bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial experiences with amyloid‐related imaging abnormalities in patients receiving aducanumab following accelerated approval
Authors: Howe Matthew D. , Britton Karysa J. , Joyce Hannah E , Faust Melanie A. , Dawson Brittany C. , Riddle Meghan C. , Salloway Stephen 
Published: December 2023

AbstractBackgroundAducanumab is the first approved amyloid‐lowering immunotherapy for Alzheimer’s disease (AD). There is little real‐world data to guide the management of amyloid‐related imaging abnormality (ARIA), a potentially serious side‐effect requiring surveillance with serial magnetic resonance imaging (MRI). The current study seeks to characterize the symptoms, clinical course and management of ARIA in memory clinic patients treated with aducanumab.MethodWe conducted a non‐blinded, observational case series of patients who received aducanumab from June 16, 2021 to August 1, 2022 at the Butler Hospital Memory and Aging Program. Inclusion: (1) Clinical diagnosis of mild cognitive impairment (MCI) or mild dementia due to AD, (2) confirmed amyloid positivity (PET/CSF), and (3) Mini Mental State Exam (MMSE) = 20‐30. Exclusions: (1) MRI with > 4 microhemorrhages, > 1 area of superficial siderosis or significant cerebrovascular disease, (2) MRI contraindication, (3) anticoagulation and (4) unstable medical/psychiatric conditions. Participants received monthly aducanumab infusions, titrated to a dose of 10 mg/kg, with ApoE genotyping and enhanced MRI monitoring adapted from the phase 3 trials. The primary outcome of the study was the identification of ARIA‐E by MRI. Secondary outcomes included severity of ARIA, clinical course, and time to resolution.ResultOut of 24 patients treated with aducanumab, we identified ARIA‐E in 6 patients (25%), all ApoE‐ε4 carriers, and 4 of whom had moderate‐severe radiographic severity. Comorbid ARIA‐H occurred in 3 patients, 1 of whom also had new onset of cerebellar metastatic cancer. Symptomatic ARIA occurred in 3 patients and included headache, confusion, gait instability, and word‐finding difficulties. Treatment was discontinued in 4 cases of moderate‐severe ARIA‐E, temporarily held in 1 moderate/asymptomatic case, and dosed through in 1 mild/asymptomatic case. All cases of ARIA‐E resolved without hospitalization or corticosteroids (mean duration = 3 months, range, 1 ‐ 6 months).ConclusionAdditional amyloid‐lowering antibodies, associated with ARIA, may soon become clinically available. These data support the careful patient selection, ApoE genotyping, MRI surveillance and individualized dosing recommended in the updated FDA prescribing information and Appropriate Use Recommendations.
Synthetic FDG‐PET hypometabolism sensitivity validation in AD
Authors: Collin‐Castonguay Pénéloppe , Gourdeau Daniel , Potvin Olivier , Duchesne Simon 
Published: December 2023

AbstractBackgroundThe availability of 18‐F fluorodeoxyglucose positron emission tomography (FDG‐PET) is not universal. We hypothesized that synthetically generated FDG‐PET images would be as sensitive to detecting the pattern of hypometabolism associated with AD as real images.MethodWe developed a deep learning‐based method to produce synthetic FDG‐PET images from 1,828 T1‐weighted MRI / real FDG‐PET image pairs from the ADNI dataset, and validated the technique on a further 284 image pairs. The technique generated synthetic FDG‐PET images which were then processed to compare Standardized Uptake Value Ratio (SUVR) with the pons as reference in 81 brain regions as defined in the Desikan‐Killiany‐Tourville and subcortical default FreeSurfer atlases.ResultWe tested the differences between synthetic and real FDG‐PET on 745 image pairs (205 controls, 365 mild cognitive impairment (MCI) and 175 AD)(Table 1). Correlations in SUVR values between synthetic and real FDG‐PET ranged between weak (r = 0.13) to strong (r = 0.63), with moderate results in key regions for AD (bilateral precuneus, r = 0.43; bilateral posterior cingulate, r = 0.37). There were significant between‐group (control vs MCI and control vs AD) differences in SUVR values for all regions between synthetic and real PET‐FDG (Figure 1) with synthetic FDG‐PET having lower values. Inter‐group effect sizes were not significantly different in the majority of brain regions (76/81)(Figure 2), with similar effect sizes in the right precuneus (synthetic: ‐0.98 vs original: ‐1.37), left (‐0.77 vs ‐1.0459) and right (‐0.80 vs ‐1.04) posterior cingulate, but different for the left precuneus (‐0.91 vs ‐1.33).ConclusionSynthetic images would increase patients’ accessibility to a meaningful modality for disease assessment while decreasing their exposure to radiation and resources in the health care system.
Assessing bidirectional longitudinal associations between changes in social network structures and cognitive decline in late life
Authors: Zhang Yun , Clouston Sean A.P. , Hou Wei , Scott Stacey B , Smith Dylan 
Published: December 2023

