bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain Function Entropy Analysis during Dual‐Tasking: Application of Functional Near Infrared Spectroscopy to Screen Alzheimer’s Disease
Authors: Petrillo Kelsi , Flores Hector , Mayoral‐Ortega Isabellah , Javed Bilaval , Dagar Meenakshi , Toosizadeh Nima
Published: December 2023

Background

Despite a high prevalence, over half of patients with dementia never receive an evaluation, indicating a need for a quick and objective routine test for screening cognitive decline in older adults. Due to neural death and disconnections, Alzheimer’s disease (AD) is associated with a low value of nonlinear complexity of brain function, which can be quantified using multiscale entropy analysis.

Method

Our proposed solution is an upper extremity function dual‐task screening method, during which, brain function is measured by functional near infrared spectroscopy (fNIRS). The aim of this study was to investigate association between fNIRS entropy during upper‐extremity dual‐tasking and cognitive status in older adults. The sample population for this data includes 40 older adults with ages ranging from 65‐96 years. Participants were categorized into cognitive normal (CN), mild cognitively impaired (MCI), and AD based on MoCA test results. The fNIRS device took measurements over the frontal (right and left) and parietal (right and left) brain regions. Participants were first instructed to rest for three minutes, during which they were asked to relax and not think about any specific topic. Participants were then asked to flex and extend their right arm consistently for three minutes, while counting backwards by intervals of three.

Result

We used multivariable repeated measures analysis using mixed effects modeling to assess the effect of cognitive status on multiscale entropy, with task condition (rest and dual‐task) as within‐subject parameter and sex as covariate. We observed a significant effect of cognitive status on multiscale entropy of left frontal (p = 0.0196) and right frontal brain regions (p = 0.0448), with 0.198, 0.267, and 0.301 entropy values on average across AD, MCI, and CN, respectively. There was also a significant effect of task on multiscale entropy of right frontal (p = 0.0165), left frontal (p = 0.0209) and left parietal regions (p = 0.0011), with 39.79% higher entropy during dual‐task compared to rest trials.

Conclusion

The results of this study indicate potential for the use of fNIRS multiscale entropy analysis as a screening tool for cognitive impairment. More research is necessary to better understand other potential confounding factors as well as validate this approach in a larger sample size.
Successful Recruitment of Low‐income and Minority Patients in the Southern United States: Implementation of Intensive Blood Pressure Control to Slow Cognitive Decline (IMPACTS‐MIND) Trial
Authors: Mills Katherine , Williamson Jeff D. , He Jiang
Published: December 2023

Background

Black communities, low‐income populations, and those living in the stroke belt bear a disproportionate burden of dementia and are underrepresented in previous trials on preventing cognitive decline and dementia. Improved methods to implement interventions to slow cognitive decline and reduce health disparities are needed. The Implementation of Multifaceted Patient‐Centered Treatment Strategies for Intensive Blood Pressure Control to Minimize Cognitive Decline (IMPACTS‐MIND) trial is testing a multifaceted strategy for implementing an intensive blood pressure (BP) intervention protocol on cognitive decline in racial minority and low‐income hypertensive patients in primary care.

Method

The IMPACTS‐MIND study is a cluster‐randomized trial in 10 primary care organizations with 40 clinics in Louisiana and Mississippi. The included organizations predominantly treat low‐income and minority patients, and 9 of the organizations (with 36 included clinics) are federally‐qualified health centers (FQHCs). We are recruiting a goal of 1,260 patients who are at least 40 years of age (2/3s over age 60 years) with have uncontrolled systolic BP. Recruitment has been conducted in partnership with primary care organizations. Using electronic health record systems, potentially eligible patients based on BP are contacted via a letter and phone call to assess willingness and preliminary eligibility. Provider and staff referrals are also encouraged and incentivized.

Result

We have enrolled 581 participants in the study to date. Participants are an average of 63.0 years of age, 68% are Black, and 59% are female. More than 60% have a high school education or less, and 72.8% have an annual household income <$25,000. Over 44% have diabetes, 28.9% depression, and mean body mass index of 33.6 kg/m2. Mean baseline Montreal Cognitive Assessment (MoCA) score is 19.7. Successful recruitment of low‐income and minority participants has hinged on strong relationships with primary care partners through study steering committee membership for each organization and state FQHC organizations, manuscript co‐authorship for all members, monthly meetings to support study conduct, and building research capacity and opportunities for partnering organizations.

Conclusion

Effectively recruiting low‐income and minority patients is possible through partnership with primary care providers who treat these patients. Building relationships with these organizations around common interests and priorities is critical to effective recruitment.
Amyloid models for quantitative x‐ray brain amyloid imaging
Authors: Suresh Karthika , Dahal Eshan , Badano Aldo
Published: December 2023

Background

A range of human neurological disorders are related to amyloid fibrillar deposits including Alzheimer’s disease (AD). AD is linked to the presence of amyloid‐β (Aβ) fibrils and those are comprised of β‐sheet motifs. The precise mechanism through which Aβ leads to AD are not completely understood. The scarcity of human derived Aβ fibrils and high cost of recombinant Aβ fibrils further restrict the research in this area. However, intrinsically disordered proteins (IDPs) have been reported as amyloid model proteins. Even though, these models qualitatively mimic β‐sheet structure of Aβ fibrils but often fail to quantitatively match the β‐sheet content. Therefore, this study aimed to develop model proteins to closely mimic Aβ fibrils structure and produce them in a large quantity to evaluate emerging X‐ray methods to detect and quantify amyloid plaques.

