bluuebunny/crossref_metadata_2025 huggingface dataset:
Two novel cerebrospinal fluid markers for vascular injury are associated with CSF markers of AD, neurodegeneration, and gliosis
Authors: Van Hulle Carol A. , Ince Selvi , Jonaitis Erin M. , Betthauser Tobey J , Kollmorgen Gwendlyn , Wild Norbert , Bendlin Barbara B , Love Seth , Asthana Sanjay , Johnson Sterling C , Carlsson Cynthia M , Blennow Kaj , Zetterberg Henrik , Miners James Scott
Published: December 2023

Background

Vascular dysfunction often occurs concurrently with Alzheimer’s disease (AD). Breakdown of the blood–brain barrier (BBB) and vascular injury may be related to amyloid and tau pathology. In preliminary analyses, we examined the relationship between cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, and glial activation, and two novel CSF markers of vascular dysfunction: soluble platelet‐derived growth factor receptor beta (sPDGFRβ) a marker of BBB integrity, and angiopoietin‐2 (Ang2), a marker of vascular injury.

Method

CSF samples from participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) or the Wisconsin Alzheimer’s Disease Research Center (WADRC) studies were assayed for markers of AD, neurodegeneration, and gliosis, using Roche NeuroToolKit® immunoassays (Roche Diagnostics International Ltd, Switzerland). A subset of serially sampled participants (N = 209, Nob

s = 531) who spanned the AD clinical spectrum (cognitively unimpaired, MCI, dementia) underwent sPDGFRβ measurement (ELISA); a sample of N = 121 (Nobs
= 276) was also assayed for Ang2 (ELISA) (Table 1). Pearson correlations were calculated for all CSF biomarkers. Linear mixed‐effects models with random intercepts, age‐at‐lumbar‐puncture as the measure of time, and CSF vascular biomarker as the outcome were used to test associations with tau positivity (>24.8 pg/mL), and cognitive status.

Result

sPDGFRβ correlated with all CSF biomarkers (rs range .18 to .45, ps<.001, Figure 1A) except AB42/40. Ang2 correlated with all CSF biomarkers (rs range .21 to .45 ps <.001, Figure 1B) except AB42/40, and S100B. sPDGFRβ and Ang2 correlated most strongly with Aβ40 and biomarkers of synaptic function (neurogranin and α‐synuclein). Tau positivity was associated with sPDGFRβ in the whole sample (estimate = 64.5, p<.001) and excluding participants with MCI/dementia (estimate = 77.7, p<.001). Tau positivity was associated with Ang2 (estimate = 18.1, p = .007), however the association was not significant after excluding participants with MCI/dementia. There was no difference in sPDGFRβ across the AD clinical spectrum. Ang2 was higher among participants with MCI than cognitively unimpaired participants (estimate = 21.0, p = .037, Figure 2).

Conclusion

CSF markers of vascular injury were elevated in MCI and were moderately related to tau pathology and markers of neuronal injury and neuroinflammation, but not amyloid pathology, providing insight into the association of of vascular injury to AD related disease
Late‐life hypertension acts together with amyloid‐β pathology to promote early cognitive decline
Authors: Da Ros Lucas Uglione , Ferrari‐Souza João Pedro , Bastiani Marco Antônio De , Hauschild Lucas Augusto , Lussier Firoza Z , Chamoun Mira , Bezgin Gleb , Benedet Andrea Lessa ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Pascoal Tharick A. , Rosa‐Neto Pedro
Published: December 2023

Background

Midlife hypertension (HTN) is a known risk factor for Alzheimer’s Disease (AD) development. However, whether the same effect is observed in older individuals, at risk for AD, remains to be elucidated. Here, we aimed to assess whether late‐life HTN and the presence of amyloid‐β pathology (Aβ) interact to promote longitudinal cognitive decline in cognitively unimpaired (CU) individuals, and if systolic blood pressure (SBP) levels moderate this interaction. Interactive effect of disease pathophysiology is crucial for dementia prevention strategies.

Method

We used two independent cohorts. We evaluated 475 CU individuals over 65 years of age from the ADNI cohort, with available baseline medical data and CSF Elecsys biomarkers (Aβ1‐42 and p‐tau181), as well as longitudinal clinical assessments with neuropsychological testing (up to 6 years); the individuals were classified as (A)+ or (A)‐ based on a previously proposed cut‐off of CSF p‐tau181/Aβ1‐42 lower than 0.025. We also evaluated 162 CU individuals over 65 years of age from the TRIAD cohort with baseline clinical data and Aβ‐PET, as well as longitudinal clinical assessments with neuropsychological testing (up to 3 years). The individuals were classified as (A)+ or (A)‐ based on Aβ‐PET positivity. All individuals were classified as positive or negative for hypertension based on medical history. For the ADNI cohort, we could also evaluate the SBP levels as a continuous variable.

Result

Linear mixed‐effects (LME) models showed that HTN and Aβ acted together to promote longitudinal cognitive decline (ADNI: HTN X Aβ X Time, β = ‐0.44, p = 0.001, figure 1, TRIAD: HTN X Aβ X Time, β = ‐0.64, p < 0.001, figure 2). Also, we could see that higher SBP levels acted together with Aβ to promote further cognitive decline (SBP values X Aβ X Time, β = ‐0.011, p = 0.03, figure 3).