AbstractBackgroundThe role of social networks in maintaining cognitive health is unclear, in part because few longitudinal studies have explored bidirectional associations between changes in social network structures and cognition.MethodSecondary analyses of data collected during nine waves of the National Health and Aging Trends Study (NHATS; 2011‐2019) were conducted. Global cognition was the main outcome, but domain‐specific analyses examined episodic memory, orientation, and executive function. Linear mixed models were used to investigate longitudinal effects of neighborhood social cohesion and physical environment on cognitive decline. Dual‐outcomes models were used to examine bidirectional associations between social network structures and cognitive decline. Covariates included socioeconomic status, physical measurements, mental health, and lifestyle indicators.ResultEligible participants (N = 7,325) were recruited at baseline and followed for an average of 4.86±3.22 years. Bivariate correlations indicated that slopes of changes in social networks or participation and cognitive decline were positively correlated. Having more friend ties and a higher percentage of college graduates at baseline were associated with slower declines in global cognition and episodic memory, whereas higher global cognition at baseline was associated with smaller changes in social network size. Less disorientation at baseline was associated with a slower decline in social participation.ConclusionFindings indicate bidirectional longitudinal relationships between social network structure and cognitive decline. Social networks may improve cognitive health but are also vulnerable to cognitive decline related to disorientation.
Vitamin B12 deficiency and cognitive impairment: Is there a distinctive cognitive domain affected? A descriptive study in Buenos Aires
Authors: Boccazzi Julian Fernandez , Rojas Galeno , Guillen Jonathan Cubas , Gatto Emilia , Persi Gabriel Gustavo , Hierro Xavier Merchan , Aldinio Victoria , Seguí Josefina , Camino Victoria , Muniagurria Santiago , Gilbert Afra , de Silva Nahuel Pereira , Eizaguirre Barbara 
Published: December 2023

AbstractBackgroundVitamin B12 deficiency is associated with cognitive‐behavioral disorders, which may be potentially reversible. No specific associated cognitive domain has been established and alterations in episodic memory, verbal fluency, attention and executive functions, praxia and visuoconstruction have been described. The objective of this work is to evaluate and describe the cognitive domains affected in patients with cognitive impairment associated with vitamin B12 deficiency.MethodCross‐sectional observational study conducted at the Trinidad Mitre sanatorium of Buenos Aires City. Patients with cognitive impairment and vitamin B12 deficiency were analyzed. Information was collected on the cognitive domain affected (taking as altered value the Z score ≤‐1.5 according to age and educational level, obtained in the neurocognitive evaluations), cognitive profile, magnetic resonance imaging features and mean consultation‐supplementation time.Result25 patients with vitamin B12 deficiency and cognitive complaint were analyzed, with a mean age of 68.5 years. 83% presented multidomain mild cognitive impairment being 60% with subcortical pattern. Memory and attention were the most affected domains in 80% of the sample, followed by executive functions with 52%. The most deficient tests were the direct digit test (68%), serial memory (56%), deferred logical memory (52%) and Trail Making B (52%). Nearly 52% presented mild depressive symptomatology. A 56% of the sample presented with severe B12 deficiency with 32% elevation of plasma homocysteine. Supplementation was performed intramuscularly in 68% of the patients with a mean symptomatology‐supplementation onset time of 10.8 months. 92% of the patients presented subjective improvement after supplementation, 32% had control global test evaluation with improvement in all of them and 50% of this group presented control cognitive evaluation with improvement in previously deficient domains.ConclusionAccording to our findings we conclude that these patients with vitamin B12 deficiency present a multidomain pattern with special affectation of memory, attention and executive functions; of mild degree and potentially reversible. The reversibility of the picture could be related to high doses of B12 and early supplementation, using control cognitive assessments as an objective measure of improvement.ReferencesReynolds E. Lancet Neurol. 2006 Nov;5(11):949‐60. Eastley R. Int J Geriatr Psychiatry. 2000 Mar;15(3):226‐33. Robins Wahlin. Biol Psychol. 2001 Jun;56(3):247‐65.
Naturalistic Assessment of Reaction Time Variability in Older Adults at Risk for Alzheimer’s Disease
Authors: Welhaf Matthew S. , Wilks Hannah M , Aschenbrenner Andrew J. , Schindler Suzanne E. , Benzinger Tammie L.S. , Gordon Brian A. , Cruchaga Carlos , Morris John C , Hassenstab Jason J. 
Published: December 2023

