bluuebunny/crossref_metadata_2025_split huggingface dataset:
Data driven criteria for genetic testing result in an efficient selection of patients with genetic dementia in a clinical setting
Authors: Lee Sven J , Hulsman Marc , van Spaendonk Rosalina M.L. , Schaar Jetske , Dijkstra Janna I.R. , van der Flier Wiesje M. , Elting Mariet , Reinders Marcel JT , Rojas Itziar , Haelst Mieke M. , Geus Christa , Pijnenburg Yolande A.L. , Holstege Henne 
Published: December 2023

AbstractBackgroundIdentification of patients with familial dementia is important as this may explain disease in families, raises the possibility of predictive testing for relatives and enables participation in trials. Previously proposed clinical criteria to offer genetic testing based on diagnosis, age, and familial history do not capture the diversity of clinical presentation of patients. We aimed to develop data‐derived clinical criteria and prospectively validated these by applying them in a memory clinic.MethodIn a 2,5‐year period (1‐1‐2010 until 30‐6‐2012) 1138 patients visited the Alzheimer Center Amsterdam and underwent routine diagnostic work‐up (van der Flier et al 2018). The average age of individuals was 62 years, 41% of the patients being female. Patients provided DNA for research purposes, which allowed us to test 1022 (90%) of the patients for variants in 54 dementia related genes (exome sequencing), APP duplications and C9orf72‐repeat expansions. Data driven clinical criteria for genetic testing were formulated to optimally identify carriers of a causal mutation. Subsequently, we offered genetic testing according to the new clinical criteria to all patients in the Alzheimer Center Amsterdam for 1 year (9‐2021 to 9‐2022).ResultWe identified genetic mutations causing dementia in 34 patients, which accounted for 3.3% of all patients. Previous criteria would have selected 23% of these patients for testing and identified 47% of the mutation carriers. We formulated optimized clinical criteria(as shown in Figure 1), that would have identified 88% of mutation carriers(30/34 carriers) in 26% of all patients. This efficient selection was prospectively validated in 2021. A 149 out of 517 patients(29%) were eligible for genetic testing based on the new criteria. Of these 90 patients(60.4%) opted for testing and 59(39.6%) declined testing or clinicians decided against offering the test. We found 12 out of 90(13%) to carry a mutation. This confirms the efficient selection as 10 mutation carriers were anticipated in the tested group based on our research data.ConclusionData driven clinical criteria for genetic testing efficiently selected individuals with genetic dementia in a real‐life implementation. Memory clinics can adopt these clinical criteria to offer genetic testing to the patients most likely to benefit.
Associations of Gait and Cognitive Impairment and Dementia in Individuals with Down Syndrome
Authors: Gonçalves Aline Souza , Mattar Guilherme Prado , Sant'Ana Livea Carla Fidalgo , da Silva Maria de Fátima Rebouças , Martinez Luana Dongue , De‐Paula Vanessa V.J. , Carvalho Claudia Lopes , Martine Alexandra , Fonseca Luciana Mascarenhas , Forlenza Orestes Vicente 
Published: December 2023

AbstractBackgroundLife expectancy of individuals with Down syndrome (DS) has increased considerably over the years. Atypical aging in Down syndrome (DS) is associated with neuropathological characteristics consistent with Alzheimer disease (AD). Significant gait alterations are associated with an increased risk of dementia for the general population. The aim of this study was to determine whether gait performance is associated with cognitive performance and dementia in adults with DS.MethodThis study included 66 individuals with DS over 20 years of age, divided into three diagnostic groups: stable cognition, prodromal dementia, and dementia. They were evaluated with the Performance‐Oriented Mobility Assessment (POMA), Timed Up and Go test, and Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities (CAMDEX‐DS), which includes the Cambridge Cognitive Examination (CAMCOG). Logistic regression model was used to assess the effects of gait and balance on the diagnosis (prodromal dementia and dementia versus stable cognition) adjusting for age, sex, body mass index (BMI), degree of intellectual disability and physical inactivity.ResultThe score on the POMA‐Gait subscale score and body mass index (BMI) were found to be independent predictors of prodromal dementia and dementia (Poma‐Gait OR = 0.67, 0.53‐0.85 CI, p<0.001; and BMI OR = 1.12, 1.021.24 CI, p<0.001). A lower POMA‐Total score indicates a higher fall risk. With the exception of perception, all cognitive domains correlated with the POMA total score (P<0.05).ConclusionThese data indicate that poor gait performance, as assessed by the POMA, as well as a high BMI, were associated with a diagnosis of prodromal dementia or dementia. In those individuals, applying the POMA could facilitate the early diagnosis of dementia, help identify fall risks, and promote the adoption of geriatric interventions focused on improving functional mobility. There is a need for longitudinal studies to characterize the true nature of the associations found, to validate gait instruments specifics to this population, and for future analyses in order to clarify the role that gait and balance play in cognitive decline and the development of dementia.