Conclusion

Our results support a framework in which late‐life HTN is a modifiable risk factor for cognitive decline in CU individuals at increased risk for AD. This supports further investigation in determining the best target of SBP levels for individuals at risk for AD, in the context of offering precision medicine for this population.
The Neuropathological Correlates of White Matter Hyperintensities in Cerebral Amyloid Angiopathy
Authors: Makkinejad Nazanin , Zotin Maria Clara Zanon , Brink Hilde , Auger Corinne A. , Iglesias Juan Eugenio , Greenberg Steven M. , Perosa Valentina , Veluw Susanne J
Published: December 2023

Background

Cerebral amyloid angiopathy (CAA) is a common cause of intracerebral hemorrhage and cognitive impairment in older individuals. Hallmark manifestations of CAA on MRI include cortical hemorrhages, as well as perivascular spaces (PVS) in the white matter centrum semiovale and white matter hyperintensities (WMH) in a subcortical multi‐spot pattern. We performed an ex vivo MRI‐neuropathological study to: 1) determine the relationship between WMH volume and CAA severity, and 2) assess the histopathological substrate of confluent WMH, WMH in a multi‐spot pattern (WM_MS), and normal‐appearing white matter (NAWM).

Method

Nineteen autopsy cases with pathologically confirmed CAA (age 75±8y; 7F) and five non‐CAA controls (age 88±5y; 3F) were included. Formalin‐fixed hemispheres underwent 3T MRI, including a T2‐weighted (500µm isotropic resolution, to obtain manual WMH segmentations) and a T2*‐weighted sequence (1mm isotropic resolution, to automatically segment hemisphere volume using SynthSeg). After scanning, five pre‐defined standard areas were sampled from each brain, then processed to obtain manually assessed arteriolosclerosis scores and AI‐derived cortical and leptomeningeal CAA area measurements. In the CAA cases, specific areas with ex vivo MRI‐observed WM_MS (n = 7), confluent WMH (n = 9), and NAWM (n = 9) were sampled. Sections were stained with LH&E (to determine WM rarefaction, % PVS area, and degree of arteriolosclerosis), and CD68 (a marker of activated microglia, to assess density of CD68‐positive cells).

Result

Total normalized WMH volume did not differ between CAA cases (0.037±0.024) and non‐CAA controls (0.027±0.026) (Mann‐Whitney U test 36, p = 0.31). Within the CAA cases, a multivariable regression model corrected for age at death revealed that normalized WMH volume was associated with cortical CAA area (p = 0.010) and arteriolosclerosis (p = 0.066), but not leptomeningeal CAA area (p = 0.94). Targeted neuropathological assessment revealed that WM rarefaction, arteriolosclerosis score, and density of CD68‐positive cells were higher in areas with WMH compared to WM_MS and NAWM. In contrast, % PVS area was higher in WM_MS compared to WMH and NAWM.

Conclusion

The observed differences in neuropathological correlates between WMH in a multi‐spot pattern and confluent WMH in CAA suggest different pathophysiological mechanisms. Future studies are needed to determine these mechanisms as well as the causal relationship between cortical CAA severity and WMH burden.
Pupillometry as a marker of arousal and in relation to cognition and cortical dynamics in Alzheimer’s disease
Authors: David Michael CB , Mallas Emma‐Jane , Karakoc Hanim , Tsoi Chris ML , Hoang Karen , Scott Gregory PT , Sharp David J , Malhotra Paresh A
Published: December 2023

Background

Pupil dilation is an established measure of noradrenergic activity. Cortical EEG alpha power, a measure of attentional engagement, can be recorded simultaneously with pupillometry. Dysfunction in the noradrenergic system in Alzheimer’s disease (AD), contributes to the attentional deficits seen in patients. We investigated whether pupillometry recorded at rest can be used to show reduced noradrenergic activity in AD and how this relates to cortical dynamics.

Method

We recorded simultaneous EEG and pupillometry during 5min of eyes‐open resting‐state in 28 AD patients and 22 age‐matched controls (HC). Pupil dilations – peaks of both pupil diameter and velocity – were identified (Fig. 1A/B). Average pupil diameter and velocity were calculated across all dilations, and compared between groups (Fig. 1 C/D). We plotted EEG power spectra for the 2s pupil dilation‐centred epochs (Fig. 2A). The frequency at which there was the greatest power within the alpha band – the peak alpha frequency (PAF) – was calculated for each individual and compared across groups (Fig. 2B). We then measured the alpha power during the pupil‐dilation epochs and looked at the relationship with the pupils (Fig. 3).

Result

In HCs, the mean pupil dilations – peaks in diameter and peaks in velocity – were greater than in AD; t = ‐2.62 p = 0.01 and t = ‐2.26 p = 0.03, respectively (Fig. 1C/D). Power spectra for the 2s pupil dilation‐centred epochs showed patients’ PAF was significantly lower than HC’s; t = 2.92 p<0.01 (Fig. 2). There was a corresponding peak in alpha power associated with the pupil dilations, in both groups. Regarding peaks in pupil diameter, the alpha power peaked approximately 0.5sec earlier (Fig. 3A). Regarding peaks in pupil velocity, the alpha power peaked simultaneously with the pupils (Fig. 3B).

