bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interregional Gene Expression Analysis Identifies Signature of Cerebellar Resistance to AD Tauopathy
Authors: Ayoub Christopher A , Wagner Connor , Kuret Jeff 
Published: December 2022

AbstractBackgroundThe appearance of neurofibrillary tangles (NFTs) reflects both their spatial location within affected connectivity networks and the intrinsic vulnerability of neuronal populations to their formation. Here we disaggregate human gene expression data on the basis of connectivity to identify differentially expressed genes (DEGs) associated with neuroprotection against tauopathy.MethodTranscriptomic analysis focused on prefrontal cortex (PFC) and cerebellum, which both associate with the default mode and other AD‐affected networks. However, whereas PFC is vulnerable to tauopathic neurodegeneration, the cerebellum atrophies without NFT formation or cell loss. To identify candidate mediators of selective vulnerability, gene expression patterns in both regions from AD and control brains were calculated and then subjected to cell‐type specific enrichment analysis (CSEA), gene set enrichment analysis (GSEA), and transcription factor interaction network (TFIN) analysis. To validate candidate effector genes, prioritized chaperones were incubated with tau protein to test for suppression of biochemically induced fibrillization. The resulting distribution of soluble and aggregated tau was measured by sedimentation.ResultsCSEA revealed DEGs that changed in parallel between regions originated primarily in glia and microglia. GSEA identified these as belonging to Gene Ontology (GO) categories associated with host response and ion homeostasis. Of 446 genes, 379 were linked in a TFIN, with the most central nodes including transcriptional regulators HBP1, EGR1, SERTAD1, and PER1. In contrast, DEGs changing in opposition were primarily neuronal. GSEA identified 14 heat shock genes, including nine chaperone proteins reported to regulate protein folding. Of 402 candidate vulnerability genes, 319 were linked in a TFIN, in which the most central hubs were long noncoding RNA NEAT1, and transcription factors BHLHE40, ZC3H10, and CREB3L4. Finally, aggregation and sedimentation of tau showed all nine chaperones antagonized biochemical fibrillization of 2N4R tau with octadecyl sulfate at substoichiometric ratios of chaperone to tau.ConclusionsOur study takes advantage of a selective vulnerability informed approach to gene expression and highlights the role of proteostasis and neuronal genes in protecting the cerebellum from tau lesions. This approach successfully identified biologically active effector genes and can be applied broadly to other neurodegenerative diseases featuring prion‐like pathology and will orient the field toward endogenous strategies of neuroprotection.
Gamma‐Frequency Sensory Stimulation is Safe and Well‐Tolerated Treatment Option for Patients with Alzheimer’s Disease
Authors: Hajos Mihaly , Boasso Alyssa , Hempel Evan , Cimenser Aylin , Seshagiri Chandran , Megerian Jonathan Thomas , Vaughan Brent , Malchano Zach 
Published: December 2022

AbstractBackgroundRecent experimental findings demonstrate that sensory‐evoked brain gamma oscillation reduces Alzheimer’s disease (AD) pathologies in AD‐related transgenic mice, including decline in synaptic function, neurodegeneration, and brain atrophy (Adaikkan & Tsai, Trends Neurosci. 2020;43:24‐41). Based on these findings, gamma‐frequency sensory stimulation has been evaluated in multiple clinical trials, including the long‐term Overture a randomized, controlled trial (Clinicaltrials.gov: NCT03556280) assessing safety, tolerance, and efficacy of using Cognito Therapeutics medical device in patients with AD.MethodPatients with clinical presentation of AD spectrum (MMSE 14‐26, inclusive) were randomized 2:1 to receive daily, one‐hour, EEG‐calibrated, 40Hz noninvasive audio‐visual stimulation or sham stimulation over a 6‐month period. Therapy was self‐administered at home with the help of a care partner. Safety was evaluated by magnetic resonance imaging (MRI), physical and neurological exams at baseline, 12‐, and 24‐weeks, and monthly assessments of adverse events (AEs). Tolerability was measured by device use data, daily diary, and user experience interviews.ResultA total of 135 subjects were screened, of whom 74 (55%) were randomized and 53 completed (72%). The safety population included all subjects who performed at least one day of treatment. During the 6‐month (168 days) treatment period, both groups completed daily therapies at a similar rate (147 active vs 139 sham). Treatment‐related AEs occurred in 19 subjects (41.3%) in the active treatment group and 8 subjects (28.6%) in the sham group. The incidence of treatment‐related AEs was similar between treatment groups except for headache (21.7% active group vs 10.7% sham group) and tinnitus (15.2% active group vs 0% sham group). All treatment‐related AEs were mild in intensity except tinnitus and anxiety (1 active group subject) and agitation (1 sham group subject) which were considered moderate. Review of MRI data demonstrated absence of ARIA in all subjects. High adherence rates (over 83%) were observed in both sham and treatment subjects; 60% of enrolled participants entered open label extension.ConclusionGamma‐frequency sensory stimulation is safe and well tolerated by trial participants. Together with efficacy shown on functional and cognitive abilities and brain atrophy (Hajós et al., JPAD 2021;8:S60‐61), gamma‐frequency sensory stimulation can be considered as viable treatment option for patients with AD.
Resting heart rate (variability) predicts cognitive function and suggests different heart‐brain connections in cognitively healthy individuals with abnormal CSF amyloid/tau
Authors: Arakaki Xianghong , Choy Elizabeth Hok Yee , Arechavala Rebecca Johnson , Nolty Anne , Spezzaferri Mitchell , Sin Caleb , Rising Shant , Buennagel David P , Molloy Cathleen , Fonteh Alfred N. , Kloner Robert A , Kleinman Michael T. 
Published: December 2022