WITHDRAWN: Understanding the progression of Alzheimer’s Disease in 5XFAD transgenic female mice using 1H‐[13C]‐NMR Spectroscopy
Authors: Nag Rishav ,   NMR Microimaging and Spectroscopy Lab, CCMB, Hyderabad, India
Published: December 2023

AbstractThe above abstract, published online on 25 December 2023 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors; the journal Editor in Chief, Dr. Donna M. Wilcock, PhD; the Alzheimer's Association; and Wiley Periodicals LLC. The withdrawal has been agreed to because the authors informed the journal that they did not have permission to communicate the data and protocols included in the abstract.
Spatial interplay between synaptic loss, UCH‐L1 deficiency, and pTau accumulation in the retina of MCI and AD patients
Authors: Rentsendorj Altan , Jallow Ousman , Fuchs Dieu‐Trang , Sheyn Julia , Gaire Bhakta Prasad , Davis Miyah R , Shi Haoshen , Black Keith L , Koronyo Yosef , Koronyo‐Hamaoui Maya 
Published: December 2023

AbstractBackgroundSynaptic dysfunction occurs early during Alzheimer’s disease (AD) progression and is considered a strong predictor of cognitive decline. However, it has never been investigated in the AD retina. The ubiquitin‐proteasome system (UPS) is a major degradation pathway for damaged proteins and has been implicated in synaptic integrity and AD pathogenesis. Deficiency in ubiquitin hydrolase (UCH‐L1), a vital UPS component known for its neuroprotective and synaptoprotective properties, was previously linked to cerebral Aβ accumulation in AD, yet has never been explored in the AD retina.MethodWe employed a range of histological techniques to evaluate synaptic integrity and retinal pathology in postmortem retinas of patients with mild cognitive impairment (MCI) attributable to AD or AD dementia, compared to retinas from age‐matched individuals who displayed normal cognition (NC). We assessed the presence of amyloidosis, gliosis, tauopathy, apoptosis, in relation to UCH‐L1 levels, and visualized and quantified synaptic density through analysis of pre‐ and post‐synaptic markers while also assessing the spatial and cellular layer distribution of these markers.ResultWe detected extensive pre‐ and post‐synaptic losses in the IPL and OPL layers of MCI and AD patients, particularly in the far peripheral regions. This was accompanied by 2‐ to 4‐fold decrease in levels of UCH‐L1 in the retinal layers of MCI and AD patients, which directly correlated with pre‐synaptic loss (p<0.0001). These changes were inversely correlated with pTau accumulation (e.g., AT8, pS396), colocalizing at sites of synaptic loss in the IPL and OPL layers. Furthermore, there were significant (1.8‐4.2‐fold) increases in apoptotic cell death in the retinas of these patients (p<0.05–0.001). Remarkably, the pre‐synaptic losses significantly correlated with decreased cognitive scores.ConclusionOur results reveal a substantial retinal synaptic loss at sites of pTau accumulation in prodromal and clinical AD patients. Expression of retinal UCH‐L1 was significantly reduced in MCI and AD patients and strongly associated with synaptic loss and cognitive decline, signifying its potential role in protecting retinal neurons against AD‐related pathology.