AbstractBackgroundBreakdowns in attentional control may underscore cognitive changes seen in the earliest stages of Alzheimer’s disease (AD). One way to measure these changes is to assess variability in cognitive performance. Variability in cognition may be most evident when repeatedly sampled over hours or days and in different environmental contexts or at different times of day. We analyzed data from an ongoing smartphone‐based study of cognition in AD which utilizes extremely brief cognitive tests taken remotely over several days in natural environments.MethodOlder adults (N = 319, aged 75 +/‐ 5 years) completed repeated cognitive testing on the Ambulatory Research in Cognition (ARC) platform and had CSF or PET amyloid biomarkers and APOE genotype available. RTSD was assessed in a brief processing speed task by taking the SD of correct RTs. All models adjusted for baseline age, education, and gender.ResultAveraging across sessions, symptomatic participants (indicated by Clinical Dementia Rating® (CDR®) > 0) showed more variability than asymptomatic (CDR 0) participants (p = 0.009). APOE ε4 carriers showed more variability than non‐carriers, although this was not significant (p = 0.067). More fine‐grained models considered RTSD within each session (e.g. from trial‐to‐trial) using mixed effects models. Symptomatic participants exhibited greater trial‐to‐trial RTSD compared to asymptomatic participants (p = 0.001). APOE ε4 carriers also exhibited greater trial‐to‐trial RTSD compared to non‐carriers (p = 0.004). When limiting the sample to asymptomatic participants to determine if there were changes in the preclinical stage of AD, there remained a strong APOE ε4 effect, with carriers exhibiting greater trial‐to‐trial RTSD than non‐carriers (p = 0.005). Interestingly, amyloid was not significant in any models.ConclusionOlder adults at risk for AD show increased RTSD even in brief assessments. These subtle fluctuations in attention were most evident in APOE e4 carriers at very short time intervals, and less so when averaged across trials and sessions. Overall, these findings suggest that fluctuations in attention in preclinical AD are most evident from moment to moment, highlighting the need for fine‐grained and repeated assessment of attentional control.
Identification of genetic regions associated with Alzheimer ‘s disease blood‐based biomarkers in Mexican American families
Authors: Almeida Marcio A 
Published: December 2023

