bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Neuroimaging in Suspected Dementia Patients: Utilization of Structural Imaging Algorithmic‐Based Diagnosis in Resource Limited Settings
Authors: Ayele Biniyam A.
Published: December 2023

Background

In 2050, it is estimated that the number of dementia patients in the sub Saharan Africa is expected to reach 5.05 million, an increase of 136% from the previous estimate of 2.14 million. The objectives of the present study were to assess the neuroimaging findings and associated factors in dementia suspected patients.

Method

A retrospective survey of the medical records of 121 suspected dementia patients whom presented to the Yehuleshet Specialty Clinic with subjective forgetfulness were reviewed. The study duration was between January 1, 2020 and December 31, 2021. Both descriptive and analytical statistics were used to analyze the data.

Result

The mean age was 70.4 (1SD = 10.3) years. Sixty four (52.9%) participants were age below 70. Male accounted for 57.9%. Hyperlipidemia was the commonest (38%) identified vascular risk factor followed by prevalence of hypertension (32.2%) and diabetes mellitus (22.3%). HIV infection was observed in 3.3%. Low mean serum vitamin D level (below 20ng/mL) was observed in individuals with focal & global cortical atrophy and those with white matter hyperintensity. Fifty two (43%) participants fulfilled the clinical and imaging criteria of vascular cognitive impairment (VCI). Nearly quarter of the patients had imaging evidences of focal or global cortical atrophy. Eleven (9.1%) had imaging evidences of surgical causes of dementia. the presences of comorbid hypertension, previous stroke, and Parkinsonism were independent predictors of vascular dementia.

Conclusion

The present study shows high burden of vascular cognitive impairment among individuals suspected of dementia.

Furthermore, the presences of comorbid hypertension, previous stroke, and Parkinsonism were independent predictors of vascular dementia.
Application of AT(N) classification using two CSF A‐markers and two CSF N‐markers to Alzheimer’s Clinical Syndrome (ACS) and non‐ACS
Authors: Kasuga Kensaku , Tsukie Tamao , Kikuchi Masataka , Ishiguro Takanobu , Tokutake Takayoshi , Shimizu Soichiro , Yoshizawa Hiroshi , Miyashita Akinori , Onodera Osamu , Iwatsubo Takeshi , Ikeuchi Takeshi ,   the Japanese Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

Cerebrospinal fluid (CSF) biomarkers reflect the pathological process underlying Alzheimer’s disease (AD) and improve the accuracy of AD diagnosis. AT(N) classification using these CSF biomarkers has been used within the research framework to identify points on AD continuum. However, there has been little research into the utility of AT(N) classification in clinical practice.

Methods

We measured the CSF levels of amyloid‐β (Aβ) 42, Aβ40, phosphorylated tau (Thr181), total tau (tTau), and neurofilament light chain (NfL) in samples from clinical cases, comprising 230 patients with Alzheimer’s clinical syndrome (ACS) and 328 patients with non‐ACS. The concordance between two A‐markers (i.e., Aβ42 alone and the Aβ42/Aβ40 ratio) and the two N‐markers (i.e., tTau and NfL) were analyzed. We evaluated the prevalence of biological AD (i.e., A+T+) and the percentage of each AT(N) category identified using the CSF biomarkers in the ACS and non‐ACS samples.

Results

The concordance of A‐markers was not significantly different between the ACS (87.4%) and non‐ACS (74.1%) groups. However, the frequency of discordant cases with AAβ42‐alone+/AAβ‐ratio− was significantly higher in the non‐ACS (23.8%) than in the ACS group (7.4%). The concordance of two N‐markers was 40.4% in the ACS group and 24.4% in the non‐ACS group. In the ACS samples, the frequency of biological AD in Ntau+ cases was 95% and that in NNfL+ cases was 65%. When the Aβ42/Aβ40 ratio was used as the A‐marker, the proportion of biological AD was 64.3% in ACS samples and 24.4% in non‐ACS samples. Notably, the proportion of AD continuum in the non‐ACS group was substantially different when the A‐marker was Aβ42 alone than when it was the Aβ42/Aβ40.

Conclusions

Although the AT(N) classification system was intended for use in research, it may also be also useful for clinical diagnosis. As an A‐marker, the Aβ42/Aβ40 ratio reflects Aβ deposition more accurately than Aβ42 alone. As an N‐marker, NfL reflects neurodegeneration more accurately than tTau, particularly in non‐ACS patients. Thus, we recommend the use of AT(N) classification in clinical practice that is defined by CSF levels of AAβ‐ratioTNNfL.
The rs‐gamma connectivity alterations related to the atrophy pattern and CSF p‐tau in early‐onset AD
Authors: Fide Ezgi , Yerlikaya Deniz , Ada Emel , Yener Görsev
Published: December 2023

Background

Among the other frequencies, the gamma frequency has received the least attention in the study of Alzheimer’s disease (AD). Previous studies point to association between amyloid accumulation and gamma alterations, suggesting that gamma activity may serve as a potential biomarker for the pathophysiology of AD. The goal of the current study is to examine changes in resting‐state (rs) gamma activity in patients with CSF‐proven early‐onset AD (EOAD) and their relationship to structural pathology associated with the disease.

Method

Drug‐naive CSF‐proven EOAD patients [mean age: 57.92 (4.35) years] and age‐, gender, and education‐matched healthy controls (HC) [mean age: 57.58 (4.01) years] were included. Gamma imaginary part of coherency (ICoh) was measured in total gamma (30‐48 Hz), gamma‐1 (30‐35 Hz), gamma‐2 (35‐40 Hz), and gamma‐3 (40‐48 Hz) frequencies. Gray matter volumes compared between groups. The rsEEG gamma activity was used for discriminant analysis. The relationships between rsEEG, MRI, and CSF p‐tau measurements were investigated.