AbstractBackgroundBoth resting heart rate variability (HRV) and resting heart rate (HR) are regulated by the central autonomic network linking prefrontal cortex with cardiac regulation. To better understand the interactions between the heart and cognition we determined the relationships between resting HR/HRV and cognitive function.MethodWe compared and correlated resting HR with Mini‐Mental State Exam (MMSE) in cognitively healthy (CH, n=137) individuals when their CSF amyloid/tau ratios were normal (CH‐NATs, n=51) or pathological (CH‐PATs, n=68), in participants with mild cognitive impairment (MCI, n=54), and Alzheimer’s disease (AD, n=42). We also compared and correlated HRV with behavioral performance (accuracy and response time) or alpha event‐related desynchronization (ERD) during Stroop (interference) or task switching testing between subsets of CH‐NATs and CH‐PATs. Cognitive tasks include: 1) Stroop during low load (congruent trials) and high load (incongruent trials); 2) task switching during low load, repeat trials (color‐color or word‐word) and high load, switch trials (color‐word or word‐color). HRV was assessed from 5‐minute resting ECG recording, including: HR and root mean squared of successive differences (RMSSD) that reflect vagal activities.ResultNo differences of resting HR or HRV were observed between CH‐NATs, CH‐PATs, MCI, and AD. Interestingly, resting HR negatively correlated with MMSE only in CH‐PATs (r=‐0.57, p=0.002), but not in CH‐NATs (r=0.07, p=0.71), CH (r=‐0.09, p=0.57), MCI (r=‐0.14, p=0.41), or AD (r=‐0.11, p=0.59) (Fig 1). For Stroop interference testing, resting HR (preceding task) positively correlated with frontal alpha ERD during high load trails (r=0.78, p=0.017) in CH‐PATs, but not in CH‐NATs (Fig 2). For task switch testing, resting RMSSD positively correlated with accuracy during switch trials (r=0.64, p=0.004) in CH‐NATs, but not in CH‐PATs (Fig 3).ConclusionThese results suggest: 1) resting HR is linked with cognition in CH‐PATs; 2) resting HR is related to inhibitory control in CH‐PATs: higher HR linked with less negative alpha ERD (less activation); 3) resting HRV predicts task switching performance in CH‐NATs: higher RMSSD linked with higher accuracy. Overall, resting HR and HRV potentially reflect cognition and executive functions that differentiate CH‐NATs and CH‐PATs, suggesting different cerebral‐cardiovascular integration in these two populations.
Association of hippocampal subfield volumes with amyloid‐beta deposition in Alzheimer’s disease
Authors: Baek Min Seok , Lee Narae , Kim Jin Woo , Hong Jin Yong 
Published: December 2022