Conclusion

There is a reduction in size and velocity of spontaneous pupil dilations in AD. EEG alpha is shifted to lower frequencies in AD. There is a preserved relationship between pupil dilations and alpha peaks in AD. Pupillometry offers a means of measuring noradrenergic dysfunction in AD that relates to altered cortical dynamics.
A Vocal Assessment Method (VAM) to Evaluate the Effectiveness of Interactive Drawing Therapy for Patients with Dementia (PwD) (A Prospective Paper)
Authors: Parsapoor Mahboobeh , Parsapour Sepideh
Published: December 2023

Background

It is crucial to develop non‐pharmacological interventions to help people with dementia. Among different types of non‐pharmaceutical interventions for dementia, art therapy interventions have been shown helpful for improving patients’ physiological and mental states, in particular their cognitive performances, cognitive functionalities, including emotional states, verbal fluency, and behavioral reactions. We use Interactive Drawing Therapy (IDT), proposed by Russell Withers, as an art therapeutic method for people with dementia and to explore the method’s effectiveness, we suggest developing a vocal assessment method.

Method

We will recruit participants with mild AD and individuals without dementia and divide them into two groups, an experimental group that will attend the IDT sessions and a control group that won’t be offered the IDT sessions. All participants will attend two picture description sessions while they describe the cookie theft picture or the picnic scene. For the experimental group, we will offer attending two IDT sessions between two picture description sessions. During the first IDT session, the art therapist helps participants draw their thoughts about what he is doing during the day and describe their feelings. During the second IDT session, the art therapist shows one of the pictures, “Man changing the bulb” or “The Cat in the Tree,” and asks them to describe the picture with drawing and writing words. We collect speeches of participants during picture description and IDT sessions. The cognitive status of each participant will be measured using the Mini‐mental state examination (MMSE) test.

Result

We will aim to develop a binary classifier to distinguish patients with improved verbal fluency from patients without any enhancements in verbal fluency. It can be a part of a vocal assessment method to assess improvements in verbal fluency of patients attending IDT sessions which will be designed by combing the picture description. We also expect that such IDT sessions can enhance the verbal fluency of patients with dementia.

Conclusion

This study will promise to develop a vocal system to discover the effectiveness of IDT for peoplewith dementia. As a part of this study we aim to identify linguistic and acoustic features that might change during the IDT sessions.
AD and ADRD Differences in Luminex and Lumipulse ATN Categories
Authors: Jain Lavanya , Khrestian Maria , Formica Shane , Tuason Elizabeth D. , Pillai Jagan A. , Rao Stephen M. , Leverenz James B , Bekris Lynn M.
Published: December 2023

Background

Cerebrospinal fluid (CSF) biomarkers for amyloid (A), tau (T), and neurodegeneration (N) can be utilized to define pre‐mortem pathological status (ATN research framework). However, potential differences across methods present challenges when comparing studies. Our objective was to determine the ATN status in an AD/ADRD cohort using two different methods for measuring CSF AD‐related biomarkers; Fujirebio Lumipulse G1200 and the Luminex 200. The hypothesis was that the proportion of individuals in a given ATN category would differ between these two methods.

Method

Participants were recruited from the Cleveland Alzheimer’s Disease Research Center (CADRC), and Cleveland Clinic Lou Ruvo Center for Brain Health (CBH) and included cognitively normal (CN), mild cognitive impairment (MCI), AD, dementia with Lewy Bodies (DLB), and PD patient groups. Aβ42/40 (A), p‐Tau181 (T) and t‐Tau (N) were quantitated using both Lumipulse and Luminex systems. Receiver Operating Characteristic (ROC) curve was utilized to identify optimal cutpoints for the three biomarkers (A, T, and N) based on the CN and AD cohorts. Youden index was calculated to identify the strength of these biomarkers.

Result

Correlation analyses between the two platforms, indicated that there was a significant correlation for Aβ42/40 (A), p‐Tau181 (T) and t‐Tau (N) among most patient groups, especially for Aβ42/40. The cut‐points were 0.0562 (A), 65 pg/mL (T) and 345 pg/mL (N) for Lumipulse, and 0.1600 (A), 106.77 pg/mL (T) and 399.41 pg/mL (N) for Luminex. Out of the overall cohort of 283 individuals, over half had identical ATN status for both Lumipulse and Luminex.

Conclusion

There was a strong correlation for CSF AD‐related biomarkers between the two platforms. However, there was a lack of complete ATN category overlap between platforms suggesting that across study comparisons using ATN categories derived from different platforms (e.g. Luminex and Lumipulse) should be approached with caution. In light of different techniques that are available, it is important to understand the difference between them to inform standardization and data harmonization efforts. A definite and effective method to quantitate AD related biomarkers holds the promise of better differential diagnosis in individuals with AD and ADRD.
Bilingual neurocognitive resiliency, vulnerability, and Alzheimer’s disease biomarkers in Latino older adults enrolled in the Health and Aging Brain Study‐Health Disparities (HABS‐HD)
Authors: Grasso Stephanie M , Clark Alexandra L , Petersen Melissa , O'Bryant Sid E.
Published: December 2023

Background

Although bilingualism has been associated with cognitive reserve and a later age of dementia onset (e.g., Alladi et al., 2013, 2017; Bialystok et al., 2007, 2010; de Leon et al., 2020), the effects of bilingualism on neuropsychological test performance in bilinguals with and without cognitive impairment have not yet been thoroughly investigated (e.g., Briceño et al., 2021; Cherner et al., 2021; Padilla et al., 2016).