Result

In the EOAD group, gray matter volume in temporal, parietal, and occipital areas were decreased by over 20%. We discovered that the volume of frontal and neighboring regions, that were intact in this patient group, was negatively correlated with F8‐TP8 and F4‐C4 ICoh of sub‐gamma bands. On the contrary, the volume of temporal and parietal regions where the atrophy was prominent, was positively correlated with P8‐O2 and C3‐O1 ICoh of sub‐gamma bands. In the EOAD, executive function and F7‐TP7, P3‐O1 sub‐gamma bands were negatively correlated.Regarding CSF, p‐Tau and C3‐C4 gamma‐1 showed strong positive correlation (r = 0.615). Lastly, a set of gamma ICoh measurements displayed a correct classification rate of 83% between groups.

Conclusion

Gamma coherence follows pair‐specific alterations related to atrophy pattern in EOAD. The gamma connectivity becomes greater where atrophy is increased and when CSF p‐tau is higher in EOAD. This study establishes the significance of sub‐gamma oscillations as a non‐invasive biomarker candidate with achieving an 83% correct classification rate between groups.
Modeling Aberrant Dynamic Causal Brain Circuits in Alzheimer’s Disease
Authors: Lee Byeongwook
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive and severely debilitating disease that negatively affects cognitive and memory function and is linked to increased disability in everyday functioning and risk of mortality. Neurodegeneration of focal brain areas in AD progressively impacts large‐scale brain circuits, leading to significant cognitive impairments. However, little is known regarding aberrant context‐dependent dynamic causal interactions between distributed brain regions, and their links to cognitive impairments and neuropathology, across AD clinical stages.

Method

We addressed critical gaps in our knowledge of functional circuit mechanisms underlying cognitive dysfunction in AD by leveraging innovative computational tools and state‐of‐the‐art clinical, phenotypic, cognitive, experimental, fMRI data from AD Human Connectome Project database.

Result

To this end, we identified that (1) dynamic causal interaction patterns between DMN‐MTL‐FPN‐SN nodes distinguish between clinical stages of AD in working memory task, (2) dynamic causal interactions between DMN‐MTL‐FPN‐SN nodes become progressively weaker along clinical AD disease stages in both memory tasks, and (3) dynamic causal interaction patterns between DMN‐MTL‐FPN‐SN nodes are significantly associated with task performance.

Conclusion

These findings will identify aberrant dynamic causal circuits associated with episodic and working memory deficits across AD clinical stages.
Utility of Baseline Pathological, Neuroimaging and Clinical Markers for Progression Prognosis and Subtype Classification in Early Parkinson’s Disease: Implications for Cognitive Impairment
Authors: McNamara Angus , Ellul Benjamin , Baetu Irina , Lau Stephan , Jenkinson Mark , Collins‐Praino Lyndsey E
Published: December 2023

Background

Cognitive dysfunction is a well‐recognised PD symptom, but it is highly heterogenous and under‐assessed clinically. Interestingly, PD motor subtypes are associated with different risk of cognitive decline. However, subtype classification is currently reliant on subjective clinician assessment and may consequently be misdiagnosed. Therefore, objective biomarkers of PD progression are critically needed, but must be validated prior to clinical deployment. We assessed the utility of various clinical, neuroimaging and pathological measures as predictors of cognitive outcomes up to 5‐years follow‐up in early PD.

Method

Data was extracted from the Parkinson’s Progression Markers Initiative. Cognitive assessments were compiled into an overall cognition score via principal component analysis. Distinct subgroups were identified via Fuzzy C‐Means clustering on Year‐5 Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores. Models predicting cluster membership were created via logistic regression and a stratified cross‐validation machine learning pipeline, comparing two predictor inputs: 1) baseline motor assessments; and 2) incorporating additional measures, including prodromal assessments (sleep, olfactory and autonomic function), neuroimaging (proxy SN volume, striatal DaT binding) and biofluid markers (CSF alpha‐syn, p‐tau, a‐beta, and serum IGF‐1) at baseline. Finally, cluster membership was used for retroactive assessment of baseline and follow‐up cognitive data.

Results

Two clusters were identified, with cluster two (n = 117) demonstrating higher rigidity, lower DaT binding, worsened motor outcomes and increased mood dysfunction at follow‐up compared to tremor‐dominant cluster one (n = 183). Additionally, rigid‐dominant membership was predicted by male sex, higher p‐tau, along with lower a‐beta, predicting 40% of variance (n = 111). This was significantly higher (P<0.001) than baseline motor scores alone, only accounting for 18% of variance. This was supported by machine learning, whereby incorporating additional assessments corresponded to a classification accuracy of 62%, compared to 26% when omitted. Finally, higher probability of belonging to the rigid‐dominant cluster yielded significant negative correlations cognition at baseline and follow‐up.