Methods

We used a commercially available β‐lactoglobulin A and B genetic mixture (LGAB) protein as our amyloid model to mimic the structural properties of Aβ fibrils. Here, the alteration in the protein conformation was induced by altering the net charge on the polypeptide chain by changing the pH from 2 to 7. Additionally, we studied the fibrillization of these proteins in presence of more cooperative transitions at 90°C. The secondary structural compositions of LGAB were studied using attenuated total reflectance Fourier transform infrared (ATR‐FTIR) spectroscopy. The nanostructures of LGAB fibrils were characterized using small angle X‐ray scattering (SAXS). We further varied the mass fraction of LGAB fibrils (amyloid model) and quantitatively measured their amyloid content using a SAXS based method.

Results

ATR‐FTIR (Fig.1) and SAXS (Fig.2) studies confirm that thermally aggregated LGAB fibrils exhibited parallel β‐sheet secondary structure similar to Aβ fibrils. Systematic variation in LGAB fibril concentration in the tissue mimicking environment showed a linear correlation between protein mass fraction and area under the curve of a peak (∼ 6 nm−1) corresponding to inter β‐sheet spacing (Fig.3).

Conclusion

Our study suggests that the amyloid model based on LGAB fibrils can likely be used to simulate Aβ fibrils in phantom studies for the evaluation of emerging X‐ray methods to detect and quantify amyloid plaques.
The Prevalence of Leg Spasticity and it’s Clinical Correlates among a Cohort of persons carrying ADAD mutations
Authors: O'Dowd Connor Daniel , Sagare Abhay P , Zlokovic Berislav V , Montoya Lucy , Chui Helena C , Ringman John M
Published: December 2023

Background

Motor deficits, including gait problems due to dysfunction of the pyramidal tracts, become increasingly problematic as Alzheimer’s disease (AD) advances. Leg spasticity can be more common and severe in the early stages of autosomal dominant AD (ADAD), particularly in association with specific PSEN1 mutations. We sought to define the frequency of leg spasticity in ADAD and its relationship to other features of the disease.

Methods

103 carriers of ADAD mutations (MCs, 84.4% PSEN and 15.6% APP) underwent comprehensive cross‐sectional clinical phenotyping including the Clinical dementia rating scale (CDR), assessment of leg tone using the Ashworth scale (n = 99 MCs), and measurement of walking speed standardized to meters per second (n = 46 MCs). Subjects’ ages were characterized relative to the median age of dementia diagnosis in their families (adjusted age).

Results

Among non‐demented (CDR < 1) MC’s with severe spasticity (Ashworth ≥ 2), 4 had the A431E mutation and 1 had the F388S mutations in PSEN1. Carriers of A431E showed a high prevalence of increased leg tone prior to the age of dementia onset with 12/25 (48%) of A431E carriers exhibiting mild spasticity (Ashworth > 0) at an adjusted age < 0. Carriers of this mutation showed an increased prevalence of spasticity after the onset of cognitive symptoms. Every individual (N = 3) bearing the F388S PS1 mutation displayed severe spasticity. Of these MC’s, CDRs were 0.5, 1, and 3. Among MC’s, walking speed correlated significantly with Ashworth score (r = ‐0.765, p < 0.01) and verbal fluency (r = 0.304, p < 0.05) and Ashworth scores also correlated significantly with CDR sum of box scores (r = 0.414, p < 0.01).

Conclusions

Physical signs of pyramidal dysfunction may manifest before cognitive symptoms in association with some PSEN1 mutations. The correlation of spasticity with slowed cognition suggests a common underlying pathophysiology. Understanding the natural history of ADAD subgroups is helpful in delineating this underlying pathophysiology and therefore our ability to treat it.

This study was funded by NIH P30AG066530, U01AG051218, R01AG062007
The effect of APOEƐ4 on neurocognitive decline is accentuated by female sex and menopause: Identification of mitigating interventions
Authors: Saleh Rasha , Hornberger Michael , Pontifex Matthew , Vauzour David , Ritchie Craig , Minihane Anne‐Marie
Published: December 2023

Background

Two thirds of those living with AD are female. Age‐standardised AD prevalence is consistently higher at all ages over 70 years in women versus men. The aetiology of the accelerated neurophysiological decline in females is poorly understood. Here we investigate the independent and interactive impact of APOE4 carrier status and menopause.

Method

Targeted replacement (APOE3‐TR and APOE4‐TR) rodent models and human cohort studies (European Prevention of Alzheimer’s Dementia (EPAD) and UK Biobank (UKB)) were used to investigate the impact of APOE4, menopause and hormone replacement therapy (HRT) on cognition, brain volumes (assessed by MRI), omega‐3 fatty acid status and synaptic function. In rodents, menopause is elicited by the administration of 4‐vinylcyclohexene diepoxide (VCD), which induces a human‐like “perimenopausal” phenotype, whilst maintaining ovarian tissue integrity.

Results

In EPAD, using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test battery, HRT use in APOE4 only was associated with higher overall cognition and (delayed) memory scores and larger entorhinal and amygdala volumes in APOE4 only. Earlier HRT introduction was associated with larger hippocampal volumes. In UKB, HRT use was associated with improved memory in APOE4/E4. In mice, VCD administration reduced recognition memory, brain docosahexaenoic acid (DHA, omega‐3 fatty acid) levels, and altered synaptic plasticity biomarkers in APOE4‐TR animals, which was mitigated by DHA supplementation (1).