Method

The present study explored patterns of cognitive performance and impairment across a large sample of bilingual and monolingual Latino older adults from the Health and Aging Brain: Health Disparities cohort (O’Bryant et al., 2021). In addition to examining differences between bilinguals and monolinguals, the associations between specific bilingual factors (i.e., dominance and age of acquisition) and cognitive performance were examined in order to elucidate which components of the bilingual experience explain such associations.

Result

Bilingual speakers demonstrated a pattern of cognitive resiliency in the form of better performance on attention/processing speed that can be observed across the cognitively unimpaired (Trails A, p = .001; Trails B, p = .02; Digit Substitution p = .004, and Logical Memory I p = .04) and mild cognitive impairment (Trails A, p < .001 and Digit Substitution, p < .02) diagnostic spectrum. In contrast, bilingual speakers demonstrated a pattern of cognitive vulnerability in the form of poorer performance and higher rates of impairment on a language measure that is only evident in the MCI phase (letter fluency, p = .001). Follow‐up analyses revealed bilinguals that 1) had a later age of language acquisition or 2) unbalanced language dominance performed more poorly on cognitive testing (Table 1) and had higher rates of impairment (Table 2). Exploratory analyses revealed that bilinguals with impaired language scores demonstrated lower levels of plasma Ab 42/40 relative (indicative of greater AD pathology) to unimpaired bilinguals (p = .02; Figure 1).

Conclusion

Results suggest that patterns of cognitive performance and impairment differ as a function of bilingualism. Bilingual factors must be considered in clinical and research investigations centered on evaluating cognitive outcomes of Latino older adults.
Multivariate white matter differences links to cognition in individuals with family history of Alzheimer’s disease and APOE4 genetic risk
Authors: Tremblay Stefanie A , Spreng R. Nathan , Alasmar Zaki , Pirhadi Amir , Tardif Christine L , Chakravarty M. Mallar , Villeneuve Sylvia , Leppert Ilana R , Carbonell Felix , Medina Yasser Iturria , Steele Christopher J , Gauthier Claudine J ,   The PREVENT‐AD Research Group
Published: December 2023

Background

Growing evidence suggests Alzheimer’s disease (AD) develops from a complex cascade of events that vary between individuals. Multivariate approaches have the potential to capture the complexity and heterogeneity of pathologies underlying AD in a more holistic manner compared to univariate approaches.

Method

The MRI data of 105 older adults with a family history of AD from the PREVENT‐AD dataset were analysed. Forty six of these individuals had the APOE4‐3 genotype (greater risk of developing AD), while 59 subjects had the APOE3‐3 genotype (normal risk). Diffusion‐weighted imaging and multi‐echo magnetization transfer, proton density and T1‐weighted data were used to compute several WM metrics (Fig1 b‐c). We computed the voxel‐wise Mahalanobis distance (D2) in WM between APOE4‐3 individuals and a reference group (APOE3‐3) (Fig1). D2 is a multivariate measure that combines several MRI metrics, accounting for their covariance, and yielding a score indicative of the degree of abnormality at each WM voxel (Fig2). Associations between WM D2 and cognitive performance were then investigated (Fig3). Independent component analysis (ICA) was performed on spatial dimensions and linear regression analyses were conducted between D2 in ICA components and scores on items of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We then extracted the contribution of each MRI feature to D2 in the regions where significant associations were found.

Result

A significant negative association (R = ‐0.36, p = 0.014) was found between D2 in a component corresponding to the splenium of the corpus callosum (CC) and scores on RBANS‐immediate memory (Fig3), indicating a link between a greater degree of WM abnormality and poorer performance. Proton density (MPM_PD) and longitudinal relaxation rate (MPM_R1), potentially indicative of WM loss, contributed most to D2 in this region.

Conclusion

Our findings suggest that microstructural alterations in the posterior part of the CC may play a role in memory deficit in older adults who are at greater risk of developing AD. This is in line with other studies that showed a link between CC degeneration and memory impairments in early AD stages.1

1. Qiu et al. (2016). Inter‐hemispheric dysconnectivity in AD and aMCI. Sci.Rep.
Fosgonimeton, a Small‐Molecule Positive Modulator of the HGF/MET System, Attenuates Amyloid‐β – Mediated Toxicity in Primary Neuron Culture
Authors: Reda Sherif , Wu Wei , Helton Leah , Taylor Robert W , Johnston Jewel L , Church Kevin J.
Published: December 2023

Background

Positive modulation of the hepatocyte growth factor (HGF)/MET system may represent a promising therapeutic strategy for Alzheimer’s disease (AD). Downstream effectors of HGF/MET, such as AKT or ERK, have been shown to activate pro‐survival signaling cascades that counteract pathological components of AD including excitotoxicity, mitochondrial dysfunction, oxidative stress, and protein aggregation. We have previously that fosgonimeton, a small molecule positive modulator of the HGF/MET system, elicits broad neuroprotective effects (Johnston et. al, 2022). Herein, we investigate the mechanism of action by which fosgonimeton induces neuroprotective effects in beta‐amyloid and glutamate‐challenged primary cortical neurons.

Method

Primary rat cortical neurons were treated with the active metabolite of fosgonimeton (fosgo‐AM), challenged with beta‐amyloid (Aβ1‐42; 15 µM) for 24 hours, and co‐immunostained for microtubule‐associated protein‐2 (MAP‐2) and phospho‐tau (AT100). Immunofluorescence analyses were used to determine neuronal survival, neurite network integrity (total neurite length), and phospho‐tau levels. In a separate model, rat cortical neurons were treated with fosgo‐AM and challenged with glutamate (20 µM) for 24 hours, and immunostained for MAP‐2 to determine neuronal survival and neurite network. To elucidate the mechanism of neuroprotection, protein analyses via western blot and homogenous time‐resolved fluorescence were conducted to assay HGF/MET downstream signaling pathways. In addition, the effect of fosgo‐AM on mitochondrial membrane potential (MMP) was assessed in primary cortical neuron culture via fluorescent MMP dye.