Conclusion

Increased likelihood of rigid‐dominance corresponded to more profound cognitive decline, which may in part result from neuropathological marker concentrations as highlighted by predictive models. Therefore, further tracking of this cohort, specifically conversion into MCI or dementia, could provide insight into pathological contribution to differences in cognitive decline between PD subtypes.
Identification of Necessary Plasma Biomarkers for Prediction of Alzheimer’s Disease Neuropathologic Change
Authors: Bermudez Camilo , Graff‐Radford Jonathan , Syrjanen Jeremy A. , Stricker Nikki H. , Algeciras‐Schimnich Alicia , Kouri Naomi , Kremers Walter K. , Petersen Ronald C. , Jack Clifford R. , Knopman David S. , Dickson Dennis W. , Nguyen Aivi T. , Reichard Ross R. , Murray Melissa E. , Mielke Michelle M. , Vemuri Prashanthi
Published: December 2023

Background

Plasma biomarkers for Alzheimer’s disease (AD) such as phosphorylated tau protein 181 (p‐tau 181), neurofilament light chain (NfL), amyloid‐β 42/40 ratio (Aβ42/40), and glial fibrillary acidic protein (GFAP) have shown high performance in the discrimination of those with clinical mild cognitive impairment (MCI) or dementia from cognitively unimpaired individuals, but few population‐based autopsy studies have evaluated the neuropathological correlates of plasma biomarkers.

Method

We utilized a population‐based prospective study of 350 participants with autopsy and antemortem plasma biomarker data. Plasma biomarkers Aβ42/40 ratio, p‐tau181, GFAP, and NfL were measured using Quanterix Simoa assays. We predicted AD neuropathological change (ADNC), Braak staging, and neuritic plaque score using these plasma biomarkers and investigated the added utility of cognitive and demographic information. We utilized a variable selection procedure in cross‐validated (CV) logistic regression models by minimizing the Bayesian Information Criterion to identify the best set of predictors for a given outcome among plasma biomarkers, demographic variables, and neuropsychological tests included in the Mayo Clinic Preclinical Alzheimer Cognitive Composite (Mayo‐PACC).

Result

ADNC was best predicted with plasma GFAP, NfL, p‐tau181 biomarkers along with APOE ε4 carrier status and Mayo‐PACC cognitive score (CV AUC = 0.821). Braak staging was best predicted using plasma GFAP, p‐tau181, and cognitive scores (CV AUC = 0.788). Neuritic plaque score was best predicted using plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL biomarkers (CV AUC = 0.778). Inclusion of plasma biomarkers demonstrated significantly better prediction of Braak staging (p<0.01) and neuritic plaque score (p<0.01), but not ADNC (p = 0.13), when compared to models that included only cognitive and demographic information. Univariate models consistently underperformed in comparison to multivariate models.

Conclusion

Plasma biomarkers can provide valuable predictive information about the presence of AD pathology, which can facilitate earlier recognition and diagnosis of AD. Incorporation of demographic and cognitive variables along with plasma variables in multivariable models will improve prediction accuracy of AD pathology, specifically Braak staging and ADNC.
Vascular Risk Factors for Idiopathic Normal Pressure Hydrocephalus: A Systematic Review and Meta‐analysis
Authors: Cai Hanlin , Yang Feng , Gao Hui , Huang Keru , Qin Linyuan , Wang Ruihan , Liu Yi , Zhou Liangxue , Zhou Dong , Chen Qin
Published: December 2023

Background

Idiopathic normal pressure hydrocephalus (iNPH) is a clinical syndrome characterized by cognitive decline, gait disturbance and urinary incontinence. Several observational studies have indicated that iNPH patients have a high occurrence of vascular comorbidities compared to normal populations. This study aims to identify the specific vascular risk factors for iNPH and review the possible pathogenesis between vascular risk factors and iNPH development.

Method

We searched PubMed, Web of Science, Embase, and the Cochrane Library for studies that reported possible risk factors for iNPH development. Meta‐analysis of the data obtained resulted in pooled odds ratios and 95% confidence intervals.

Result

Thirteen studies conducted in 7 countries comprising 1350 iNPH patients and 80043 controls were included in this meta‐analysis. Our data suggest that hypertension (Pooled OR = 2.42, 95% CI 1.82 to 3.22, I2 = 61.7%), diabetes mellitus (Pooled OR = 2.91, 95% CI 2.17 to 3.92, I2 = 50.1%), coronary heart disease (Pooled OR = 1.92, 95% CI 1.02 to 3.61, I2 = 90.3%),and peripheral vascular disease (Pooled OR = 2.77, 95% CI 1.50 to 5.13, I2 = 0.0%) are important risk factors for iNPH. Overweight was also considered a possible vascular risk factor (Pooled OR = 2.01, 95% CI 1.34 to 3.04, I2 = 0.0%), but the result was not stable as demonstrated by sensitivity analysis. Hyperlipidemia, smoking, and alcohol use were not significantly associated with iNPH development.

Conclusion

Our meta‐analysis identified that hypertension, diabetes mellitus, coronary heart disease, and peripheral vascular disease were important risk factors for iNPH. Overweight is also considered a possible vascular risk factor, but the evidence thus far has not been robust.
Outbreak of tauopathy in the olfactory system of PS19 mice: an early marker for Alzheimer’s disease diagnosis?
Authors: Dourte Marion , Kienlen‐Campard Pascal
Published: December 2023

Background

Clinical data indicate that impairment of olfactory function is an early indicator of neurodegenerative diseases, including Alzheimer’s disease (AD)(Attems et al., 2014). Our hypothesis is that typical AD lesions could appear in olfactory neurons from the olfactory epithelium (OE). The olfactory epithelium can be easily collected in human individuals (e.g., by nasal brushing), which provides an important tool to investigate the pathology in patients. Here, we address the question of the occurrence of tauopathy in the OE of transgenic mice and its correlation with pathology in the central nervous system (CNS). We use Tau P301S mice (PS19 mice), a tauopathy mouse model. These mice express human tau protein (1N4R) carrying the P301S mutation. They develop neurofibrillary tangle‐like inclusions in the cortex and hippocampus, leading to progressive neurodegeneration at eight months (Yoshiyama et al., 2007).

