bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of diverse pathological Tau forms in the retina of MCI and AD patients
Authors: Shi Haoshen , Mirzaei Nazanin , Davis Miyah R , Koronyo Yosef , Fuchs Dieu‐Trang , Sheyn Julia , Jallow Ousman , Kramerov Andrei A , Ljubimov Alexander V , Kayed Rakez , Miller Carol A , Black Keith L , Koronyo‐Hamaoui Maya 
Published: December 2023

AbstractBackgroundNeurofibrillary tangles (NFTs) formed by abnormal accumulation of the microtubule‐associated protein tau is a key pathological hallmark of Alzheimer’s disease (AD). Presence of abnormal tau forms has been shown to correlate with the degree of neurodegeneration and cognitive decline. A few studies have previously described increases of hyperphosphorylated tau (pTau) in postmortem retinas of AD patients. However, it remains largely unknown if these and other abnormal tau forms are present in the retina of mild cognitively impaired (MCI) and AD patients and their relations with brain pathology is undefined.MethodFifty‐three postmortem human eyes and thirty‐nine paired brains were obtained for this study. Retinas were isolated from 22 AD and 10 MCI patients, and 21 age‐ and sex‐matched cognitively normal (CN) controls. Retinal cross‐sections spanning along ora serrata to optic disc were prepared from four pre‐defined quadrants: superiortemporal, temporalinferior, inferiornasal, and nasalsuperior. Histological analyses were conducted by immunostaining brain and retinal cross‐sections by specific antibodies for NFTs and oligomeric Tau. pTau were explored by using antibodies to detect pS396+, AT8+ (Ser202, Thr205) and AT100+ (Thr212, Ser214). Quantification of tauopathy forms were measured by stereological examination then correlated with the neuropathological reports of these patients.ResultOur examination by both immunofluorescence and peroxidase‐based staining identified the presence of NFTs and novel oligomeric tau forms in AD‐afflicted retina. Stereological analyses of retinal cross‐sections and brains demonstrated a significant upregulation of NFTs and AT8+, pS396+ pTau forms in retinas from MCI patients compared to CN controls; exacerbated tauopathy was found in the retina of AD patients. NFTs and pTau were more frequent in the peripheral retina compared with the central retina. We found intense staining patterns of tauopathy along the synaptic‐rich regions (OPL and IPL). Preliminary correlation analysis suggest significant associations between retinal pS396+ pTau burden and cerebral pathologies including NFT burden, neuropil threads, and cognitive deficit.ConclusionThis study identifies NFTs in the AD retina and demonstrates the accumulation of both soluble and fibrillar forms of tauopathy in the retina of MCI and AD patients. Future retinal imaging of tauopathy may allow a noninvasive means to screen and monitor AD progression.
The performance of AlzoSure® Predict in stratifying the risk to experience a significant cognitive deterioration, due to Alzheimer’s Disease
Authors: Agus Shmuel , Piccirella Simona , Van Neste Leander , Fowler Christopher J , Masters Colin L , Fripp Jurgen , Doecke James D , Uberti Daniela , Kinnon Paul 
Published: December 2023

AbstractBackgroundTreatments for patients with Alzheimer’s Disease (AD) are now available, and are associated with certain risks. There is an increased need from providers, to have tools that will aid in clinical decision‐making.MethodThe AlzoSure® Predict test, is an IP‐LC‐MS/MS based method, to quantify the AZ284® peptide of an unfolded variant of the p53 protein (U‐p53AZ).A dataset from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, with 479 participants, aged 60‐85, 237 being cognitively normal (CN), 98 with minimal cognitive impairment (MCI), 141 with dementia due to AD (ADD), and 3 with non‐AD dementia (OD), was used to validate the performance of AlzoSure® Predict to identify the risk individuals, to experience a significant cognitive deterioration (CN to MCI or ADD and MCI to ADD) and to stratify them according to the time frame, during which, this will occur (6 or 2 years).Result316 participants had a follow up of up to 6 years, and 294 had a follow up of up to 2 years.The performance of AlzoSure® Predict, as measured by AUC, is high, regardless of the follow‐up time frame. For prediction of deterioration within 6 years, the obtained AUC is 0.9842 with DeLong 95% CI: 0.9727‐0.9956 (68 case, who experienced a deterioration, and 248 controls), ho didn’t and for prediction of deterioration within 24 months, it is 0.9891, with DeLong 95% CI: 0.9789‐0.9994 (46 cases, and 248 controls).The cut‐off values of AlzoSure® Predict are defined to stratify individuals, at the time of testing, according to the time frame, during which they may experience a significant cognitive deterioration.AlzoSure® Predict showed high performance to identify rapid progressors to AD within 2 y, with a PPV/ NPV >90%, Sens>80%, and Spec>95%ConclusionAlzoSure® Predict has the capability to identify individuals, who are at risk to experience a significant cognitive deterioration, and stratify this risk according to the time frame, even in a period within 2 years, during which this deterioration will occur.AlzoSure® Predict can become a tool, to strengthen a personalized clinical decision‐making, with improved precision, to be used by providers, who care for patients with AD.