Result

Fosgo‐AM treatment significantly improved survival of cortical neurons, protected neurite networks, and reduced tau hyperphosphorylation after injury with Aβ1‐42. Additionally, fosgo‐AM reduced glutamate‐mediated cortical neuron death and neurite degeneration. Analyses of downstream signaling effects indicate that the neuroprotective effects of fosgo‐AM treatment may, in part, be the result of activation of AKT signaling and subsequent rescue of mitochondrial membrane potential, thereby reducing protein pathology and oxidative stress.

Conclusion

Our in vitro data demonstrate the address pathological of AD reduce tau . neuroprotective effects of fosgonimeton, in addition to its neurotrophic and pro‐cognitive effects in preclinical models, highlight its therapeutic potential to interrupt disease progression and restore neuronal health. Fosgonimeton is currently in clinical for mild‐to‐moderate AD (NCT04488419; NCT04886063).
Deep quantitative proteomics analysis of the brain vasculature in Alzheimer’s disease and related tauopathies.
Authors: Wojtas Aleksandra
Published: December 2023

Background

Dysfunction of neurovascular unit represents a major pathological hallmark of Alzheimer’s disease (AD) and age‐related cognitive impairment. Diminished blood flow and blood‐brain barrier breakdown have been linked to the accumulation of amyloid‐b (Ab) peptide in brain parenchyma and cerebral blood vessels. Additionally, cerebrovascular dysfunction has been associated with tau pathology in primary tauopathies, including progressive supranuclear palsy (PSP) where amyloid deposition is not present. Despite the significance of brain vasculature in maintaining the proper neuronal function, the proteomic profiles of cerebrovasculature remain poorly characterized.

Methods

Here, for the first time we implemented a tandem mass tag spectrometry (TMT‐MS) approach to thoroughly examine proteomic features of human cerebrovasculature from postmortem brain tissues from AD, PSP, and non‐demented control individuals (N = 20‐24 cases/diagnosis) from the University of Pennsylvania School of Medicine Brain Bank. The human cerebrovasculature was isolated from frontal cortex using density‐mediated separation to purify blood vessels from parenchymal components.

Results

The quantification of over 9,800 proteins allowed us to generate deep TMT protein co‐expression network consisting of 93 communities of proteins displaying wide biological heterogeneity associated with diverse brain pathologies. Importantly, the comparison of vascular proteome with proteomic data obtained from bulk brain tissues from the same individuals gave us a unique opportunity to interrogate the relationship and preservation between different data sets. We also explored how candidate gene products that confer the risk for AD or PSP map to the discovered protein modules.

Conclusions

In summary, by taking advantage of our network‐driven approach we nominated pathways strongly correlated with AD‐like neuropathological traits and vascular biology that could provide the foundation for our understanding of the mechanisms governing AD‐linked breakdown of BBB, dysregulation of the cerebral blood flow, and pathological accumulation of protein aggregates in human vasculature.
Apolipoprotein (APOE4) allele as a predictor for Amygdala structure and Anxiety in normal aging‐ Results from the Triple‐A (Amygdala, Anxiety, and Ageing) study
Authors: Issac Thomas Gregor , Sundarakumar Jonas S. , Stezin Albert , Malo Palash Kumar
Published: December 2023

Background

Apolipoprotein E4 (APOE4) gene is an important risk factor based on available literature for late onset Alzheimer’s dementia and its effect on normal brain aging in Low and Middle‐income countries has been less studied. The evolutionary benefit that APOE4 confers against various infections during the younger age versus the vulnerability it offers that predisposes to the development of late‐onset cognitive decline is quite exciting but very less studied. We attempt to look into the effects of APOE4 carrier status and its influence on Amygdala structure and as an independent predictor for the development of late‐life anxiety symptoms.

Method

The subjects were recruited from the Tata Longitudinal Study of Ageing (TLSA) cohort, which is an Urban cohort wherein cognitively healthy participants ≥45 years, evaluated for baseline clinical cognitive, genetic, and imaging studies and followed up annually. About 102 participants whose APOE4 genotyping were done were included in this study and compared with their imaging characteristics especially looking into the amygdaloid volumes. Data was analyzed using SPSS v.24

Result

More than half of the participants were females (52%). The APOE4 carrier status (homozygous or heterozygous to APOE4 allele) was present in 51% of the individuals, and only 2.2% of the subjects had overt anxiety symptoms. The mean age of females were 63.89土9.6 and Males 64.82 土 9.3 years, respectively. With normalized imaging data, it was found that males had significantly higher left and right amygdaloid volumes than females(P<0.001) irrespective of the carrier status, and when the Hindi Mental Status Examination (HMSE) scores were considered as an outcome measure, there was a significant reduction in the Right amygdala volumes in the carriers versus non carriers.