Method

Mouse samples were collected from heterozygous PS19 and wild‐type (WT) mice. Immunohistochemical staining (DAB) was used to demonstrate the presence of hyperphosphorylated human tau protein (hTau). We investigated regions of the olfactory system to correlate with data obtained in CNS regions (e.g., hippocampal formation, entorhinal cortex). Mouse heads decalcification was also implemented to preserve the olfactory epithelium structure. Western blots were performed to monitor tau levels and tau phosphorylation pattern.

Result

The hyperphosphorylated human tau protein (Ser202, Thr205) is only detected in PS19 mice sections while the endogenous murine tau protein is expressed both in WT and PS19 mice. The localization and expression of these proteins vary according to the region (OE or CNS subregions), the age (3, 6 or 9 months), and the genotype of the mice (WT or heterozygous PS19). It also seems that tau lesions may spread between brain regions that are directly connected, notably through the olfactory pathway.

Conclusion

In PS19 mice, a pathological phosphorylation pattern peaked in the OE prior to vulnerable CNS regions or olfactory bulbs. We hypothesize that tau lesions appearing early in the OE may spread in the olfactory bulb and finally reach the entorhinal cortex and piriform cortex, highlighting the significance of the olfactory system investigation as an early diagnosis tool.
African initiatives on stroke and dementia to improve health outcomes and international trial participation
Authors: Akinyemi Rufus O.
Published: December 2023

Background

Globally, 1 out of every 3 persons alive has a risk of developing either a stroke or dementia. 68% of the 78 million individuals projected to have dementia by 2050 will be from LMICs where the burden of vascular risk factors is rising at an alarming rate, stroke occurrence is on the rise and infrastructure for stroke surveillance, prevention, care and rehabilitation are also lacking. There are global initiatives from the World Stroke Organization towards improving primary prevention globally and the recently launched Blueprint for Dementia Research by the World Health Organization has identified six themes and eight drivers for scaling up dementia research with accompanying strategies and timelines.

Method

We describe the development of two African ‐ led initiatives with similar goals of providing platforms for diverse African experts in the fields of stroke and dementia to work collaboratively to improve research, care, prevention, advocacy and build capacity to reduce the burden of stroke and dementia in Africa as well as improve African participation in global research efforts to improve health outcomes and participation in global trials.

Result

The African Stroke Organization (ASO) and the African Dementia Consortium (AfDC) were established in 2020 and 2022 respectively with clear visions and robust governance frameworks organized into steering committees and working groups. Both organizations are currently involved in regional programs and vital research collaborations with international partners.

Conclusion

It is feasible to establish regional initiatives that can enhance diversity in global stroke and VCI research and international trial participation.
Memory Keepers Medical Discovery Team: addressing Indigenous dementia disparities through deep exploration of culture and community‐specific context
Authors: Jacklin Kristen , Blind Melissa J , Warry Wayne , Ketcher Dana , Lewis Jordan P. , Pederson Collette , Johnson January , Trudeau Rhonda , Pitawanakwat Karen , Strong Lois , Summers Marlene , Martin Wesley , Lambrou Nickolas H. , Zuelsdorff Megan , Gleason Carey E.
Published: December 2023

Background

The Memory Keepers Medical Discovery Team (MK‐MDT) was established in 2016 to address brain health equity for Indigenous and rural populations. Indigenous populations are under‐represented in Alzheimer’s disease and related dementias (ADRD) research studies and clinical trials, yet there is a dire need to address ADRD disparities in this population. In this paper we outline our research approach and studies underway at the MK‐MDT that are designed to address the ADRD disparity in Indigenous populations in the US and Canada. We highlight our flagship study “Indigenous Cultural Understandings of Alzheimer’s Disease and Dementia – Research and Engagement” (ICARE) as a key foundational ethnographic study necessary to advance the field.

Method

The MK‐MDT incorporates a community‐based participatory research (CBPR) approach with two‐eyed seeing. Two‐eyed seeing ensures the inclusion and valuing of Indigenous knowledge throughout the research process. In ICARE, we maintain a consistent focus on ethnographic research with Indigenous communities to ensure deep understanding of how culture and context shape the dementia experience. Interviews, sequential focus groups, participant observation and fieldnotes are used to populate an ethnographic database on the lived experience of dementia in Indigenous populations. We incorporate a diversity perspective by working with multiple Indigenous communities for each study. We invest in community engagement infrastructure such as community advisory committees, elder advisors, community‐based researchers and outreach workers to ensure our methods follow local ethical protocols, is culturally safe, and community controlled.

Result

We have successfully initiated NIH‐funded programs of research aimed at reducing dementia disparities. ICARE was launched in 2018 and included 54 interviews and 14 sequential focus group sessions (n = 17) in four diverse Indigenous communities, establishing the first stage of a robust ethnographic database. Findings support the existence of an Indigenous specific understanding of dementia that impacts the dementia care experience.