Conclusion

An increased penetrance of the APOE4 genotype during the menopausal transition is likely to contribute to the higher incident AD in females, and in APOE4 females versus non‐carriers. HRT and DHA intervention during the menopausal transition, as a critical window of opportunity, may represent effective strategies to support cognitive health into older age in this ‘at‐risk’ (APOE4 female) group, which typically represent 12% of Caucasian populations compared and 33‐50% of AD.

1. Pontifex MG et al., FASEB J. 2021 May;35(5):e21583
Novel mechanisms to enhance omega‐3 brain metabolism with APOE4
Authors: Wang Shaowei , Ebright Brandon , Duro Marlon Vincent V. , Cai Zhiheng , Galvan Jasmin , Tsiknia Amaryllis A , Asante Isaac , Louie Stan G , Yassine Hussein N.
Published: December 2023

Background

Neuroprotective nutritional interventions involving greater consumption of polyunsaturated fats (Mediterranean diet, fish consumption or DHA supplements) are less effective in APOE4 carriers with dementia compared to non‐carriers. We recently demonstrated greater activation of calcium dependent phospholipase A2 (cPLA2) in APOE4 compared with non‐APOE4 using both postmortem human brains and in brain tissues from APOE4 animal models. Activation of cPLA2 is associated with lower omega‐3 brain levels and lower measures of blood‐brain barrier (BBB) integrity as assessed using 7T DCE MRI to derive contrast transfer values (K trans).

Method

Here, we present new data on aging (18 months) old APOE mouse models on a low DHA diet, APOE4‐TR mice treated with LPS and APOE knock out mice as a model of lower BBB integrity. All models were treated with the brain penetrant cPLA2 inhibitor ASB14780 at 10 mg/kg IP daily over 8 weeks in the aging model and acutely (7 days) in the younger LPS and APOE KO models.

Result

cPLA2 inhibition was associated with increased brain omega‐3 levels in both the aging APOE4 model and in the younger APOE4 mice treated acutely with LPS. In the aging APOE4 mouse model, cPLA2 inhibition associated with better performance on novel object recognition, improved synaptic markers, and lower microglial activation. In the APOE KO model, treatment was associated with improved measures of BBB with lower K trans following treatment (Figure).

Conclusion

The results here demonstrate how neuroinflammation associated with APOE4 depletes brain omega‐3s via activation of cPLA2 and how reducing cPLA2 activity can rescue this phenotype. The development of specific and potent brain penetrant cPLA2 inhibitors promises to enhance the brain effects of omega‐3 enriched diets by limiting the effects of neuroinflammation on the aging APOE4 brain.
Association of Cardiometabolic Multimorbidity with Dementia and Alzheimer’s Plasma Biomarkers in Older Adults: a population‐based study
Authors: Liu Cuicui , Tian Na , Fa Wenxin , Liu Keke , Wang Nan , Wang Yongxiang , Hou Tingting , Du Yifeng , Qiu Chengxuan
Published: December 2023

Background

Individual cardiometabolic disorders are associated with an increased dementia risk. However, the relationship of cardiometabolic multimorbidity (CMM) with dementia has not been studied in Chinese older adults and the underlying mechanisms are poorly understood.

Method

This population‐based study included 5665 rural‐dwelling adults (age ≥60 years, 57.3% women) in the baseline examination (March‐September 2018) of the Multimodal Interventions to Delay Dementia and Disability in Rural China study. Cardiometabolic diseases (CMDs), which included heart disease, stroke, type 2 diabetes, and obesity, were assessed through clinical and neurological examinations. CMM was defined as the concurrent presence of two or more CMDs. Amyloid‐β(Aβ), total tau, and neurofilament light chain (NfL) were measured using Simoa platform in a subsample (n = 1434). Dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) were clinically diagnosed following international criteria. Data were analyzed using the general linear and logistic regression and mediation models.

Result

Of the 5665 participants, 1091 (19.26%) were detected with CMM, and 302 (5.33%) were diagnosed with dementia (193 with AD and 98 with VaD). The multivariable‐adjusted odds ratios of CMM (vs. no CMD) were 3.00 (95% confidence interval [CI] 2.19‐4.11) for all‐cause dementia, 1.66 (1.11‐2.47) for AD, and 12.5 (6.47‐24.18) for VaD. There was a significant interaction between CMM and sex on the likelihood of dementia and subtypes (P for interaction<0.05), such that the associations of CMM with dementia and subtypes were stronger in men than in women. In the biomarker subsample, CMM was significantly associated with higher plasma NfL (demographic‐adjusted β coefficient = 0.059; 95% CI 0.028‐0.091), Aβ40 (0.034; 0.018‐0.049), and Aβ42 (1.068; 0.636‐1.501); the observed association remained significant even in the multivariable‐adjusted model (P<0.001). The mediation analysis showed that plasma NfL could mediate 19.46% of the association between CMM and AD (P<0.05), whereas plasma Aβ and total tau showed no significant mediation (P>0.05).