Conclusion

Amygdala is an integral part of the limbic system mediating emotions tagged to cognition, and its structure is likely modulated by the APOE4 carrier status. It could likely impact global cognition even when there is no significant difference in neuropsychological test scores between the carriers and non‐carriers in a cohort of cognitively normal individuals. However, ApoE4 carrier status does not seem to predict anxiety or depression early in cognitively healthy individuals, especially among the Indian population.
The investigation of hippocampal free‐water as a biomarker for cognitive impairment and decline in older adults
Authors: Sathe Aditi , Shashikumar Niranjana , Moore Elizabeth E. , Pechman Kimberly R. , Landman Bennett A. , Gifford Katherine A. , Hohman Timothy J. , Jefferson Angela L. , Archer Derek B
Published: December 2023

Background

While diffusion MRI derived free‐water (FW) metrics have shown promise in predicting cognitive impairment and decline in aging and Alzheimer’s disease (AD), it is unclear whether hippocampal FW metrics would be superior to traditional structural neuroimaging biomarkers (i.e., hippocampal volume, AD Schwarz Signature, AD McEvoy Signature). We examined the relationships between hippocampal FW metrics and traditional neuroimaging biomarkers with longitudinal memory and executive function.

Method

Vanderbilt Memory & Aging Project participants [n = 298, age at baseline: 73 ± 7 years, 40% mild cognitive impairment (MCI)] underwent longitudinal neuropsychological assessment and brain MRI over a 7 year follow‐up (mean: 3 ± 2 years) period. Structural MRI was used to quantify hippocampal volume in addition to Schwarz and McEvoy signatures. Diffusion MRI in conjunction with the FW elimination technique was used to quantify hippocampal FW and FW‐corrected fractional anisotropy (FAFWcorr). Linear regression was used to determine the association of each biomarker with baseline memory and executive function. A subsequent competitive model analysis was conducted to determine how much additional variance was provided by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein‐e4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. Additionally, linear mixed‐effects regression was used to determine the association between baseline biomarker values with longitudinal memory and executive function scores. All analyses were corrected for multiple comparisons using the FDR procedure.

Result

At baseline, all biomarkers (excluding hippocampal FAFWcorr) were significantly associated with cognitive performance (Table 1), with hippocampal FW exhibiting the most significant association for memory (pFDR = 3.92×10−6) and executive function (pFDR = 5.35×10−3). Competitive models revealed that hippocampal FW contributed the most unique variance beyond covariates for memory (ΔRadj
2 = 3.87%) and executive function (ΔRadj
2 = 1.59%). Longitudinal models (Table 2, Figure 1) largely mirrored cross‐sectional models by demonstrating that hippocampal FW was most significantly associated with longitudinal decline in memory (pFDR = 5.04×10−13) and executive function (pFDR = 6.15×10−5).

Conclusion

This study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.
Astrocyte reactivity moderates the effect of education on cognitive reserve
Authors: Borelli Wyllians Vendramini , Antônio De Bastiani Marco , Bieger Andrei , Ferrari‐Souza João Pedro , Castilhos Raphael Machado , Rosa‐Neto Pedro , Zimmer Eduardo R. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Cognitive reserve and resilience account for differential susceptibility to brain aging and disease across individuals. Previous data suggest that functional connectivity among different brain areas is associated with cognitive reserve. However, its neural basis is yet unclear. In this study, we investigated the moderating effect of astrocyte reactivity in cognitive reserve.

Method

Cognitively unimpaired individuals who had plasma GFAP analyzed were selected from ADNI at baseline (n = 130). Years of education were used as a proxy of cognitive reserve; the Montreal Cognitive Assessment (MoCA) total score was retrieved from all individuals. A moderation analysis was performed according to the most recent framework for reserve and resilience in aging concepts. The total MoCA score was the outcome, and we investigated the moderation of plasma GFAP in the association of years of education and MoCA. Data are shown as mean+‐SD.

Result

A total of 130 individuals had complete data for all variables (72.3+‐6.3 years of age; 16.36+‐2.75 years of education; 43.1% females). A significant moderating effect was found in plasma GFAP and years of education (beta = 0.004, p = 0.0006) as a predictor of total MoCA scores (Model R2 = 0.37, p < 0.0001) when correcting for age and gender. Plasma GFAP and sex were also predictors of total MOCA scores independently (p<0.001 for both). Plasma GFAP was a moderator in individuals below 18 years of education (p = 0.003), but not above 18 years of education (p = 0.9).

Conclusion

Astrocyte reactivity may play a potential role in the neural basis of cognitive reserve. The neuroprotective effect of astrocytes in cognitive reserve may have a ceiling effect. Further studies may investigate the importance of glial interactions with brain regions and its ability to predict cognitive changes in a longitudinal analysis.
Cognitive profiles are associated with brain morphometry years later in Hispanics/Latinos: Preliminary findings from the SOL‐INCA‐MRI study
Authors: Sapkota Shraddha , Maillard Pauline , Stickel Ariana M , Tarraf Wassim , Gonzalez Kevin A , Ivanovic Vladimir , Paredes Alejandra Morlett , Zeng Donglin , Cai Jianwen , Isasi Carmen R , Kaplan Robert C. , Lipton Richard B. , Daviglus Martha L , Testai Fernando Daniel , Lamar Melissa , Gallo Linda C , Talavera Gregory A , Gellman Marc D , Ramos Alberto R , González Hector M , Decarli Charles
Published: December 2023

Background

Hispanics/Latinos are the largest and most diverse ethnoracial group at high risk for Alzheimer’s disease and related dementias across the US. However, this population is largely understudied. We present preliminary findings on the association between cognitive profiles and brain morphometry measures in a large Hispanic/Latino cohort of older adults.