Gut Microbiome Predicts Cognitive Function and Depressive Symptoms in Late Life
Authors: Kolobaric Antonija , Andreescu Carmen , Jašarević Eldin , Hong Chang Hyung , Roh Hyun Woong , Kim Yoon Keun , Aizenstein Howard J , Karim Helmet T. , Son Sang Joon 
Published: December 2023

AbstractBackgroundDepressive symptoms in older adults with cognitive impairment increase the likelihood of progression to dementia. Current mood and cognitive function associate with microbial composition, but the extent to which the microbiome may predict clinical trajectory is unknown. We investigated the capacity of the gut microbiome to reflect current and predict future cognitive function and depressive symptoms.MethodClinical assessments and stool samples were collected from 268 participants with varying cognitive function and depressive symptoms. Seventy participants underwent a 2‐year follow‐up. Microbial community diversity, structure, and composition was assessed using high‐resolution 16S rRNA marker gene sequencing (Figure 1). We implemented multiple linear regression to characterize the relationship between microbiome composition, current cognitive impairment, and depressive symptoms. We leveraged elastic net regression to discover microbial community metrics and microbial functional pathways that reflect current or predict future cognitive function and depressive symptoms (Figure 2).ResultGreater microbial community diversity, indicating a higher number and even distribution of species within a community, was associated with worse current cognitive function in the sample, as well as greater depression severity in participants not on antidepressants. Poor current cognitive function was associated with lower relative abundance of Bifidobacterium. On a functional level, we demonstrate an association between greater GABA degradation and greater current depression severity (Figure 2). Future cognitive decline was associated with lower cognitive function and increased anxiety at baseline. Future cognitive decline was also associated with decreased relative abundance of Firmicutes and Intestinibacter, higher glutamate degradation, and higher baseline histamine synthesis (Figure 2). Future increase in depressive symptoms was associated with higher baseline depression and anxiety, lower cognitive function, and lower relative abundance of Bacteroidota (Figure 2).ConclusionWe display utility in microbiome composition for predicting future cognitive function and depressive symptoms in late life. Our results suggest the gut microbiome may present a noninvasive prognostic for cognitive and psychiatric states. Advancing our understanding of gut‐brain axis in aging may inform the development of neurobiologically driven interventions to ameliorate cognitive decline and depressive symptoms in late life.
Hispanic/Latino perspectives about participation in online recruitment registries for research
Authors: Duran Edwin , Moya‐Fajardo Ciria , Meza Novelle , Grill Joshua D , Salazar Christian R. 
Published: December 2023

AbstractBackgroundOnline recruitment registries have emerged as a novel approach for accelerating enrollment of participants in Alzheimer’s disease (AD) research. While investigators may benefit from having access to a large research‐ready and often prescreened population, older Hispanic/Latino adults enroll less frequently in online recruitment registries, particularly for AD. Using qualitative data from focus groups, we elicited perspectives from community dwelling older Hispanics/Latinos about barriers and facilitators to participation in online registries that recruit to AD research studies.MethodWe conducted 4 focus groups via Zoom in May 2022 and enrolled a total of 15 older Hispanic/Latino adults aged 50+ years who participated in the University of California, Irvine Consent‐to‐Contact (C2C) registry. The C2C is a local online recruitment registry that enrolls individuals from Orange County (OC), California and collects minimal data for the purpose of better matching participants to recruiting studies. We used a semi‐structured interview guide to assess Hispanic participants’ perceptions and experiences about AD research, motivators and barriers to enrolling into an online recruitment registry and suggestions for framing messages to improve enrollment.ResultHispanic/Latino participants were predominately female (60%), US born (80%), college educated (80%) and had a mean age of 60. Reflexive thematic analysis identified 3 emergent themes: (1) being personally affected by AD as a driving factor in participants’ desire to participate; (2) a lack of digital literacy and access to digital devices as a barrier to enrollment; and (3) framing messages that are culturally tailored and aimed at reducing fear towards research.ConclusionUnderstanding the factors that drive decisions to enroll in online registries among Hispanics/Latinos will be crucial for the development of interventions to improve participation. Our preliminary results highlight key concerns among older Hispanics/ Latinos already in registries. Additional focus groups will include other key stakeolders from Hispanic/Latino communities in OC to compare findings.