Conclusion

CMM is associated with increased likelihoods of dementia, AD, and VaD in older adults, especially in men. Neurodegenerative pathway might play a part in the association of CMM with AD.
Direct Electrophysiological Imaging Measure as a Novel Method for Detection of Onset of Medial Temporal Atrophy in Healthy Population
Authors: Shainer Tamara , Bregman Noa , Trabulus Noa , Hadad Rafi , Maynard James , Brill Silviu , Tanne David
Published: December 2023

Background

Medial temporal atrophy (MTA) has long been demonstrated as a prognostic measure for transition from normal cognition to MCI and from MCI to Dementia, often but not only due to Alzheimer’s disease (AD). However, brain scans availability and costs do not allow for it to be implemented as common practice, for early detection of MTA in cognitively normal patients.

We tested “Delphi”, a non‐invasive measure that probes brain network responses via induction of focused magnetic stimulation over selected brain networks in order to detect MTA.

Method

A multicenter study (3 US, 2 OUS), in which one site recruited the derivation cohort (n = 220) which was used for establishing “Delphi” thresholds, and four sites recruited the validation cohort (n = 263, mean age 61.5 (±7.1), 57% females).

The study included healthy subjects aged 50‐75 with at least one risk factor for stroke or dementia and no history of neurodegenerative disease.

All subjects underwent multiple evaluations including a neurological exam, cognitive tests, MRI scans and “Delphi”. Three experienced neuroradiologists blindly rated the scans for MTA (Schelten’s scale, ‘Normal’‐MTA = 0, ‘Abnormal’‐MTA> = 1) and other findings.

Result

263 subjects were included in the validation cohort, out of which 23 subjects were rated MTA≥1 (69% MTA = 1, 17% MTA = 2 and 13% MTA = 3) while the rest were MTA = 0 on MRI scanning.

Out of the total sample 11% had abnormal result in MMSE (≤27) and 15% had abnormal result in MoCA (≤23) and only 13% had abnormal result in each of MMSE and MoCA in the MTA≥1 subgroup.

“Delphi” discriminated subjects with MTA = 0 from MTA≥1 with AUC = 0.81, sensitivity = 82% [95%CI 62.86%:93.02%], specificity = 75% [95% CI 63.62:81.0%].

Conclusion

Brain network physiology evaluation using the “Delphi” technology may serve to detect early stages of MTA, preceding cognitive impairment with substantial accuracy in the outpatient office setting in a generally healthy population. This could allow the expansion of the physician’s in‐office tools, potentially improving patient management.
Development of TDP‐43 immunotherapy blocking transmission of seeding‐competent species from ALS/FTD
Authors: Afroz Tariq
Published: December 2023

Background

Accumulation of pathological transactive response DNA binding protein 43 (TDP‐43) into intracellular inclusions underlies frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP), amyotrophic lateral sclerosis (ALS) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). TDP‐43 pathology is present as a co‐pathology in other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and chronic traumatic encephalopathy (CTE). Multiple mechanisms contribute to spreading of TDP‐43 pathology including transmission across synaptic terminals, exosomes and release of misfolded TDP‐43 from dying neurons. In fact, cerebrospinal fluid (CSF) obtained from ALS/FTLD‐TDP patients contains seeding‐competent TDP‐43 species. Therefore, antibody‐mediated clearance of pathological TDP‐43 represents an attractive therapeutic strategy. Our approach is to develop a TDP‐43‐specific immunotherapy that exploits Fcγ receptor‐mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP‐43 function.

Method

High affinity monoclonal antibodies (mAbs) were generated against various regions of TDP‐43 using AC Immune’s SupraAntigen® platform and evaluated in mechanistic assays in vitro and in vivo models of TDP‐43 proteinopathies. A real‐time quaking‐induced conversion (RT‐QuIC) assay was established using patient’s CSF to evaluate the inhibitory properties of the lead therapeutic mAb on the seeding mechanism. Studies to evaluate the pharmacology and safety of the antibody were carried out in non‐human primates.

Result

Targeting the C‐terminal domain of TDP‐43 but not the RNA recognition motifs reduced TDP‐43 pathology and prevented neuronal loss in vivo. This rescue was dependent on Fcγ receptor‐mediated immune complex uptake by microglia. The latter also promoted phagocytic capacity of ALS patient‐derived microglia. Importantly, the antibody efficiently neutralized seeding‐competent pathological TDP‐43 species in CSF from ALS patients. These beneficial effects were achieved while preserving physiological TDP‐43 function demonstrating safety of targeting TDP‐43 by immunotherapy. Modelling from non‐clinical pharmacokinetic studies of the antibody predicted a half‐life supporting target saturation in humans when administered monthly.

Conclusion

Our studies confirm the presence of extracellular seeding‐competent TDP‐43 species in the CSF of patients with ALS/FTLD‐TDP patients, providing an explanation for the spread of pathology including the non‐contiguous pattern of clinical manifestations observed in ALS. In addition, the binding and inhibitory properties of our lead therapeutic mAb in multiple patho‐mechanistic assays support clinical development in TDP‐43‐driven neurodegenerative diseases.
Linguistic features correlate with biomarkers in very early AD
Authors: Liu Yi‐Chien , Chou Chia‐Ju , Lee Chia‐Ying , Chang Chih‐Ting
Published: December 2023

Background

Linguistic features in speech have been proven to be sensitive in detecting early Alzheimer disease (AD). However, whether linguistic features correlate with clinical cognitive tests or biomarkers is still debated.

Method

In this study, we recruited 35 AD subjects and 25 normal controls from the memory clinic from 2020 to 2022. Subjects with positive amyloid PET (based on visual rating and quantitative SUVr) and evidence of cognitive impairment (MMSE≦26 or CDR≧0.5) were recruited. On the other hand, negative amyloid PET and no evidence of cognitive impairment were required for normal controls. All participants also received 3.0 T brain MRI and completed comprehensive neuropsychological tests. Among these tests, we collected speech samples from picture description test. The picture descript test includes three Taiwanese‐culture‐based pictures. The collected connected speech was analyzed based on 16 standard linguistic features.