AbstractBackgroundCharacteristic atrophy patterns of hippocampal subfield volumes and cortical amyloid‐beta (Aβ) deposition are two important neuroimaging biomarkers in Alzheimer’s disease (AD). We investigated the relationship between hippocampal subfield volumes and cortical Aβ deposition in AD.MethodFifty participants (11 cognitively unimpaired [CU], 10 with mild cognitive impairment [MCI], and 29 with AD) who underwent 18F‐florbetaben positron emission tomography, magnetic resonance imaging, and neuropsychological tests were enrolled. The hippocampal subfield volumes were obtained using an automated brain volumetry system with the Winterburn atlas and were compared among the diagnostic groups, and the correlations with the Aβ deposition and AD risk factors were determined.ResultPatients with MCI and AD showed decreased volume in the stratum radiatum/lacunosum/moleculare (SRLM) of the cornu ammonis (CA)1 and CA4‐dentate gyrus (DG) than the CU. Decreased SRLM and CA4‐DG volumes were associated with an increased Aβ deposition in the global cortex (R = ‐0.459, p = 0.001; R = ‐0.393, p = 0.005, respectively). The SRLM and CA4‐DG volumes aided in the distinction of AD from CU (areas under the receiver operating characteristic [AUROC] curve = 0.957 and 0.930 respectively, p < 0.001), and Aβ+ from Aβ‐ individuals (AUROC curve = 0.763 and 0.763, respectively, p < 0.001).ConclusionHippocampal subfield volumes demonstrated potential as imaging biomarkers in the diagnosis and detection of AD and Aβ deposition, respectively.
Diagnosis of mixed dementia by double dichotomy
Authors: Rosenberg Gary A , Adair John , Knoefel Janice , Prestopnik Jillian , Hillmer Laura , Erhardt Erik B , Arvind Caprihan 
Published: December 2022

AbstractBackgroundProper classification of patients with dementia is critical in clinical trials. Dual Alzheimer’s disease (AD) and vascular pathology (mixed dementia‐MX) is the most common form of dementia estimated to be as high as 70% in pathological series. However, separation clinically is difficult, which has led to use of biomarkers. A biological definition of AD based on biomarkers has been proposed for research studies with identification of amyloid and tau in CSF or PET. Including in the ATN formula, biomarkers for vascular disease (V), obtained from MRI, separates MX subjects, improving diagnosis of AD and vascular cognitive impairment (VCI).MethodsWe used vascular disease biomarkers from MRI and AD biomarkers from CSF with a double dichotomy statistical approach to more precisely define four major groups of patients in the UNM and Alzheimers's Disease Neuroimaging Initiative (ADNI) cohorts. We compared the UNM dataset (N=80) with subjects from ADNI (N=538). Diffusion tensor imaging (DTI) biomarkers (mean free water and PSMD) were combined with CSF amyloid (A) and tau (T) to identify MX patients. We formed a composite vascular disease score (cVDS) with DTI, and a composite AD score (cADS) with CSF amyloid and phosphoTau181.ResultsPlotting cVDS on the x‐axis and cADS on the y‐axis placed subjects in one of four biologically defined quadrants: bAD (biological AD) in the upper left, bSIVD (biological subcortical ischemic vascular disease) in the lower right, bMX (biological mixed dementia) in the upper right, and bCN (biological controls) in the lower left quadrant (Figure). We identified MX, using a double dichotomy statistical method. The UNM cohort had 25% MX, while in ADNI there were 11.5% (Table). The ADNI group had a higher percentage of bCN (43%) and bAD (35%) than the UNM cohort; this was because UNM was one of 7 sites in the MarkVCID consortium with enriched VCI subjects and ADNI excluded vascular disease subjects.ConclusionsOur results show that adding a vascular factor (V) to the ATN formula creates a MX group, improving classification of patients by creating a more homogeneous AD group, which permits AD clinical trials with fewer subjects
On the evaluation of disease progression modelling in Alzheimer's Disease
Authors: Saint‐Jalmes Martin , Goudey Benjamin , Beck Daniel , Masters Colin L. , Fedyashov Victor 
Published: December 2022

