurodegenerative pathology underlying neuropsychiatric symptoms in ADAD and that these relationships can be detected using plasma measures. Future longitudinal analyses, examining other pathological mechanisms, and GDS‐items are needed to understand these symptoms more clearly in individuals with ADAD and whether they may be useful targets for AD prevention efforts.