Development of Potent and Selective Negative Allosteric Modulators of the Metabotropic Glutamate Receptor 2 for the Potential Treatment of Alzheimer’s Disease
Authors: Coleman Jeremy S , Capstick Rory A , Rathnayake Upendra A , Parr Lauren , Chang Sichen , Thompson Analisa D , Qi Aidong , Niswender Colleen M , Boutaud Olivier , Plumley Hyekyung , Jones Carrie K , Engers Darren , Lindsley Craig W 
Published: December 2023

AbstractBackgroundThe metabotropic glutamate receptor 2 (mGluR2) is a group II mGluR that binds glutamate and utilizes Gi/o signaling within the central nervous system (CNS) to modulate synaptic transmission and neuronal excitation.1 The alteration of basal glutamate signaling has been implicated in a variety of neurodegenerative diseases including Alzheimer’s disease (AD).2 mGluR2 has been found to be overexpressed in the hippocampal neurons of AD patients and receptor overactivation has been shown to induce plaque formation in in vitro AD models.3, 4 Thus, the utilization of a mGluR2 negative allosteric modulator (NAM) may prevent neurodegeneration. The utility of mGluR2 NAMs for neurodegenerative diseases remains unclear due to the lack of mGluR selectivity of historical compounds.1. Niswender, C.M. and P.J. Conn, Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annual review of pharmacology and toxicology, 2010. 50: p. 295‐322.2. Li, S.H., K.S. Abd‐Elrahman, and S.S.G. Ferguson, Targeting mGluR2/3 for treatment of neurodegenerative and neuropsychiatric diseases. Pharmacology & Therapeutics, 2022. 239: p. 108275.3. Lee, H.‐g., et al., Aberrant expression of metabotropic glutamate receptor 2 in the vulnerable neurons of Alzheimer’s disease. Acta Neuropathologica, 2004. 107(4): p. 365‐371.4. Caraci, F., et al., Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer’s disease: selective activation of mGlu2 receptors amplifies beta‐amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective. Mol Pharmacol, 2011. 79(3): p. 618‐26.MethodNovel mGluR2 NAMs were synthesized using an iterative library synthetic approach to improve potency, selectivity, and provide an overall sufficient drug metabolism/pharmacokinetics (DMPK) profile. Compound potency (IC50) and selectivity were evaluated in an in vitro GIRK cell‐based T1 flux assay expressing mGluR2 or mGluR3 receptors. Lead compounds were tested in in vitro plasma protein binding assays and rat in vitro and in vivo clearance values were obtained.ResultThe successful discovery and development of a potent and selective mGluR2 NAM as an in vivo tool compound to elucidate the biological effects associated with mGluR2 antagonism was achieved.ConclusionmGluR2 NAMs may be useful therapeutic agents for the potential treatment of AD and other neurodegenerative diseases.