Method

We used a longitudinal cohort of cognitively normal older adults (n = 2028; mean baseline age = 54.19 (6.75) years, 69.5% female) from the Study of Latinos‐Investigation of Neurocognitive Aging‐Magnetic Resonance Imaging (SOL‐INCA‐MRI). First, to establish a latent memory variable, we examined confirmatory factor analysis to test loadings of four manifest variables (Spanish‐English‐Verbal‐Learning Test learning and recall, digit symbol, word frequency) at the first (2008‐2015) and second (2015‐2021) cognitive visits. Second, we examined whether tertiles of our latent cognitive score were associated with two measures of brain integrity (white matter hyperintensities [WMH] and hippocampus) measured between 2018‐2022. The brain morphometry measures were regressed independently on cognitive tertiles at both visits. Age at each visit, sex, education, Hispanic/Latino background, and cognitive‐MRI lag time were included as covariates.

Result

First, a two‐factor latent memory profile (episodic memory and working memory) best represented our four manifest variables at both visits 1 and 2. Each tertile corresponded to low (1), intermediate (2), and high (3) performing groups. Second, increase in cognitive tertile (from low to intermediate to high) on episodic memory (β = ‐0.157, SE = 0.040, p< 0.001) and working memory (β = ‐0.192, SE = 0.043, p< 0.001) at visit 1 was associated with lower WMH. Increase in cognitive tertile on episodic and working memory at visit 2 was associated with lower WMH (β = ‐0.241, SE = 0.036, p< 0.001 and β = ‐0.260, SE = 0.043, p< 0.001, respectively) and greater hippocampus (β = 0.051, SE = 0.015, p = 0.001 and β = 0.040, SE = 0.018, p = 0.025, respectively).

Conclusion

Our preliminary findings showed that cognitive profiles and key brain integrity measures are associated years later in Hispanic/Latino adults. Careful monitoring of cognitive aging profiles in the Hispanic/Latino community may lead to early detection and intervention of older adults at high risk for future neurodegeneration.
Alzheimer’s disease phenotypes in human induced pluripotent stem cell‐based models of Down syndrome
Authors: Johnson Noah R , Dooling Breanna , Ahmed Md. Mahiuddin , Summers Rose , Chial Heidi J , Potter Huntington
Published: December 2023

Background

By age 40, all people with Down syndrome (DS) develop Alzheimer’s disease (AD) brain neuropathology, including Aβ plaques and neurofibrillary tangles of phosphorylated microtubule associated protein tau (MAPT), and most go on to develop early‐onset dementia. People with Down syndrome (DS) have triplication of chromosome 21 (trisomy 21) and they develop AD neuropathology due to triplication of the amyloid precursor protein gene (APP) which resides on chromosome 21. Here, we developed and characterized human induced pluripotent stem cell (hiPSC)‐derived neurons, astrocytes, microglia, and cerebral organoid (CO) models of DS and familial AD and used them to evaluate the AD‐related pathological mechanisms caused by trisomy 21.

Method

We obtained hiPSC lines derived from individuals with DS, healthy control individuals (HC), and individuals with familial AD, including duplication of APP on one chromosome (APPdup) or carrying the London mutation in APP (APPV717I). All donors had the apolipoprotein E (APOE) ε3/ε3 genotype. We generated hiPSC‐derived neurons, astrocytes, microglia, and COs using validated techniques. We evaluated the hiPSC‐derived neural cells and COs at different ages for AD‐related neuropathology, neuroinflammation, and neurodegeneration by performing RNA sequencing, immunohistochemistry, immunoblotting, and enzyme‐linked immunosorbent assay.

Result

AD‐related size phenotypes characteristic of neurodegeneration were observed in DS hiPSC‐based models relative to HC models. Dysregulated gene and protein expression of APP, MAPT, and APOE, in addition to chromosome 21 genes, were also observed in DS hiPSC‐based models. In particular, neuroinflammatory markers, especially those previously shown in APOE‐related pathways, were also increased in DS models.

Conclusion

We characterized new hiPSC‐based models of DS and familial AD which will be useful for identifying commonalities in disease mechanisms as well as for dissecting the roles of chromosome 21 genes other than APP. We identified several AD‐related phenotypes in hiPSC‐based DS related to neuropathology, neuroinflammation, and neurodegeneration. We expect that these hiPSC‐based models will be useful for testing therapeutics in the future to address AD in people with DS, for which there is no cure.
Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer’s disease in the EMIF‐AD Multimodal Biomarker Discovery study
Authors: Smith Rebecca G. , Imm Jennifer L , Dobricic Valerija , Sommerer Yasmine , Bos Isabelle , Vos Stephanie J. B. , Verhey Frans R.J. , Scheltens Philip , Engelborgs Sebastiaan , Frisoni Giovanni B , Blin Olivier , Richardson Jill C , Bordet Régis , Tsolaki Magda , Popp Julius , Martinez‐Lage Pablo , Lleo Alberto , Johannsen Peter , Freund‐Levi Yvonne , Lutz Frölich , Vandenberghe Rik , Wittig Michael , Frank Andre , Lovestone Simon , Streffer Johannes , Andreasson Ulf , Blennow Kaj , Visser Pieter Jelle , Zetterberg Henrik , Bertram Lars , Lunnon Katie
Published: December 2023

Background

The aim of this study was to identify DNA methylation signatures that were associated with 15 CSF biomarker measures of Alzheimer’s disease (AD) or neurodegeneration.