Results

In our cohort, the MMSE scores of the AD group are lower (20.17 ± 4.99 V.S. 29.04 ± 1.21, p<0.001). 66% of AD group were still in MCI stage and 60% progressed (CDR‐SB change≧1) during follow‐up (1.71 years). Linguistic features including total word frequency, mean length of utterance (MLU), passive ratio and long pause ratio were statistically different between AD and controls. SUVr (standardized uptake value ratio) of amyloid in AD group didn’t correlate with MMSE or CDR‐SB. SUVr correlated with total words, content words, total number of sentences and scores of Wechsler Logical Memory test in AD group. Hippocampal volume correlates with MMSE and CDR‐SB in AD group. Hippocampal volume also correlates with unique words, long pause ratio, scores of digit span test and Boston naming test in AD group.

Conclusion

Amyloid load didn’t correlate with clinical severity in very early stage of AD. But it correlates with the amount of speech production and episodic memory test. On the other hand, hippocampal volume correlates with clinical severity, the number of unique words in speech, dysfluency, executive function and naming ability.
Omics analysis of Alzheimer’s disease stratified by the microglial polygenic effect
Authors: Kikuchi Masataka , Miyashita Akinori , Hirota Yu , Hara Norikazu , Hasegawa Mai , Sakakibara Yasufumi , Sekiya Michiko , Saito Yuko , Murayama Shigeo , Iijima Koichi M. , Ikeuchi Takeshi
Published: December 2023

Background

Recent single‐cell omics analyses have revealed that microglia change into reactive microglia when Aβ accumulates in the brain and exhibit Aβ phagocytosis. However, reactive microglia are less likely to be induced in TREM2 mutation carriers. This microglia‐centred pathological mechanism may be considered one of the pathologies of Alzheimer’s disease (AD). However, a single gene mutation, such as a TREM2 mutation, can rarely explain the pathology of AD. Therefore, polygenic effects involving multiple gene mutations have been proposed. In this study, we propose a polygenic risk score (PRS) to quantify the microglial polygenic effect. We stratified patient groups by this PRS and examined differences in pathogenesis based on omics analysis using postmortem brains.

Method

Whole‐genome sequencing and bulk brain tissue RNA‐seq of the frontal cortex were performed using postmortem brain samples from 100 subjects with Braak senile plaque (SP) and neurofibrillary tangle (NFT) staging information. In addition, single‐nuclei RNA‐seq (snRNA‐seq) was performed on 15 of these subjects (healthy subjects: 8 subjects, AD patients: 7 subjects).

Result

We divided AD patients into low and high groups by microglial PRS and performed bulk brain tissue RNA‐seq analysis. We identified 112 differentially expressed genes and found that those genes were related to autophagy and inflammation. To further validate these findings at the single‐cell level, we identified cell clusters containing microglia based on snRNA‐seq. Gene expression analysis of microglia in 3 AD patients with low PRS and 4 AD patients with high PRS suggested altered transcriptional profiles of immune cells and phagocytosis. The expression of APOE and TYROBP, signature genes of reactive microglia, was significantly upregulated in the AD patients with low PRS compared to the AD patients with high PRS and healthy subjects. In contrast, CX3CR1 and P2RY12, signature genes of homeostatic microglia, were downregulated.

Conclusion

The stratification analysis of AD by PRS suggests that microglial reactivity differs among AD patient groups. Future detailed microglial observations in postmortem brains from AD patients with low PRS and those with high PRS will further elaborate our results.
Human interlaminar astrocytes with different APOE variants differentially contribute to Alzheimer’s disease pathology
Authors: Arranz Amaia M
Published: December 2023

Background

Increasing evidence for a direct contribution of astrocytes as well as different APOE variants to Alzheimer’s disease (AD) main pathological hallmarks comes from cellular and molecular studies in rodent models. Yet these models cannot fully mimic how human astrocytes affect AD pathology as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.

Method

To address these challenges, we established an approach to study human astrocytes carrying APOE3 and APOE4 isoforms within the AD brain environment by transplanting human induced pluripotent stem cell (hiPSC)‐derived astrocyte progenitors into neonatal brains of suitable AD model mice.

Result

APOE3 and APOE4 transplanted cells similarly differentiate into astrocytes within the mouse host brain and very often integrate in upper layers of one cortical hemisphere, where they acquire morphological phenotypes resembling human interlaminar astrocytes (h‐ILAs). Interestingly, in AD model mice APOE3 and APOE4 h‐ILAs differentially express and secrete the apoE protein (Figure 1), and differentially affect amyloid‐beta load (Figure 2), microglial responses (Figure 3) and neuritic dystrophy.