Feasibility and acceptability of automated cognitive assessment over the telephone in the SpeAK study
Authors: Hunter Matthew B , Gregory Sarah , Harrison John E , Jenkins Natalie D , König Alexandra , Linz Nicklas , Luz Saturnino , Mallick Elisa , Pullen Hannah , Welstead Miles , Tröger Johannes , Ritchie Craig W 
Published: December 2023

AbstractBackgroundThere is growing interest in the development of speech markers as novel, non‐invasive biomarkers of early Alzheimer’s disease (AD). Before including such speech assessments in clinical trials, the technology must be tested to confirm feasibility of administration and acceptability with the target population to ensure future engagement. This study aimed to assess feasibility and acceptability in an at‐risk population receiving automated administration of cognitive tasks over the telephone during the Speech on the Phone Assessment (SPeAk) study [35]. A second goal of the study was to assess participant acceptability of receiving cognitive test results ‐ an important consideration for psychological safety.MethodParticipants (n = 68, mean age 70.43 years, 52.9% male) completed a baseline – administered by a trained researcher ‐ and three month follow up visit – administered by an automated phonebot. Tasks included a spontaneous speech assessment and cognitive battery (immediate and delayed recall, digit span and verbal fluency). Participants were randomized to receive their cognitive test results after the final or after each study visit. Participants completed acceptability questionnaires electronically after each study visit.ResultRetention was high (98.5%), with few technical issues (n = 6.7%), there was good inter rater reliability, and test scores were similar when administered by phonebot compared to human administrator in most subtests. A significant lower mean score in digit span was noted at follow up. These findings indicate general feasibility of the assessment. Participants preferred a human tester but rated the automated assessments as acceptable and would be happy to complete a phonebot assessment again, confirming the ease of use of the technology and comfort of completing cognitive tasks on the phone. Participants generally reported feeling happy to receive their cognitive tests results, and this disclosure did not cause participants to feel worried.ConclusionThe results from this usability and acceptability analysis suggests that completing this brief battery of cognitive tests via a telephone call is both acceptable and feasible in a midlife‐to‐older adult population in the UK, living at risk for AD.
Beta to Theta Power Ratio in Electroencephalogram Periodic Components to Discriminate Mild Cognitive Impairment and Alzheimer’s Dementia
Authors: Azami Hamed , Zrenner Christoph , Brooks Heather , Zomorrodi Reza , Blumberger Daniel M. , Fischer Corinne E. , Flint Alastair , Herrmann Nathan , Kumar Sanjeev , Lanctôt Krista L. , Mah Linda , Mulsant Benoit H. , Pollock Bruce G. , Rajji Tarek K. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease dementia (AD) and mild cognitive impairment (MCI) are often associated with abnormalities in full power spectrum of electroencephalogram (EEG), including the ratio of beta/theta. Full spectrum EEG consists of aperiodic and periodic components with the latter being better associated with cognition. We investigated whether the aperiodic and periodic power components of EEGs are disrupted differently in individuals with MCI vs. AD vs. healthy controls (HC), and whether a periodic based beta/theta ratio better differentiates the three groups than a ratio based on the full spectrum.MethodData were collected in 199 participants ‐ 44 with HC (mean (SD) age: 69.1 (5.3) years), 114 with MCI (72.3 (7.5)), and 41 with AD (75.6 (6.5)). We cleaned the data using a band‐pass filter with cut‐off frequencies 1 and 45 Hz and then independent component analysis. We then used the “fooof” toolbox to decompose the EEGs into their aperiodic and periodic components. We used the area under the receiver operating characteristic curve (AUCROC) of a logistic regression classifier to distinguish HC from MCI and AD participants, and MCI from AD participants, using beta/theta ratios based on the periodic power spectrum vs. full power spectrum.ResultThere was an increase in full spectrum powers for delta, theta, and gamma, and a decrease of relative power for beta in AD participants compared to HC and MCI participants. In contrast, there were no differences in aperiodic background EEG components among HC, MCI, and AD participants. Overall, the periodic and full spectrum comparisons among the three groups were comparable except for the periodic based analysis that showed a difference between MCI and HC in the occipital beta/theta ratio (Bonferroni corrected p = 0.036). Classifiers based on beta/theta power ratio in EEG periodic components distinguished AD from HC and MCI with high AUCROC values (0.94 and 0.83, respectively), and outperformed classifiers based on beta/theta power ratio in EEG all oscillations (0.078 and 0.67, respectively).ConclusionThis study supports an advantage of a periodic based analysis over a full EEG spectrum analysis and the use of occipital beta/theta power ratio based on periodic components as a screening tool for AD.