AbstractBackgroundDementias are heterogeneous age‐associated neurodegenerative disorders generally included in the broad term, Alzheimer’s disease (AD) and related dementias (ADRD). ADRD affects individuals of all ethnicities, but Hispanic individuals show a 1.5‐fold higher risk when compared to non‐Hispanic whites. Many AD risk biomarkers have been proposed but not much is known about how genetic elements control their expression. We used 2000 genome sequenced Mexican Americans from extended pedigrees to identify genetic regions associated with AD blood‐based biomarkers.MethodA total of 70 Mexican American subjects were diagnosed as ADRD cases (h2 = 0.75, p = 2.6×10−5). We quantified plasma concentrations, using a QuanterixÒ elisa assay, of four AD candidate biomarkers AB40, AB42, TAU and NFL. We identified genomic regions associated with these biomarkers using a linear mixed model as implemented in SOLAR on a set of 28 million SNPs. Our genetic variance decomposition model is tailored for relatively rare diseases where extended pedigrees are available. Candidate SNPs identified were extensively annotated and their individual eQTL contribution to the expression of flanking genes defined.ResultThe heritability component of each AD biomarker was defined, and the most significant estimate observed for NFL (h2 = 0.33, p = 6.96×10−17). We tested the association between circulating tau and identified two genome‐wide significant associations for SNPs rs242557 (3.11×10−14) and rs242562 (1.34×10−13)(Figure 1). Both SNPs are common and located in the first and second introns of the gene MAPT, respectively, and are in a conserved region with chromatin accessibility for transcription factors, suggesting regulatory functions (Figure 2). We tested the association between both SNPs and flanking gene expression, identifying strong evidence of cis‐regulation with the expression of the antisense‐RNA (KANSL1_AS1) of the gene KANSL1.ConclusionThe identification of genetic variants associated with AD biomarkers is key to providing a reliable and cost‐effective genetic test for AD risk for the Hispanic population. The gene KANSL1 encodes a subunit of a histone acetylation enzyme and has been associated with Koolen‐de Vries Syndrome and cognitive impairment. The genetic associations are promising, but demand an independent validation to confirm their impact for the AD risk estimation.
Associations of plasma GFAP, NfL, and p‐tau231 with early‐onset Alzheimer’s Disease pathology
Authors: Logan Paige E. , Dage Jeff L. , Hammers Dustin B. , Manchella Mohit K. , Eloyan Ani , Mundada Nidhi S. , La Joie Renaud , Iaccarino Leonardo , Fagan Anne M. , Foroud Tatiana M. , Zetterberg Henrik , Blennow Kaj , Koeppe Robert A. , Aisen Paul S. S , Carrillo Maria C. , Rabinovici Gil D. , Dickerson Brad C. , Apostolova Liana G. 
Published: December 2023

AbstractBackgroundIncreased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this population. We aimed to demonstrate the effect of each biomarker on EOAD pathology by investigating their associations with amyloid burden, tau burden, and gray matter density (GMD).Method183 EOAD participants from the Longitudinal EOAD study with available baseline plasma GFAP, NfL, p‐tau231, MRI, amyloid PET, and tau PET data were included (mean age = 58.7, 55.2% female, 54.1% APOE‐ε4 carrier, mean MMSE = 21.9). Voxel‐wise multiple linear regression models of amyloid PET, tau PET, and T1‐weighted MRI images yielded statistical maps with GFAP, NfL, or p‐tau231 as predictors. Covariates were hierarchically added: Model 1: age, sex; Model 2: age, sex and APOE‐ε4; Model 3: age, sex, APOE‐ε4 and MMSE. All models are displayed at a family‐wise error adjustment of p<.05.ResultHigher levels of GFAP, NfL, and p‐tau231 were significantly associated with greater amyloid burden and tau burden. Higher levels of GFAP and NfL were also significantly associated with lower GMD. No significant associations were found for p‐tau231 and GMD (Figures 1, 2 & 3). When controlling for APOE‐ε4 carrier status, the effect of GFAP on amyloid burden was no longer significant (Figure 1). After additionally controlling for MMSE, the effects of NfL and p‐tau231 on amyloid burden were no longer significant, while the effects of all three biomarkers on tau burden were reduced but remained significant. In terms in of GMD, the effect of NfL survived correction for dementia severity, while the effect of GFAP did not.ConclusionThese results suggest that all three plasma biomarkers show stronger associations with neurodegeneration (cortical atrophy and/or tau burden) than with amyloid burden. Furthermore, this study highlights the importance of plasma biomarkers for AD diagnosis and monitoring. Future work should investigate longitudinal associations and the mediational role of APOE‐ε4 and dementia severity.
Continuum of measurement: Reviewing the advantages and disadvantages of self‐administered remote cognitive tests and their examiner administered alternatives
Authors: Ho Emily 
Published: December 2023