Conclusion

We describe here a promising model that allows for the first time studying h‐ILAs in the AD brain environment. Importantly, our model reveals a differential contribution of h‐ILAs with different APOE variants to main pathological hallmarks of AD, which can potentially have important implications when developing novel astrocyte‐specific targeting therapeutics.
Inhibition of D3 receptors restores synaptic plasticity and memory impairment in aged and Alzheimerʼs disease mouse models
Authors: Tropea Maria Rosaria , Melone Marcello , Vacanti Valeria , Gulisano Walter , Leggio Gian Marco , Conti Fiorenzo , Puzzo Daniela
Published: December 2023

Background

Dopamine D3 receptors (D3‐Rs) are involved in several functions such as reward and social behavior and they have been proposed as a therapeutical target for addiction, schizophrenia, and Parkinson’s disease. However, the role of D3‐Rs in cognition has been poorly investigated, with few studies demonstrating that the activation of D3‐Rs impairs attention and working memory. Results obtained in our laboratory suggested that D3 inhibition exerts a pro‐cognitive effect on long term potentiation (LTP) and recognition memory on healthy wild‐type (WT) mice. Based on these findings, here, we aimed to investigate whether the positive effect shown by D3 inhibition at the synapse could be exploited to counteract the synaptic plasticity and memory impairment found in aged and AD mice.

Method

We used D3 knock out (D3‐KO), WT at 18‐22 months of age as a physiological model of aging, the 3XTg transgenic mouse model of AD and a7 KO mice, recently found to present an AD‐like phenotype. The pharmacological inhibition of D3‐Rs was obtained with the selective antagonist NGB‐2904. To test whether the pharmacological inhibition of D3‐Rs or their genetic deletion could rescue LTP and memory impairment, we performed electrophysiological recordings at CA3‐CA1 synapses in hippocampal slices and behavioral experiments of novel object recognition, novel object location and Morris Water Maze.

Result

We found that D3‐Rs antagonism rescued the impairment of LTP, and different forms of memory in aged WT mice. Consistently, aged D3 KO mice showed no alteration of LTP and memory, suggesting that the genetic deletion of D3 receptors prevented the synaptic plasticity and memory decline that occurs with aging. The pharmacological inhibition of D3‐Rs was also able to rescue the memory impairment in both 3XTg and a7 KO mice.

Conclusion

In conclusion, our findings suggest that the pro‐cognitive effect exerted by D3‐Rs inhibition or genetic deletion could represent a viable therapeutic strategy to treat the cognitive dysfunction occurring during aging and AD.
Upregulation of Wnt2b produces neuroprotective effects by alleviating mitochondrial dysfunction in Alzheimer’s disease
Authors: Xu Lingzhi , Li Bingqiu , Li Fangyu , Zhao Yu , Quan Meina , Jia Jianping
Published: December 2023

Background

Alzheimer disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly worldwide. Wnt signaling participates in multiple aspects of cellular function, and contributes to synapse formation, synaptic activity and neurogenesis in the brain, and dysfunction of Wnt signaling may aggravate the pathogenesis and progression of AD. Wnt2b has been studied in cancers or tumor‐related diseases, while the roles of Wnt2b in AD is still unknown. Wnt2b is also characterized as a mitochondria‐expressed protein which shuttles between mitochondria and the nucleus, and mitochondrial dysfunction contributes to the development and progression of the pathological process that underlies AD, especially at the early stage. This study investigated the relationship between plasma Wnt2b levels and AD, and explored the effect of Wnt2b on mitochondrial dysfunction in AD.

Method

Normal cognitive (NC) and AD subjects, AD transgenic mice and in vitro model were used to investigated the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT‐qPCR, immunoblotting and immunofluorescence analysis were performed to assay canonical Wnt sign aling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis.

Result

In this study, we found plasma Wnt2b levels were lower in AD patients than NC subjects and positively correlated with cognitive performance (Figure 1). Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models (Figure 1). Next, Wnt2b overexpression and recombinant Wnt2b was used to endogenously (Figure 2) and exogenously (Figure 3) upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated.

Conclusion

Our study highlights that Wnt2b decline is associated with cognitive impairment in AD, and Our findings may advance the understanding of the importance of Wnt family in AD, and we propose that Wnt2b might be a potential diagnostic indicator and therapeutic target for AD.
Examination of the utility of the gold standard cutoff score for the Montreal Cognitive Assessment (MoCA) in Chinese American older adults: A pilot study
Authors: Ying Gelan , Spat‐Lemus Jessica , Xia Tianxu , Cai Dongming , Lai Randy , Neugroschl Judith A. , Aloysi Amy , Sano Mary , Zhu Carolyn W , Akrivos Jimmy , Hong Yue , Huang QiYing , Zeng Xiaoyi , Liu Linghsi , Cao Yiyu , Wang Wei‐Qian , Li Clara
Published: December 2023

Background

The gold standard cutoff (<26) for the Montreal Cognitive Assessment (MoCA) was developed using a predominantly White and English‐speaking sample. However, the diagnostic value of this cutoff score in a culturally and linguistically diverse population, such as older Chinese Americans, has been understudied and remains inconclusive. As such, this pilot study aimed to examine specific psychometric properties of the standard cutoff score on Chinese language versions of the MoCA for detecting mild cognitive impairment (MCI) and dementia in Chinese American older adults.

Method

The Chinese language versions of the MoCA was administered to 88 older Chinese Americans (19 MCI, 26 dementia, and 43 normal cognition ‐ NC) from Mount Sinai’s Alzheimer’s Disease Research Center (ADRC) in Mandarin/Cantonese by trained psychometricians. All participants self‐reported as Chinese Americans who were primarily Cantonese‐ or Mandarin‐speaking. Exclusion criteria included: not proficient in Cantonese/Mandarin and history of psychiatric disorder(s). Diagnoses were assigned at a consensus conference. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to detect MCI and dementia from NC and were then compared to previously published findings in a primarily White English‐speaking sample.