Conclusion

The CBPR approach coupled with two‐eyed seeing has allowed for authentic engagement with multiple Indigenous communities and has supported the collection of ethnographic data that can be used to develop culturally appropriate health promotion materials and interventions. The community‐based infrastructure that has been established is currently supporting multiple projects, including clinical research.
Modern trial outcome measures increase trial participation and recruitment of representative peoples
Authors: Elahi Fanny M
Published: December 2023

Background

Clinical trials have been one size fits all, despite evidence that dementia ensues from a combination of pathologies with effects from environment, sex/gender, race/ethnicity and other factors influencing disease course. Cardiovascular diseases and cancer have measures (imaging and molecular biomarkers) that aid in capturing targetable biology. These biomarkers are used for risk stratification, precise diagnostic classification, in addition to inclusion as outcomes in trials. Clinical trials for brain degenerative disorders would benefit from a similar precision approaches.

Method

We performed proteomics analyses on banked plasma samples from longitudinal observational studies of vascular cognitive impairment and dementia (VCID) and a clinical trial (SPRINT‐MIND) targeting hypertension, a major VCID risk factor. Using multi‐modal analytical approaches we combined molecular measures with imaging and clinical outcomes to identify promising molecular markers for risk stratification for VCID clinical trials and maximizing benefit of interventions for VCID.

Result

Proteins related to angiogenesis as well as innate immune activation were found to be dysregulated in cases versus controls. With multivariate analyses, components with high loading from proteins involved in these multi‐cellular phenotypes were associated with cognitive outcomes. Using network analyses, key molecular nodes were validated via orthogonal methods.

Conclusion

A simple molecular panel with key proteins involved in dysregulated molecular networks mediating the effect of vascular disease on cognition could be developed and used for risk stratification in clinical trials of VCID. Greater precision in clinical trials would ensure higher benefit at lower cost, at all levels.
Re‐evaluating the choice of gamma stimulation frequency for potential treatment of Alzheimer’s disease: Novel invisible spectral flicker evokes gamma responses at various frequencies
Authors: Henney Mark Alexander , Hansen Bianca Laura , Hansen Luna Skytte , Grønberg Manja Gersholm , Thorning‐Schmidt Martin William , Hansen Henrik Enggaard , Nguyen Mai , Petersen Paul Michael , Clemmensen Line Katrine Harder , Carstensen Marcus Schultz , Madsen Kristoffer Hougaard
Published: December 2023

Background

With recent advances in the potential usage of visual gamma stimulation at 40 Hz for treatment of Alzheimer’s disease, there is reason to evaluate the use of other low gamma frequencies. The choice of 40 Hz is based on studies that describe “40 Hz” oscillations with considerable frequency variability. Results are also ambiguous on the acute effects of varying the frequency when stimulating with stroboscopic flicker in the low gamma range (30‐50 Hz). As stroboscopic visual stimulation may also affect adherence in clinical trials due to its inherent flickering, invisible spectral flicker (ISF) was proposed as a more comfortable alternative for entraining 40 Hz. This study investigates the ability of ISF to entrain gamma responses at several frequencies in the range of 36‐44 Hz.

Method

Twenty healthy young volunteers were included in an electroencephalography (EEG) experiment (DTU Compute IRB Approval: COMP‐IRB‐2021‐01) with an initial eyes‐open baseline recording followed by a stimulation paradigm using ISF at nine different frequencies (36‐44 Hz, 1 Hz interval) in a randomized complete block design with five blocks. The responses were evaluated as the signal‐to‐noise ratio (SNR) averaged over the O1 and O2 electrodes at the stimulation frequency and analysed using mixed‐effect models with frequency as a fixed factor and subject and block as random factors. All two‐way interactions were included as random factors. Evoked responses were compared to baseline and between frequencies post hoc, correcting for multiple comparisons with Tukey’s method.

Result

The EEG power (Figure 1) showed that stimulus SNR values were significantly higher than baseline for all frequencies (P<.05, see Figure 2), but no stimuli resulted in significantly different SNR. There was significant subject effect (P<<.05), and one subject responded 1‐2 orders of magnitude higher than the others. This suggests higher variability between subjects than frequencies alone.

Conclusion

Our results indicate that ISF can induce steady‐state visually evoked potentials at several frequencies in the low gamma range of 36‐44 Hz. Across the population of participants, we found no preference or trend for any specific gamma stimulation frequency in the tested range.
Tau propagation out of the MTL areas to the isocortex is facilitated by the presence of amyloid.
Authors: Garbarino Sara , Campi Cristina , Pardini Matteo
Published: December 2023

Background

Amyloid and tau proteins are known pathological signatures of Alzheimer’s disease. Tau in particular spreads in the brains following stereotypical spatiotemporal patterns which seem to be mediated by brain connectivity. Novel imaging techniques allow visualisation of in vivo tau distribution and, in combination with state‐of‐the‐art computational tools, provide new insights into its dynamics.

Method

We propose a network diffusion model to describe tau evolution from longitudinal Positron Emission Tomography data of 872 subjects from the Alzheimer’s Disease Neuroimaging Initiative. The model accounts for time‐ and region‐dependent production, clearance, propagation and saturation terms. Tau dynamics is enforced “trans‐synaptically” over an ideal healthy anatomical connectome. We use Bayesian inference, providing a tool for simulation and prediction of tau deposition and its dynamics parameters along its progression. We fit the model on 2 datasets: “amyloid+” and “amyloid‐“ (identified based on Ab42 levels in the CSF; 338 and 534 subjects respectively).

Result

The estimated tau progression and dynamic parameters show that propagation of tau out of the MTL areas (middle/inferior‐temporal; entorhinal; hippocampal) to the isocortex is facilitated by the presence of amyloid (Figures 1‐3) and progresses along the connectomes. Indeed, amyloid+ subjects show, on average, a progression of tau that (i) accumulates earlier in the entorhinal, hippocampal and MTL areas than amyloid‐ subjects; and (ii) reaches the isocortex within the estimated 25‐years progression window by propagating along the connections between the MTL areas and the isocortex (esp. frontal and parietal).