AbstractBackgroundAlzheimer's Disease (AD) is a heterogeneous condition that can be viewed as a continuum involving multiple stages from cognitively normal to mild cognitive impairment and finally dementia. Recent works in Disease Progression Modelling (DPM) have attempted to use biomarkers to construct representations of progression that are more informative of patients' status than clinical diagnosis alone. However, there is no clear consensus (Figure 1) regarding the choice of evaluation methods or metrics to facilitate model comparison. We propose the use a simple, universally applicable biomarker‐based baseline to estimate patient‐realigning time‐shifts and subsequently evaluate it against multiple released DPM methods.MethodWe computed an abnormality score for 2439 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) by averaging the normalised values collected for 12 biomarkers representative of amyloid, tau, neurodegeneration, and cognition. Abnormality ranges were determined from 251 amyloid‐positive patients. These scores were compared to values from published DPM models (Figure 3). Additionally, all methods were benchmarked in different ways, including diagnosis classification and cluster analysis.ResultWe found that, despite its simplicity, our abnormality score reasonably separated patients according to their diagnosis (Figure 2). Computed scores also correlated significantly with those of other methods (Figure 3, Pearson correlations up to 0.891). While our approach only required cross‐sectional information, other methods rely on longitudinal data. Our method performed similarly to others in the cutoff‐based disease classification task, with test F1‐scores of 0.734 and 0.890 in the harder tasks of CN/MCI and AD/MCI, respectively (Table 1). In a three‐class setting, all methods including our baseline showed a good level of agreement, with Rand indices all above 0.6 (Figure 4).ConclusionA significant challenge in DPM for AD lies in estimating a proxy for patient realignment, which is crucial to describe individuals on a common disease continuum. We have proposed a method to calculate an abnormality score at the baseline visit, which can be trivially extended to longitudinal data and help interpret progression in follow‐ups. We hope that future work considers more principled evaluation procedures, facilitating meaningful comparisons between DPMs.
The Peruvian Alzheimer Disease Initiative (PeADI): An international effort model to increase diversity in AD research
Authors: Illanes‐Manrique Maryenela , Mena Pedro Ramon , Milla‐Neyra Karina , Adams Larry D. , Mejía Koni K. , Rios‐Pinto Julia , Isasi Rosario , Medina‐Colque Angel , Beecham Gary W. , Cornejo‐Herrera Ivan , Vance Jeffery M. , Ochoa‐Valle Edward , Castro‐Suarez Sheila , Cuccaro Michael L. , Sarapura‐Castro Elison , Cornejo‐Olivas Mario , Pericak‐Vance Margaret A. 
Published: December 2022

AbstractBackgroundPeru is one of the five largest countries in Latin America and harboring a high Amerindian ancestry component in this population. The Latin American population, including Peruvians, are underrepresented in research studies of Alzheimer disease (AD).We have developed an international collaborative research initiative to ascertain a Peruvian cohort for AD and other related dementias for genetic studies of Amerindian individuals.MethodsThe Peruvian Alzheimer Disease initiative (PeADI) was developed to recruit and enroll Peruvian adults aged 65 and older to a comprehensive genetic AD study. Individuals will get whole genome sequencing and plasma biomarkers. Participants included cases with AD and ADD,healthy controls as well as multiplex AD families. Since 2019, we have established a multisource ascertainment approach including recruitment at main hospitals, outreach community activities and more recently due to the COVID19 pandemic remote recruitment and home visits. Our recruitment has expanded since our initial efforts in which we enrolled individuals from Lima, the capital city. We are now ascertaining participants in three regions from the Andes highlands (Puno,Huancayo, and Cusco) and one region from the southern coast (Tacna).All participants are enrolled using a standard protocol administered by neurologists and neuropsychologists. This protocol includes clinical interviews and neurocognitive assessment.ResultsAs of December 2021, we have enrolled 103 AD and other dementia cases, 202 controls and 4 multiplex AD families. While the majority of participants are from Lima, 25% controls and 1% of cases have been recruited in regions outside Lima. We have confirmed a significant association between APOE and AD in Peruvian Population higher than we have observed in non‐Hispanics. In addition to ascertainment activities, we are working closely with the respective sites to develop a network for AD research across Peru. To date, we have developed local research capacities within each region,including training opportunities for investigators, coordinators and lab technicians. In addition, we are developing resources for health and medical support and basic equipment for all regions.ConclusionThe PeADI study shows the importance of equitable international north‐south cooperation and local network cooperation to increase representation of understudied admixed populations to help us understand Amerindian ancestry in drug target discovery.
Investigating a CD8+ T cell age‐associated gene signature in Alzheimer's disease
Authors: Young Juan J , Park Hong‐Jai , Par‐Young Jennefer , Bartlett Hugh H. , Kim Hye Sun , Shin Min Sun , You Sungyong , Kim Min Hyung , Allore Heather G. , Mecca Adam P , Kang Insoo 
Published: December 2022