Result

The gold standard cutoff yielded poor sensitivity to detect MCI and dementia from participants with NC (both 0.47) in this study cohort, but comparable specificity (MCI vs. NC = 0.84; dementia vs. NC = 1.00) to previously published findings (MCI: sensitivity = 0.90, specificity = 0.87; dementia: sensitivity = 1.00, specificity = 0.87). NPV was poor (MCI: NPV = 0.41; dementia: NPV = 0.53), while PPV was similar in detecting both MCI and dementia (MCI: PPV = 0.87; dementia: PPV = 1.00) to previous findings (MCI: PPV = 0.89, NPV = 0.91; dementia: PPV = 0.89, NPV = 1.00).

Conclusion

The MoCA cut off score had poor sensitivity and NPV, but excellent specificity and PPV in detecting MCI and AD in our cohort. These findings suggest that the traditional cutoff score may not be appropriate for screening of cognitive impairment in older Chinese Americans. As the most frequently administered cognitive screening tool, the MoCA cutoff score should be adjusted for older Chinese Americans with limited to no English proficiency. Future studies in a larger cohort of older Chinese Americans are needed to establish a true gold standard for this specific population.
Using an integrated multi‐omics approach to predict dementia: Explainable variational autoencoder (E‐VAE) classifier model
Authors: Vivek Sithara
Published: December 2023

Background

Alzheimer’s disease (AD) and AD related dementias (ADRD) are complex multifactorial neurodegenerative diseases. Application of deep learning methods to analyze large scale whole genome‐wide SNP data and transcriptomic data may be a powerful approach to utilize early molecular changes for early detection of ADRD and elucidate the biological mechanisms in AD/ADRD.

Method

We harmonized the definition of dementia in the Health and Retirement Study (HRS) and an external study Religious Orders Study/Memory and Aging Project (ROSMAP) using a diagnostic algorithm previously validated in the HRS based on cognitive tests. The cognitive tests included immediate and delayed word recall, and backward counting that measure working memory and episodic memory. We developed an explainable variational autoencoder (E‐VAE) classifier model using genetic variants (genome‐wide SNP data, 5474 SNPs) and RNAseq data (592 differentially expresses genes in ADRD) from 204 study participants (102 participants with dementia and 102 controls) in the HRS to predict dementia. We validated the prediction performance in a test set of the HRS participants (26 participants with dementia and 26 controls), and further assessed the generalizability of the multi‐omics‐based VAE classifier model in the ROSMAP data (12 participants with dementia and 222 controls).

Result

Our results showed a predictive accuracy of 0.73 (95% CI [0.61, 0.85]) with an AUC of 0.80 in the HRS validation data and an accuracy of 0.58 (95% CI [0.51, 0.64]) with an AUC of 0.66 in the ROSMAP study data. The E‐VAE model outperformed a penalized logistic regression model (Figure in supplementary file). We identified genes that involved in the apoptotic process, neuron and nervous system development were highly weighted in the multi‐omics‐based VAE model and found that genes in ‘Butyrophilin interactions pathway’ were over represented in ADRD (FDR adjusted p <0.05).

Conclusion

This is the first study showing the generalizability of a deep learning prediction model for dementia in an independent dataset using an integrated multi‐omics approach. The more precise and definitive latent variables identified using E‐VAE can help us understand the complex biology in ADRD and characterize the disease status.
Motor Sequence Learning in Mild Cognitive Impairment and Alzheimer’s Disease and its Relationship to Biomarkers
Authors: Ruitenberg Marit F. L. , Duff Kevin , Koppelmans Vincent
Published: December 2023

Background

While mild cognitive impairment (MCI) and Alzheimer’s disease (AD) are primarily associated with cognitive impairments, studies have also demonstrated that individuals may experience motor impairments that can precede cognitive symptoms by several years. Here, we examine potential differences in motor sequence learning abilities in individuals with MCI and AD compared to cognitively normal individuals (CNI). Moreover, we investigate whether motor sequence learning impairments could be an early behavioral biomarker. To that end, we evaluated associations between motor learning ability and existing AD biomarkers.

Method

To date, 26 individuals with AD, 27 with MCI, and 47 CNI performed a serial reaction time task that allowed us to assess the amount of sequence‐specific learning at the end of the task and the rate of such learning across the task. Additionally, participants underwent APOE genotyping to determine the presence of e4 alleles, amyloid PET imaging to quantify amyloid deposition, and structural MRI scanning to obtain hippocampal volume.

Result

While motor responses of individuals with AD and MCI were generally slower than those of CNI, motor sequence learning occurred regardless of cognitive status and did not significantly differ among the three groups. Results of correlational analyses showed no significant associations between motor learning scores and AD biomarkers.

Conclusion

Our findings suggest that motor sequence learning abilities are relatively preserved in MCI and AD, which could have implications for the design of rehabilitation programs. However, its observed independence of existing biomarkers indicates that sequence learning may not be suitable as an early disease maker. Our ongoing work focuses on measuring general motor proficiency via a broad assessment spanning multiple motor domains, and evaluating whether such proficiency can serve as a predictor of disease status and progression.
Increased worry associated with self‐reported, but not informant‐reported, subjective cognitive decline predicts risk of incident dementia
Authors: Numbers Katya T.
Published: December 2023

Background

Subjective cognitive decline (SCD), in the absence of impaired testing, may be an indicator of early Alzheimer’s disease (AD) and other dementias. However, not all individuals with SCD have cognitive decline. ‘SCD plus’ criteria were proposed in an effort to increase the likelihood of identifying preclinical dementia in individuals with SCD. Two of these criteria include the expression of concern (worry) about the SCD and confirmation of the SCD by an observer (informant). This study investigates whether longitudinal changes in self‐ and informant‐reported SCD‐worry are associated with increased risk of incident dementia over time.