Conclusion

This supports the hypothesis that regional amyloid‐tau interactions in MTL promote onset and acceleration of AD tau spreading.
Expression patterns of astrocyte mRNA under numerous in vitro disease conditions and its applicability in drug development
Authors: Yue Qian Q , Hoi Pui Man Maggie
Published: December 2023

Background

Reactive astrocytes have been observed surrounding amyloid beta (Aβ) plaques in Alzheimer’s disease (AD) patients and animal models. Researchers have pointed out the shortcomings of A1 and A2 classification. Our study aims to discuss the potentials of applying A1 and A2 genes in indicating astrocyte states and explore the relationship between inflammation‐related protein levels and A1 and A2 expression map under the treatment of human Aβ1‐42 oligomer (hAβ1‐42O) and compound TBN.

Method

This study was conducted using murine astrocyte cell line (C8‐D1A). We compared the mRNAs levels (A1 and A2) under numerous in vitro disease conditions, including lipopolysaccharide (LPS) (800ng/ml), LPS‐induced microglial secretion, oxygen‐glucose deprivation (OGD), hAβ1‐42O (2.5μM), low glucose (11mM), high glucose (44mM) treatment. We also compared mRNA levels (cerebellum, cortex, and hippocampi) in high dose STZ (ip.) (150mg/kg, 4 weeks)‐induced C5BL/6 mouse brain, which is usually applied to as AD model. Furthermore, we explored the relationship between the A1, A2 expression map and inflammation‐related protein expression levels in C8‐D1A treated with hAβ1‐42O and TBN.

Results

A1 and A2 genes were altered in different patterns under numerous stimuli. Microglial secretion (LPS), LPS, OGD, hAβ1‐42O mostly induced mRNA upregulation, while abnormal glucose induced hypofunction of most genes. In STZ brain, mRNA expression exhibited district‐dependent differences. hippocampi mRNA were mostly activated compared to cerebellum and cortex, which indicated that Aβ plaque closely relates to astrocyte activation. In vitro, hAβ1‐42O upregulates inflammation related signal proteins. TBN inhibited hAβ1‐42O induced mRNA upregulation (A1, A2, C3, Il6, Tnfα, Tgfβ) and protein secretion (Il6, Tnfα). TBN could also inhibit LPS‐induced inflammation in astrocytes and increase mRNA levels of Aβ degrading enzymes (Ide, Ece‐1) .

Conclusions

It seems that there is not a strict paradigm of A1 and A2 mRNA expression to indicate astrocyte state and mRNA upregulation is not strictly related to detrimental effects. TBN exerted anti‐inflammatory effects may increase Aβ degrading activity. It also ameliorated inflammation induced by hAβ1‐42O, which may indicate the therapeutical potentials of targeting the activation of mRNA (S1pr3, Timp1, Hsbp1, Cxcl10, Osmr, Cp, Ligp1, Fkbp5, S100a10, slc10a6, B3gnt5) to ameliorate hAβ1‐42O‐induced astrocytic inflammation.

Cp, Ligp1, Fkbp5, S100a10, slc10a6, B3gnt5).
MRI deep learning demonstrates featured neuropathological deteriorations in the AD brain
Authors: Pan Dan , Zeng An , Song Xiaowei
Published: December 2023

Background

Deep learning (DL) of non‐invasive brain structural magnetic resonance imaging (sMRI) has shown superb performance in differentiating Alzheimer’s disease (AD) from cognitively healthy participants (HC). Attention is needed to tackle AD pathological progression on sMRI using interpretable DL methods. Here, we studied the feasibility of DL in identifying neurodegenerative progression patterns in AD.

Method

Data applied to the study were from the multi‐centre Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Open Access Series of Imaging Studies (OASIS) with 2,369 T1‐weighted brain images of 1,005 subjects. An interpretable DL technique named the ensemble 3‐dimensional convolutional neural network (Ensemble 3DCNN) was used to detect the longitudinal trajectory of sMRI changes during AD progression. The model used multiple 3D convolutional neural networks and a meta‐classifier to assess the degree of brain changes through generating an index score, named P‐score. The score was derived as the outcome of training and verifying the Ensemble 3DCNN model for difference in the whole‐brain sMRI between AD and HC. The predictive P‐scores values were used to analyze the sMRI images for mining neurodegenerative brain regions. In addition, dementia stages, and the temporal and spatial connectivity patterns of neurodegeneration progression were also analyzed.

Result

Brain regions showing high P‐scores (> 0.73/1.00) included the amygdala, nucleus accumbens, agranular insular cortex, and the hippocampus, matching the isocortex, basal magnocellular complex, and transentorhinal regions identified in Braak staging. The P‐score increased over time in 82% of the degenerative brain regions. The impaired areas were often spatially connected, consistently across multiple time points in the progression of AD. The trajectory of regional brain changes displayed multiple patterns with complex individual variability.