AbstractBackgroundNeuroinflammation has been linked with the pathologic progression of Alzheimer’s disease (AD). Previous studies focused primarily on the innate immune system; however, there are few human studies evaluating the potential relationships between adaptive immune cells and the development of AD pathology. Alterations in the immune system occur with aging, likely contributing to increased infection, malignancy and inflammation in older adults. One of the most prominent immune changes with age includes the expansion of memory CD8+ T cells in peripheral blood. Notably, cytotoxic IL‐7 receptor alpha low (IL‐7Rα or CD127low) CD45RA+ effector memory (EM) CD8+ T cells (TEMRA) have been associated with dementia and mild cognitive impairment (MCI) due to AD. In addition, our lab recently discovered an age‐associated gene expression signature of IL‐7Rα low EM CD8+ T cells. Thus, we hypothesized that individuals with AD have altered levels of IL‐7Rα low EM CD8+ T cell aging gene expression.MethodsA total of 40 genes which include 9 IL‐7Rαlow aging genes and 31 genes previously reported to be associated with AD and/or memory were analyzed in peripheral blood of 82 participants with AD and 40 cognitively normal age‐balanced participants by quantitative polymerase chain reaction (qPCR). Gene expression data was analyzed utilizing one‐way ANOVA, principal component analysis (PCA), and unbiased hierarchical clustering analysis.ResultsEight genes were differentially expressed (P < 0.05) between cognitively normal participants and participants with MCI or dementia due to AD. These genes included 5 IL‐7Ralow aging genes (GZMH, NUAK1, TGFBR3, PRSS23, OSBPL5), 2 genes related to AD and/or memory (CD163, CYP4F3) and a gene related to both aging and AD (PADI4). The expression levels of IL‐7Ralow aging genes moderately correlated with those of AD and memory genes. PCA and clustering analysis suggest IL‐7Ralow aging genes may be associated with disease status in a subset of AD subjects.ConclusionsAn altered CD8+ T cell age‐associated gene signature is present in AD patients, warranting further studies investigating biological implications of CD8+ T cells, especially highly cytotoxic and inflammatory IL‐7Rαlow EM CD8+ T cells, in AD.
Pilot Randomised, Double‐Blind, Placebo‐Controlled Crossover Trial Evaluating the Feasibility of an Intranasal Oxytocin in Improving Social Cognition in Individuals Living with Alzheimer’s Disease
Authors: Michaelian Johannes C , McCade Donna , Hoyos Camilla M , Brodaty Henry , Harrison Fleur , Henry Julie D , Guastella Adam J , Naismith Sharon L 
Published: December 2022

AbstractBackgroundIndividuals living with Alzheimer’s disease (AD) demonstrate global deficits in social cognition. These deficits have been associated with impaired interpersonal relationships amongst caregivers, in turn contributing to a greater sense of caregiver ‘burden’. In other areas of neuropsychiatric disease (i.e., autism spectrum disorder), intranasal oxytocin (INOT) administration has shown replicable improvements in social cognitive function, particularly in Theory of Mind. Recently, randomised controlled trials (RCTs) in frontotemporal dementia have reported that repeated INOT administration may be regarded as safe and well tolerated at higher doses ‐ resulting in changes to apathy and improvements in empathic concern, as rated by a caregiver. To date, no studies have investigated the feasibility of an INOT treatment in individuals living with AD. Here, we conducted a pilot feasibility trial to determine the feasibility of recruitment, the acceptability of enrolment and the adherence to an INOT treatment in order to inform the subsequent design of a future RCT. Secondly, we sought to determine the effect size estimates on key potential social cognitive function outcome measures related to both the participant and their caregiver.MethodFour individuals living with AD were enrolled in a single‐centre, randomised, double‐blind, placebo‐controlled crossover trial involving a one‐week treatment period with both INOT (72 IU) and placebo.ResultAll participants reported no treatment‐causative or serious adverse events, following repeated INOT administration. While acceptability of enrolment was excellent (100%), as well as INOT treatment adherence (placebo, 95%; INOT, 98%), our feasibility of recruitment was not acceptable (i.e., only 7% of fifty‐eight individuals with dementia screened met inclusion criteria). However, positive/large effects were associated with expected secondary outcomes around self‐reported health and wellbeing, caregiver ‘burden’, intimacy and interpersonal bonding, following repeated INOT administration.ConclusionThese data provide the first evidence demonstrating the safety and tolerability of INOT administration in individuals living with AD. Despite limitations in sample size, moderate‐to‐large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and burden as reported by a caregiver. This suggests potential broad‐ranging beneficial effects of INOT which should be assessed in future RCTs from multiple perspectives.