AbstractBackgroundFour in 10 older adults own a smartphone in their 60s and beyond (Pew Research; 2017). Correspondingly, there has been surging interest in using digital cognitive assessments remotely to inform clinical and research practice with older adults and more comparisons between self‐ and examiner‐administered tests are needed.MethodAs part of a larger study, 1120 adults completed a battery of remotely administered tests (Mobile Toolbox) and a subset of this sample completed examiner administered in‐person testing (NIH Toolbox Cognition Battery). Attention was given to making the sample reflective of the US 2020 Census during participant recruitment. Of the 1120 participants, the majority of the sample were female (57%) and Caucasian (72%) and had a mean age of 45 (SD = 21). In terms of education, equal percentages had high school (34%) or some college (34%).ResultCognitive tests of processing speed, language, executive function, attention, and episodic memory were administered via a trained examiner and correlates of these tests were self‐administered remotely via a smartphone. Using examples, we will show which aspects of cognitive assessment had the best correlations between remote self‐administration and face‐to‐face examination and which had lower correlations.ConclusionFor geriatric individuals, remote assessments can be used to help over barriers for care, such as difficulty getting to the office location due to limited mobility or lack of transportation. Remote assessments reduce participant burden and expense and increase research accessibility for older adults. Capitalizing on the omnipresent nature of internet‐connected devices, this improves opportunities to remotely monitor other dimensions relevant to cognition using smartphone apps and wearable sensors. In addition to improving access to testing, digitally administered assessments dramatically improve some individual’s tolerance to testing with shorter tests that can be administered via computer adaptive testing (CAT). Despite these benefits, some aspects of the cognitive assessment cannot be adequately replicated remotely and thus yield lower correlations to their examiner‐administered alternatives. Clinical and research implications are discussed.
Mobile Toolbox cognitive tests: validity and reliability in three samples
Authors: Nowinski Cindy J. , Kaat Aaron J. , Novack Miriam , Slotkin Jerry , Hosseinian Zahra , Adam Hubert , Gershon Richard C. 
Published: December 2023

AbstractBackgroundThe Mobile Toolbox (MTB), an app‐based assessment platform, enables completely remote, self‐administered assessment using participants’ own smartphones. We present psychometric evidence for eight MTB cognitive measures assessing language, working memory, episodic memory, executive function, and processing speed.MethodThree samples were used to evaluate convergent validity, age‐related change, internal consistency and test‐retest reliability. Sample I consisted of 94 adults ages 18‐85 who were administered “gold standard” cognitive measures followed by self‐administered MTB. Sample II, recruited for norming, included 1,020 participants ages 18‐90 who completed MTB measures remotely. Sample III was a convenience sample of 800 participants who completed MTB remotely with retest after 7, 14, or 21 days. Pearson correlation coefficients between MTB and external measures were used to evaluate convergent validity. Internal consistency was evaluated using measure‐appropriate tests: split‐half reliability, Cronbach’s alpha or IRT‐based indices. For measures with timing‐dependent scores, separate analyses were performed for iOS and Android devices. Spearman correlation coefficients were calculated to evaluate relationships between age and test scores.ResultConvergent validity data from Sample I (64% female, 52% white, 99% non‐Hispanic, age = 48+/‐18) revealed moderate to strong correlations between MTB test scores and performance on external measures of similar constructs (Table 1). Table 2 shows results derived from Sample II (44% female, 13% Hispanic, 74% white, age = 45+/‐22). Internal consistency estimates ranged from 0.69 to 0.98. On timed tests, Shape‐Color Sorting and Arrow Matching showed significant score differences between Android and iOS devices when controlling for age. However, internal consistency was equivalent between the two, as indicated by overlapping confidence thresholds (Table 3). Performance on executive function, processing speed, and some memory tasks negatively correlated with age. Word Meaning scores improved with age while Spelling remained stable. Test‐retest reliability, using preliminary Sample III data, ranged from 0.47 (memory tests) to 0.86.ConclusionInitial studies, using three diverse samples, support the validity and reliability of the first eight MTB cognitive measures. MTB tests showed satisfactory internal consistency and convergent validity and most measures correlated with age in the expected directions. Our results support the use of MTB in cognitive research.