The Genetics of Cognitive Resistance and Resilience in the Ohio and Indiana Amish
Authors: Main Leighanne R. , Song Yeunjoo E. , Laux Renee A. , Miskimen Kristy L. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Osterman Michael D. , Lynn Audrey , Dorfsman Daniel A. , Caywood Laura J. , Prough Michael B. , Adams Larry D. , Clouse Jason E. , Herington Sharlene D. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L. 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is a leading cause of death in the US, with limited treatment options. Most studies assess risk factors for AD; however, protective mechanisms demonstrate higher success rates as therapeutic targets. Here, we examine the genetics of Amish individuals maintaining cognitive preservation into advanced age, aiming to uncover protective mechanisms against AD.MethodOur dataset consisted of individuals of Amish descent, between 76 – 95 years of age and cognitively unimpaired (CU) with at least one first‐degree relative determined to be either CU or cognitively impaired (CI). 946 Amish individuals met our criteria, were genotyped across their genomes, and incorporated into a single 13‐generation pedigree containing 8,222 individuals. Their complex familial relationships were considered in linkage and genome‐wide association analyses (GWAS). GENESIS was used for GWAS, with XWAS used for the X chromosome. Several parametric and non‐parametric linkage analyses were also performed utilizing MERLIN software for the autosomes and MINX for the X chromosome.Result106 SNPs (representing 64 loci) reached an initial significance threshold (LOD≥3.3) in linkage analyses. Adjusting for number of independent SNPs in our dataset, no SNPs reached significance after GWAS (P≤6.4×10−7), but 12 loci were suggestive (P≤5×10−4). No loci were suggestive/significant on the X chromosome. For a locus to be further investigated, 1) a significant or suggestive LOD score was required in two or more linkage analyses or 2) one significant LOD score and a suggestive GWAS association within a 10 Mb region were required. After applying these criteria, 8 loci, on chromosomes 1, 2, 3, 7, 11, and 17, were selected for further evaluation. Loci on chromosomes 7 and 11 are within 10 Mb of known AD risk and protective loci, EPHA1 and PICALM, respectively. Significant LOD score results on chromosomes 7, 11, and 17 overlap with coding regions for TBXAS1, DLG2, and SPNS3, respectively. These three loci have been implicated in cognitive impairment relating to neurological disorders.ConclusionWe identified 8 loci potentially harboring genes promoting cognitive preservation. These are under further investigation and represent potential therapeutic targets but require experimental studies identifying their specific mechanisms in relationship to AD.
The Human Brain Nucleus Incertus: A New Target in Dementia?
Authors: de Avila Camila , Intorcia Anthony J , Serrano Geidy E , Suazo Crystal , Nolz Jennifer , Tallant Lauren , Plamondon Julie , Caron Alexandre , Beach Thomas G , Gundlach Andrew L , Mastroeni Diego 
Published: December 2023

AbstractBackgroundThe brainstem nucleus incertus (NI) or ‘uncertain nucleus’, was originally described by Streeter in 1903 as a midline region in the floor of the fourth ventricle of the human brain with an ‘unknown’ function. A century later, the NI has been shown to play a key role in memory formation in rodents, through direct and indirect inhibition of the hippocampus; and the anatomy of the NI and its projections throughout the brain have been systematically mapped in rats, mice, and primates, but not in humans. In these novel studies, we mapped the human NI using the neuropeptide, relaxin‐3 (RLN3), as neurochemical marker. In rodents, RLN3 is produced mostly in NI neurons with some subsidiary positive cells in the periaqueductal gray and an area dorsal to the substantia nigra.MethodsSerial, free‐floating coronal sections of formalin‐fixed postmortem tissue were prepared from the pons of an adult female (aged 96 years) without a history of dementia or other neurological disorders, provided by the Banner Brain and Body Donation Program, Sun City, Arizona, USA. Using immunohistochemistry, we first identified the NI by mapping the distribution of microtubule‐associated protein‐2 (MAP2) and RLN3. The specificity of the RLN3 antibody used was verified in a dot‐blot using native RLN3 peptide. We also investigated the presence of markers detected in the NI of rats ‐ glutamic acid dehydrogenase‐65/67 (GAD65/67) and corticotropin‐releasing factor type 1 receptor (CRF1); and used a phosphorylated‐tau (AT8) to determine if the NI displayed tau accumulation.ResultsDetection of MAP2‐immunoreactivity revealed the neuronal distribution throughout the pons. RLN3‐immunoreactivity was detected in neurons in the dorsal, anterior‐medial region, revealing the broad anatomy of the human NI. Neurons within this same area were also positive for GAD65/67‐ and CRF1‐immunoreactivity, in line with previous studies; and AT8‐immunoreactivity was also detected.ConclusionsRLN3 is present in neurons of the human NI and aspects of its anatomy are shared across species, including the macaque. Accumulation of phosphorylated‐tau in the NI suggests its possible involvement in the pathology of Alzheimer’s disease and related dementias. Further comparative studies are required to better understand the neurochemical anatomy of the human NI.