Conclusion

The interpretable 3D DL model demonstrated featured deteriorations on the AD sMRI images. The finding confirmed the neuropathological degeneration of AD and captured additional whole‐brain changes, especially, relating to the heterogeneity of AD expression.
Administration of mitochondrial fusion promoter during ischemia and at the onset of reperfusion exert neuroprotective effects in rats with cardiac ischemia/reperfusion injury
Authors: Chunchai Titikorn , Apaijai Nattayaporn , Janjek Sornram , Arunsak Busarin , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2023

Background

Acute myocardial infarction (AMI) is one of the fetal cardiovascular diseases and a leading cause of death (1, 2). Our previous study demonstrated that pretreatment of mitochondrial fusion promoter (M1) provided neuroprotective effects on the brain following cardiac ischemia/reperfusion (I/R) injury (3). However, the effects of M1 given during ischemia and M1 given at the onset of reperfusion on brain pathologies following cardiac I/R have never been investigated.

Method

Sixteen male Wistar rats were randomly divided into either a sham‐operation (n = 8) or cardiac I/R (n = 24). In the cardiac I/R group, rats were then randomly divided into 3 subgroups, including the I/R operation with vehicle (0.9% sodium chloride solution for 15 minutes before I/R protocol, intravenous (i.v.) injection), the I/R operation with M1 administration during cardiac ischemia (2 mg/kg, 15 minutes after left anterior descending (LAD) coronary artery ligation, i.v. injection), and the I/R operation with M1 administration at the onset of reperfusion group (2 mg/kg at the beginning of reperfusion, i.v. injection). At the end of experimental protocol, rats were sacrificed and brains were obtained for further molecular investigation.

Result

The results demonstrated that cardiac I/R increased brain inflammation, caused microglial dysmorphology, caused brain mitochondrial dysfunction, increased tau hyperphosphorylation, and increased brain apoptosis (p<0.05, Figure 1). M1 given during ischemia and M1 given at the onset of reperfusion effectively attenuated brain pathologies following cardiac I/R by preserving microglial morphology, improving brain mitochondrial function, decreasing tau hyperphosphorylation, and decreasing brain apoptosis (p<0.05, Figure 1). Interestingly, M1 given during ischemia had better efficacy to suppressing brain inflammation, when compared to M1 given at the onset of reperfusion apoptosis (p<0.05, Figure 1).

Conclusion

These findings suggest the administration of mitochondrial fusion promoter effectively decreased brain pathologies following cardiac I/R. The administration of mitochondrial fusion promoter during ischemia had greater suppression on brain inflammation than administration at the onset of reperfusion. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for cardiac I/R injury.
Lower Endogenous Estrogens in APOE4‐Positive Postmenopausal Women Associated with Lower Regional Brain Volumes
Authors: Schroeder Rachel A , Thurston Rebecca C , Wu Minjie , Padilla Lisbeth , Aizenstein Howard J , Derby Carol A. , Maki Pauline M
Published: December 2023

Background

During the menopause transition, levels of estradiol (E2) ecline. Although these changes are likely key determinants of cognition and brain structure during the menopause transition, how they are related to brain volume in women at elevated risk of Alzheimer’s disease (AD) is not known. We predict associations of endogenous E1 and E2 levels to regional brain volumes will depend on APOE4 carrier status, such that the associations between lower levels of E1 and E2 and lower regional brain volumes will be more positive among APOE4 carriers.

Methods

Participants were enrolled in MsBrain, a cohort study of postmenopausal women (n = 191, mean age 59.4 +/‐ 3.4 years, 45 APOE4 carriers, 84.3% white). Serum E1 and E2 were assessed using liquid chromatography‐tandem mass spectrometry. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Cross‐sectional associations of interest were analyzed with APOE4 genotype (carrier versus noncarrier; excluding APOE2)ormone levels, and their interaction, as predictors and regional brain volumes (33 regions per hemisphere) as outcome measures using lme4 Package in R. Models controlled for, years of education, and body mass index.

Results

Neither APOE4 carrier status nor hormone levels were associated with brain volumes . However, significant interactions were observed between APOE4 carrier status and E2 levels in relation to volume of the right (p<.05) and left isthmus cingulate (p<.01), right and left middle temporal lobe (p<.05), and the left posterior cingulate (p<.05), such that the positive association between E2 and regional brain volumes was more positive among APOE4 carriers (Figure 1). Further, there was a significant interaction between APOE4 carrier status and E1 levels in relation to volumes of the right and left inferior parietal lobe (p<.05), right (p<.05) and left isthmus cingulate (p<.05), left cuneus (p<.05), left precuneus (p<.05), and left lingual gyrus (p<.05)(Figure 2).

Conclusion

Although some of these findings would be expected by chance, results suggest that lower levels of endogenous estrogens may be a risk factor for regional brain volume loss in female APOE4 carriers compared to non‐carriers.

Supported by NIH RF1AG053504 and R01AG053504 (Thurston & Maki)
The electronic Person Specific Outcome Measure (ePSOM) development program in the US: A survey to understand what matters to individuals most about their brain health
Authors: Saunders Stina , Jannati Ali , Gomes‐Osman Joyce Rios , Morrow William Isaiah , Tobyne Sean , Muniz‐Terrera Graciela , Luz Saturnino , Ritchie Craig W. , Pascual‐Leone Alvaro
Published: December 2023

Background

It is essential both drug and lifestyle‐based interventions aimed to delay the onset of advanced cognitive decline deliver a meaningful outcome for the patient. In the early stages of Alzheimer’s disease and related dementias (ADRDs), patient‐reported outcome (PRO) measures should be used in parallel with biological investigations of ADRDs to provide a complementary endpoint offering further proof of intervention’s effectiveness from the patients’ point of view. The aim of the electronic Person‐Specific Outcome Measure (ePSOM) programme is to develop a scalable, easily accessible and efficient PRO tool for monitoring personally meaningful outcomes in early ADRD.