Method

We profiled DNA methylation in 886 blood samples from the EMIF‐AD study using the Illumina EPIC array, identifying differentially methylated loci, and regions consisting of multiple adjacent differentially methylated sites.

Results

We identified Bonferroni‐significant differences in DNA methylation with respect to CSF t‐tau Z‐score (five loci), Aβ42 levels (one loci), YKL‐40 levels (six loci) and NFL (seven loci). Significant differentially methylated regions were identified in 13 of the 15 analyses, with overlapping regions featuring in multiple CSF measures(MX2, RHOH, ANKMY1, ZFP57) analyses, which was unsurprising given the high correlation between measures. Interestingly, we identified several regions that overlapped between the tau and amyloid (ZBTB22), tau and NFL (S100A13), NFL and neurogranin (SORD), and neurogranin and amyloid (STRA6) regional analyses.

Conclusion

In this blood‐based epigenome‐wide association study of AD‐relevant CSF biomarkers we identified several interesting genomic loci and regions.
Age‐ and Sex‐Related Morphological Changes in Cerebral Blood Vessels: a 7T TOF MRA Study
Authors: Li Jiatai , Stetten George D , Schweitzer Noah , Shi Zonghua , Ibrahim Tamer , Yang Shaolin , Iordanova Bistra , Aizenstein Howard J , Wu Minjie
Published: December 2023

Background

In this study we evaluated age‐ and sex‐associated morphological changes of cerebral blood vessels using 7T Time‐of‐flight (TOF) magnetic resonance angiography (MRA).

Method

Our study consisted of 25 cognitively normal older adults (20 female, mean age 68.2 years). Whole‐Brain TOF MRA images were collected on a 7T Siemens scanner at the University of Pittsburgh (slice number = 354, voxel size = 0.38*0.38*0.38 mm, 12 mins). An iterative vessel segmentation algorithm, VesselMapper, was used to segment blood vessels on TOF MRA images (Li et al., 2023). For each subject, vessels are further divided into large and small vessels by median split based on vessel diameters. Mean tortuosity of large vessels, small vessels and overall vessels was computed. Linear regression analyses were performed to evaluate the main effects of age and sex, and the age*sex interaction on vessel tortuosity and diameter.

Result

As shown in Figure 1, we found age‐related increase in mean vessel tortuosity (greater age is associated with greater tortuosity, p<0.02). This age‐related difference is driven by small vessels (p = 0.002) rather than large vessels (p = 0.7). We also found that age is positively associated with mean voxel tortuosity (p<0.001, black line in Figure 2). Furthermore, women showed greater age‐related increase in mean arterial tortuosity, compared to men (age*sex interaction p = 0.04, Figure 2).

Conclusion

Our findings validated that morphological markers of cerebral blood vessels are sensitive to aging. Small vessels in the brain are particularly vulnerable. Further, compared to men, older women are at a higher risk for cerebral small vessel disease, which may contribute to elevated SVD‐related AD risk in women.

Limitation: The study has an unbalanced sample (more women than men) and a relatively modest sample size (N = 25). A cross‐sectional instead of longitudinal design was used in this analysis. Future study with a large balanced sample and a longitudinal design are required to confirm our findings.

Reference: Li, Jiatai, et al. “VesselMapper ‐ A Robust Vessel Segmentation Algorithm for 3D Images.” Annual Meeting of the Organization for Human Brain Mapping. 2023
The role of glial cells in neuroinflammation in the context of Alzheimer’s disease
Authors: Lima Corrêa Ferreira Rafaella , Heimfarth Luana , Ferreira Sergio T.
Published: December 2023

Background

Alzheimer’s disease (AD) is the world’s leading form of dementia. The pathogenesis of AD includes increased brain levels of β‐amyloid peptide oligomers (AβOs), neurotoxins associated with AD. The increase in oligomer concentration is neurotoxic and causes, among the damages, synapse loss, mitochondrial dysfunction and impairment of proteostasis mechanisms. Neuroinflammation, notably the activation of microglia and astrocytes to pro‐inflammatory states, has been associated with the pathogenesis of several neurodegenerative diseases. The current work aimed to evaluate the neuroprotective role of microglia in the context of the pathophysiology of AD.

Method

This study aims to investigate potential modulations in morphology and function of glial cells in experimental models of Alzheimer’s disease (AD), evaluating (1) the in vitro activation of microglia and astrocytes promoted by AβOs, and (2) in vivo microglia and/or astrocytic activation in mice receiving intracerebroventricular (icv) administration of AβOs. Expression of cytokines and glial markers were analyzed by RT PCR and Immunocytochemistry.

Result

Preliminary results suggest an increase in glial activation markers, such as GFAP and F4/80, and complement immune system markers such as C1q, 7 days after icv infusion of AβOs. No significant differences were observed in the expression of TNF‐α. Immunocytochemical analyzes suggest greater nuclear factor‐KB translocation in microglial cells treated with AβOs compared to vehicle.

Conclusion

Results are consistent with an important role of glial cells in the pathogenesis of AD, with glial activity altered and activated in both in vitro and in vivo models. In the face of chronic processes, these cells can remain in an activated state, releasing cytokines, complement components and chemokines, which may contribute to the production and accumulation of Aβ and further exacerbate pathology.