High dimensional Longitudinal Assessment of Ambient Home Environments and Their Association with Behaviors of People with Cognitive Decline
Authors: Au‐Yeung Wan‐Tai M. , Miller Lyndsey M. , Lindauer Allison , Rodrigues Nathaniel , Guerrero Cierra Leon , Marcoe Jennifer , Gothard Sarah , Steele Joel S. , Wu Chao‐Yi , Dodge Hiroko H , Beattie Zachary T , Kaye Jeffrey A 
Published: December 2023

AbstractBackgroundTroubling behavioral symptoms such as mood changes or agitation are highly prevalent during the course of Alzheimer’s disease and related dementias (ADRD). Effective management is dependent upon understanding the causes and precipitants of behavioral symptoms. The objective of our studies is to evaluate the role of the physical ambient environment in instigating symptoms.MethodParticipants are from two studies: 1) MOnitoring DEmentia‐Related Agitation Using Technology Evaluation (MODERATE) which focuses on agitation in people with later‐stage dementia, and 2) Monitoring Apathy, Depression and Anxiety Using Technology Evaluation (ADA) which focuses on apathy, depression and anxiety in older adults with or without cognitive decline. A commercially available, multifunction environmental sensor, Awair Omni, was deployed in the room where the participant sleeps, measuring levels of temperature, humidity, carbon dioxide (CO2), total volatile organic compounds (VOC), particulate matter 2.5 (PM2.5), noise and light every 5 minutes. Additionally, a multi‐sensor array (bed pressure mats, motion sensors, and wearables) is deployed in homes to objectively measure participants’ behaviors. Caregivers in MODERATE report agitation level/event experienced by their partners while participants in ADA self‐report their level of symptoms via weekly online surveys.ResultTo date, 9 dyads (persons with cognitive decline and their caregivers) have enrolled in MODERATE and 9 participants are enrolled in ADA. 3135 days of data have been collected for MODERATE while 849 days of data have been collected for ADA. Mean participant characteristics: age = 75±8 years; 48% women; Blind MoCA = 13.2±7.96. For 4 weeks from 12/19/2022 to 1/15/2023, ambient environmental conditions identified (mean±SD): temperature = 21 ±2.0°C; humidity = 41±7.6%; VOC = 195±263 ppm; CO2 = 651±225 ppm; particulate matter 2.5 = 2.4±13 µg/m3; noise = 52±4.3 dBA; light = 9.5±40 Lux. The home environments are individually heterogeneous with high variability over time across multiple environmental conditions. Reports of behavioral symptoms show high week‐to‐week variability as well. Proposed methods of analyzing such data include generalized linear mixed model.ConclusionThis in situ environmental sensing approach provides more objective and timely data to enable identifying the relationship between physical environments and the behaviors of older adults at risk of or with ADRD. The knowledge generated will help prevent or mediate symptoms by prospectively modifying environmental conditions.
Relationship between neurofilament light chain and cognitive decline moderated by amyloid‐β status
Authors: Kim Keun You , Shin Jiyoon ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundIn this study, we identified whether amyloid‐β (Aβ) moderates the relationship between the plasma level of neurofilament light chain (NfL) and the change of cognition or brain volume.MethodOf 723 non‐demented participants from the Alzheimer’s Disease Neuroimaging Initiative (mean age 72.1), 341 (47.2%) had cerebral Aβ deposition (Aβ [+]) and 382 (52.8%) had not (Aβ [‐]) determined by Florbetapir PET. Longitudinal changes of cognition was assessed by Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) score, and hippocampal and white matter hyperintensity volume by brain MRI.ResultAβ status moderated the relationship between plasma NfL and ADAS‐Cog score (beta = 0.002, P = 0.029), hippocampal volume (beta = ‐0.073, P = 0.004), and white matter hyperintensity volume (beta = 0.673, P = 0.048).ConclusionThese results suggest the possible interactive effect between plasma NfL and brain Aβ on the longitudinal cognition and brain structure.
Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network
Authors: Wagemann Olivia , Li Yan , Hassenstab Jason J. , Aschenbrenner Andrew J. , Benzinger Tammie L.S. , Gordon Brian A. , Wang Guoqiao , Karch Celeste M. , Renton Alan E. , Cruchaga Carlos , Morris John C , Xiong Chengjie , Perrin Richard J. , Levin Johannes , Daniels Alisha , Bateman Randall J. , McDade Eric , Llibre‐Guerra Jorge J 
Published: December 2023

AbstractBackgroundStudies suggest distinct differences in the development, presentation and longitudinal progression of Alzheimer’s Disease (AD) between women and men. However, most of these sex‐specific differences have been explored in symptomatic stages of sporadic AD. We investigated cross‐sectional sex differences in clinical‐cognitive assessments as well as fluid and imaging biomarkers in the spectrum of dominantly inherited AD (DIAD).Method319 DIAD mutation carriers of the Dominantly Inherited Alzheimer Network‐Observational study (DIAN‐OBS) were included in the analysis and, according to Clinical Dementia Rating® (CDR®) scores, classified as presymptomatic (CDR = 0, 66,1%) or symptomatic (CDR>0). All participants underwent clinical and neuropsychological assessment; lumbar puncture, structural MRI and 11C‐PiB‐PET imaging for amyloid‐β detection were conducted. Mann‐Whitney‐U‐test, Fisher’s Exact and linear mixed models with fixed effects for sex, estimated age of onset (EYO) and their interaction, a random effect for family, and years of education and CDR Sum of Boxes as covariates (where appropriate) were used to explore cross‐sectional sex differences.ResultDemographics showed no significant sex differences in presymptomatic (pMC, 56.4% women, p>0.05) or symptomatic mutation carriers (sMC, 52,7% women, p>0.05). In pMC, men showed a worse performance on the Digit Symbol test (p<0.01, Fig.1) than women, and, in interaction with EYO, a better performance in immediate (p<0.05) and delayed (p<0.05) prose recall. In contrast, sMC men performed better on the Animal Naming test (p<0.05), but, in interaction with EYO, worse on the Digit Span forward (p<0.01). CSF analysis did not indicate sex‐related differences in Aβ42/Aβ40‐Ratio, phosphorylated Tau‐181 or total Tau levels (all p>0.05) in either group. In pMC men, PET imaging revealed significantly less tracer binding in the medial orbitofrontal cortex, the frontal pole and the rostral & caudal anterior cingulate in interaction with EYO (all p<0.05, Fig. 2). Furthermore, MRI volume analysis showed a significant reduction in the amygdala in women compared to men (p<0.01) in sMC.ConclusionWe report preliminary results suggesting cross‐sectional sex differences in presymptomatic and symptomatic DIAD mutation carriers regarding episodic, verbal and working memory; processing speed; as well as differential patterns of PiB‐PET burden within cerebral areas related to emotion, decision making and cognitive flexibility.
Brain‐Penetrable Antibody Probes for in vivo Tau Imaging
Authors: Kelleher Andrew , Richardson Brandon , Banka Vinay , Sehlin Dag , Hultqvist Greta , Sigurdsson Einar M. , Syvänen Stina , Ding Yu‐Shin ,   Ding’s Research Group
Published: December 2023

AbstractBackgroundAntibody‐based PET ligands are desirable due to their high specificity; however, their brain uptakes are limited by the blood‐brain barrier (BBB). We previously demonstrated that transport of antibody across BBB can be facilitated through interaction with the transferrin receptor (TfR)1. We report here the first in vivo PET imaging studies using BBB permeable F‐18 radiolabeled bispecific antibodies specific to tau protein in mice.MethodWe performed multiple PET scans using each of the radio‐probes synthesized via conjugation of [18F]SFB with one of the four bispecific antibody constructs: 1) 6B2G12‐ScFv8D3 (full‐size Tau antibody conjugated with TfR fragment (ScFv8D3); abbreviated as TAUb), 2) ScFv235‐ScFv8D3 (small Tau‐TfR; TAUs), 3) 3D6‐ScFv8D3 (full‐size Aβ‐TfR; Aβb) or 4) ScFv3D6‐ScFv3D6 (small Aβ‐TfR; Aβs). We used a matched control design to compare a WT with one of the two types of transgenic (tg) tauopathy mice [PS19 (P301S) or JNPL3 (P301)] in each scan. Subjects were scanned on a MOLECUBES PET/CT scanner. An initial low‐dose (244 ± 54 μCi) dynamic scan (30 min) was performed, followed by two scans at 8hr and 12hr (20 min each static scans) after injection of a high dose (1832 ± 447 μCi) of the same probe. PMOD and FireVoxel were used for imaging processing. After co‐registration of PET/CT/atlas, data were quantified as SUV and SUVR [CB as a reference], and clearance was estimated as %change/hr.ResultTAUs probe displayed highest brain uptake with more specific binding retained in the brain, as compared to TAUb and Aβs. TAUs probe showed faster brain penetration in tau‐tg mice than in WT, with differences in amygdala, basal forebrain, and hypothalamus of 66%, 62% and 85%, respectively, at 8hr post‐injection (Fig. 1). Further, higher brain uptakes (TAUs > Aβs) in the same tau‐tg mouse (Fig. 2) suggest the specific binding of TAUs probe, while Aβs probe can serve as a control due to its lack of specific binding in tau‐tg mice.ConclusionWe have successfully synthesized and evaluated four novel F‐18 bispecific antibodies via in vivo PET. TAUs probe showed most promising BBB permeability and binding specificity to tau antigen with a reasonable clearance.