Method

Participants were 873 older adults (M = 78.65‐years; 55% female) and 849 informants from the Sydney Memory and Ageing Study. SCD‐worry was defined as responding “Yes” to the following: “Have you noticed growing difficulties with your/their memory?” and “Have you been concerned about your/their memory getting worse?”. Changes in SCD‐worry over time were modelled using latent growth curve analyses with logit transformation. Participants’ and informants’ propensity to report SCD‐worry at baseline and change over time were analysed using Cox regressions to determine associations with incident dementia risk over 10‐years.

Results

32% of participants who reported noticing memory difficulties at baseline also reported worry associated with this, where only 19% of informants reported worry associated with SCD at baseline. Controlling for demographics, APOE4, mood and personality, participants’ initial level (p < .001) and change in SCD‐worry over time (p = .002), were associated with dementia risk. Controlling for the same covariates, informants’ initial SCD‐worry (p < .001) was associated with dementia risk, though SCD‐worry change was not (p = .862). When modelled together, participants’ initial level of, and longitudinal change in, SCD‐worry were still independently associated with increased dementia risk (p’s < .001); informants’ initial SCD‐worry remained significant (see Table 1).

Conclusion

Our findings highlight the need to factor in concerns held by individuals that go beyond just recognising cognitive changes have occurred, as the latter is a common phenomenon in older adults. Our results suggest that worries about perceived cognitive changes may characterise individuals at greater dementia risk.
Predicting progression within the cognitive decline continuum using self‐ and partner‐reported cognitive complaints, and depressive symptomatology in Cognitively Unimpaired (CU) and Subjective Cognitive Decline (SCD) participants: Evidence from the CompAS longitudinal study
Authors: Pérez‐Blanco Lucía , Felpete Alba , Nieto‐Vieites Ana , Mallo Sabela Carme , Campos‐Magdaleno Maria , Lojo‐Seoane Cristina , Juncos‐Rabadán Onésimo , Pereiro Arturo X
Published: December 2023

Background

Self‐, informant reports and also depressive symptoms can predict the risk of cognitive decline. Our aim was to study the joint contribution of complaint reporting and depression to progression along the cognitive decline continuum to dementia.

Method

A total of 246 participants [Cognitively Unimpaired (CU): n = 144; Subjective Cognitive Decline (SCD): n = 102] over 50 years from the Compostela Aging Study (CompAS) were assessed at baseline and at three follow‐ups (intervals 18‐24 months). A short version of the QAM was administered to assess severity of complaints. At each follow‐up assessment participants were reclassified according to stability or progression. Logistic regressions were performed to predict stable and progressing CU and SCD participants at 3rd follow‐up by using self‐, informant‐ reports, agreement, and depressive symptomatology as predictive variable at baseline, 1st and 2nd follow‐ups s.

Results

For CU participants, (a) complaints at baseline predicted progression to SCD by the informant‐report, and to MCI by the self‐informant agreement; (b) complaints at 1st follow‐up predicted progression to SCD or MCI by the self‐report; (c) complaints at 2nd follow‐up predicted progression to SCD by the self‐report and the depressive symptomatology. For SCD participants, progression to MCI and/or dementia was only predicted by the informant‐report at 2nd follow‐up.

Conclusions

For CU participants, self‐report was the best predictor of progression to SCD and/or MCI from the 1st follow‐up. Regards SCD participants, only informant´s report was able to predict the progression to MCI and/or dementia by the end of the follow‐up.
EEG microstates as a “real time” feedback for rTMS treatment efficacy in MCI subjects
Authors: Glik Amir , Beninger Felix , Kleinmann Michal , Zarfati Hadar , Globerman Matan , keret Ophir , Ramot Yair , Furst Miriam
Published: December 2023

Background

New treatments for the Alzheimer’s disease (AD) are evolving. There is a need for cheap, immediate and available treatment feedback biomarker which can demonstrate rapidly treatment success/failure. We used EEG microstates for this purpose while using repetitive Trans Magnetic stimulation (rTMS) treatment. Four types of microstates are identified according to EEG topography. They are characterized by their duration, frequent appearance and the transitions among the different microstates. The possibility of using microstates properties as a biomarker for rTMS treatment efficacy in mild cognitive impairment (MCI) subjects was explored.

Methods

We recruited 14 MCI subject to receive 16 rTMS sessions. EEG microstates were analyzed immediately before and after each treatment. We used 3 rTMS predefined protocols. The preferred protocol, for each patient, was selected using microstates duration. All patients performed a comprehensive neuro‐cognitive evaluation before rTMS treatment. 11 subjects completed a second neuro‐cognitive evaluation after treatment period ended.

Results

Microstates duration change was noticed before and after each rTMS treatment. Duration variation aided deciding which rTMS protocol is preferred in all participants. Moreover, new rTMS protocol was designed, for 3 patients, using microstates parameters. Cognitive performance was associated with microstate duration (p<0.05).

Conclusions

Microstates duration may serve as a “real time” treatment efficacy biomarker for MCI subjects. Further work should be done in order to validate this method.