NOTCH2NLC trinucleotide interruptions are associated with cognitive impairment in neuronal intranuclear inclusion disease (NIID)
Authors: Tan Yi Jayne , Xu Zheyu , Chen Zhi‐Yong , Lim Weng Khong , Ting Simon Kang Seng , Yu Wai Yung , Cheng Qian Hui , Foo Jia Nee , Tan Eng‐King , Lim Tchoyoson CC , Ng Adeline Su Lyn 
Published: December 2023

AbstractBackgroundAbnormal GGC expansion within the NOTCH2HLC gene causes neuronal intranuclear inclusion disease (NIID), a rare neurodegenerative disease with variable clinical manifestations, including cognitive dysfunction. In addition to GGC repeats, there are two forms of repeated interruptions, GGA and AGC, within NOTCH2NLC repeats. Previous studies reported fewer GGA and more AGC interruptions in patients with Parkinson Disease; fewer GGA and AGC interruptions in patients with essential tremor, compared to NIID patients. These results suggest that trinucleotide interruptions within the NOTCH2NLC GGC repeats could influence the phenotype of disease, although the mechanism is not known.MethodsWe looked at the repeat compositions in NOTCH2NLC in NIID patients with and without cognitive impairment (CI). NOTCH2NLC repeats were screened by long‐read sequencing on the Oxford Nanopore platform.ResultsIn 13 NIID patients with NOTCH2NLC repeat expansion, 9 (69%) presented with CI. Patients with CI were older [mean (SD) = 69.7 (5.8) vs 63.3 (7.2)], had later age at onset [63.2 (6.5) vs 59.8 (7.1)] and longer disease duration [6.9 (5.2) vs 3.5 (3.9)] than patients without CI. The NOTCH2NLC repeats range from 89‐138 repeats in patients with CI; 82‐166 repeats in patients without CI. Patients with CI carried more GGC repeats [97.7 (1.7) vs 92.8 (9.0)] and less GGA [0.8 (1.3) vs 2.2 (2.8)] and AGC [0.6 (1.0) vs 3.5 (7.4)] interruptions within NOTCH2NLC, compared to patients without CI.ConclusionOur results suggest that NIID patients with cognitive impairment have a purer GGC repeat in NOTCH2NLC compared to patients without cognitive impairment, supporting previous studies that repeat interruptions may modify clinical manifestation of NIID.
Cerebral amyloid angiopathy frequency at baseline and after 4 years of follow‐up in the INSIGHT‐preAD study
Authors: Blanc Clémence , Houot Marion , Villain Nicolas , Younsi Nadjia , Dubois Bruno , Alamowitch Sonia , Bombois Stéphanie 
Published: December 2023

AbstractBackgroundCerebral amyloid angiopathy (CAA) diagnostic is of special interest due to its association with cognitive impairment, Alzheimer disease (AD) and Amyloid‐Related Imaging Abnormalities (ARIA) in trials with anti‐amyloid immunotherapies. We aimed to assess the frequency of CAA diagnosis and associated lesions in subjects with cognitive complaint and normal cognition enrolled in the INSIGHT‐preAD study.MethodCognitively normal elderly with memory complaint included in the INSIGHT‐preAD study were assessed with multimodal explorations for 5 years follow‐up. 3T MRI‐scans were performed at baseline and during follow‐up at 2 and 4 years. Lobar cerebral microbleeds (CMB), cortical superficial siderosis (CSS), enlarged perivascular spaces (EPVS) and white matter hyperintensities (WMH) were rated according to validated scales and guidelines. Boston criteria V2.0 were applied to diagnose possible and probable CAA.ResultAmong the 318 subjects (median [Q1, Q3] age: 76.4 [74.1, 78.5] years, 201 (63.2%) women) enrolled at baseline, 41 (12.9%) had at least one lobar CMB, 4 (1.3%) CSS, 68 (21.7%) severe EPVS in the centrum semi‐ovale and 245 (77%) WMH with a spot pattern ≥10. The median FAZEKAS score was 2.0 [1.0, 2.0]. At baseline, 251 (78.9%) subjects had CAA: 218 (68.5%) possible CAA and 33 (10.4%) probable CAA with a median number of CMB of 1.0 [1.0, 1.0]. Compared to non‐CAA subjects (n = 67), those with probable CAA at baseline were not different on demographics and vascular risk factor, had more executive dysfunction, and tended to be associated with Apoe4 status and lower hippocampal volume. After 2‐ and 4‐ years of follow‐up, 81.2% and 81.3% of the subjects still in the study had CAA, with 13.3% and 14.1% of probable CAA respectively, and the number of subjects with CMB increased to 15.9% and 18.3%.ConclusionIn the INSIGHT‐preAD study, the high frequence of CAA, with minimal change after 4 years follow‐up, was essentially due to the non‐hemorrhagic lesions. The hemorrhagic lesions (CMB and CSS) were uncommon, probably underestimated by the MRI T2* sequence. These results have implications in clinical setting and could be useful in pre‐symptomatic AD anti‐amyloid immunotherapy trial.