Method

We designed and ran an online nation‐wide study to understand what matters to people about their brain health in the US. The ePSOM US survey started in Jan 2023 and collects primarily free‐text responses along with sociodemographic information and self‐reported neurodegenerative disease diagnosis. Respondents are presented with five domains and asked to describe in their own words their brain‐health priorities. Free‐text data will be analysed using Natural Language Processing (NLP) techniques to identify the most common brain‐health priorities by key sociodemographic groups. We will also compare these results with previously published UK results to look for any notable differences between the US and UK respondents’ priorities.

Result

The survey aims to recruit n = 6,000 respondents. Data collection started early 2023 and is planned to be complete by Spring/Summer 2023. The previously published ePSOM UK study (Saunders et al., 2021) with n = 5,808 respondents resulted in over 80,000 free‐text responses and 184 unique priority themes about brain health. We will present the preliminary results of the US study at AAIC and contextualising the results in light of new pharmacological treatments approved for AD.

Conclusion

This large‐scale population‐based study will offer an evidence base for what outcomes constitute a meaningful impact of new treatments. Previous work from our group suggests that brain health priorities shift along the preclinical, prodromal and dementia continuum. The ultimate aim of the ePSOM programme is to design an electronic outcomes app which would allow an individual to define the most important outcomes against which we should measure treatment success across a range of severities.
Transitioning from paper‐based to electronic data capture of neuropsychological assessment: A HABS‐HD study
Authors: Large Stephanie E , Conger Christopher , Davidson Sean , Johnson Leigh , O'Bryant Sid E.
Published: December 2023

Background

The HABS‐HD study is an epidemiological study of aging in diverse populations and began transitioning from entirely paper‐based charting to electronic data capture (EDC) in 2018. As the study evolved, the team realized that neuropsychological testing, scoring, and quality review consumed many resources and much staff time. This abstract aims to describe how the HABS‐HD study moved from paper‐based capture of neuropsychological data to EDC with a small data team.

Method

The HABS‐HD staff recognized the time commitment for scoring and reviewing scores for the neuropsychological assessment, which created a delay between a participant completing the study and the research diagnosis. Senior research assistants worked with internal developers to create an EDC for the neuropsychological assessment. The data core is small and consists of a director, an assistant director, two developers, two data entry personnel, and a clinician. Specific components were completed on paper to prevent an increase in equipment cost and maintain methodological consistency. These components were reviewed post‐assessment, and a senior research assistant directly entered the scores into the EDC.

Result

The EDC neuropsychological assessment was tested before going live. The team adapted data capture from the older method into the EDC. The new system allows the research director to obtain statistics of individual testers and provide more training as needed. It also permits more senior personnel to review the paper components and enter them directly into the EDC, which improves throughput.

Conclusion

Smaller data core teams can transition larger projects from paper methods to EDC. The change does not need to be entirely paper or electronic, but investigators should evaluate which methodologies function best for their populations. Finally, communication between the personnel capturing the data, reviewing the quality of the capture, and writing the EDC software is essential.
DNA methylation of candidate imprint control regions associated with Alzheimer’s disease in Non‐Hispanic Blacks and Non‐Hispanic Whites
Authors: Cevik Sebnem Eren , Skaar David A , Jima Dereje , Liu Andy , Whitson Heather , Jirtle Randy L , Hoyo Cathrine , Planchart Antonio
Published: December 2023

Background

There are more than 55 million people with dementia worldwide, and it is estimated that currently 6.5 million people are living with Alzheimer’s disease (AD) in the United States. AD exhibits racial disparities whereby the prevalence is 2‐fold higher in Non‐Hispanic Blacks (NHB) compared to Non‐Hispanic Whites (NHW). It is hypothesized that epigenetics and aberrant imprinting caused by early life exposure to adverse environmental agents may contribute to AD risk later in life, although to date a comprehensive assessment of the imprinting state of the genome in AD‐affected populations has not been reported.

Methods

To address this hypothesis, we investigated cytosine methylation at candidate imprint control regions (ICRs) in post‐mortem tissues (brain) of nine AD cases (5NHB, 4NHW) and eight controls (4NHB, 4NHW), using whole genome bisulfite sequencing. Furthermore, we performed a limited clinical study in which blood samples from six individuals, three AD patients (2NHB, 1NHW) and three controls (all NHB), were subjected to methyl‐sequencing. These data were analyzed against an expanded set of candidate ICRs previously described by our group (i.e., human imprintome) to identify regions of the genome exhibiting aberrant methylation in AD patients compared to controls.

Results

We found differential methylation in DNA derived from post‐mortem tissues of AD cases compared to controls overlapping with the expanded set of ICRs in the human imprintome (79 in NHBs and 27 in NHWs), including candidate ICR on chromosome 17 near the NLRP1 inflammasome gene (5771207‐5771575; Hg38). When extended to blood from extant controls and patients, our analysis identified a single nucleotide polymorphism (CA → CG; rs12451480) within the candidate ICR on chromosome 17, that distinguishes controls (CA) from AD patients (CG), and in which the cytosine is methylated.

Conclusion

We demonstrate concordance between the methylation state of post‐mortem brain‐ and blood‐derived DNA distinguishing controls from AD patients. Furthermore, the discovery of a SNP differentiating controls from AD patients, within a candidate ICR that alters its methylation state, is consistent with an aberrant imprinting phenomenon. Our results support the hypothesis that aberrant imprinting, as can result from adverse exposures during early development, may contribute to later risk of AD.