bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alcohol consumption and cognitive impairment among Chinese older adults: 8‐year follow‐up of Chinese Longitudinal Healthy Longevity Study
Authors: Zhao Ziyi , Li Bingyu , Wei Chang , Sha Feng 
Published: December 2021

AbstractBackgroundThis is the first study examining the association between alcohol consumption and risk of cognitive impairment (CI) among Chinese older adults (65‐79 years).MethodThe study included 5,894 participants between 65 and 79 years from 2002‐2008 Chinese Longitudinal Healthy Longevity Study (CLHLS). The CI was assessed by Chinese version of Mini‐Mental State Examination (MMSE) . The self‐reported alcohol type and consumption were assessed and converted into pure alcohol consumption in gram. The adjusted cox proportional hazard model was implemented with age as time scale. With abstainers as the reference, hazard ratio (HR) for cognitive impairment was calculated for five levels of alcohol consumption (former drinker, 0.1‐175.0 g for male/0.1‐105.0 g for female per week, 175.1‐350.0 g for male/105.1‐210.0g for female per week, 350.1‐525.0 g for male/210.1‐315.0 g per week, >525.0 g for male/>315.0 g for female per week).Result837 (14.2%) participants developed CI in the follow‐up waves with mean follow‐up of 7.9 (SD 4.6, range 0.17‐17.3) years. There was no evidence that low‐to‐moderate alcohol consumption (0.1‐175.0 g for male/0.1‐105.0 g for female per week) was associated with increased risk of CI (HR: 1.25, 95% CI: 0.91‐1.74); however, heavy alcohol use (>525.0 g for male/>315.0 g for female per week) was associated with increased risk of CI (HR: 1.37, 95% CI: 1.01‐1.84). Compared with abstainers, former drinkers had higher risk of cognitive impairment (HR: 1.50, 95% CI: 1.17‐1.92). In addition, among former drinkers, previous consumption of alcohol above 175.0 g/week for male and 105.0 g/week for female was associated with higher incidence of dementia (HR: 1.61, 95% CI: 1.22‐2.11).ConclusionExcess alcohol consumption in men (>525.0 g/week) and in women (>315.0 g/week) are both significantly associated with increased risk of CI. There is no evidence that low‐to‐moderate alcohol drinking had protective effect against CI. Among former drinkers, heavy drinkers have higher risk of CI compared to non‐drinkers, suggesting heavy consumption of alcohol negatively influences one’s cognitive health in later life even after abstinence. Further investigation is required to determine whether these relationships are mediated by specific environmental or genetic factors.
Plasma and CSF biomarkers for Alzheimer’s disease among Caribbean Hispanics
Authors: Honig Lawrence S. , Kang Min Suk , Reyes‐Dumeyer Dolly , Lantigua Rafael A. , Zerlin‐Esteves Marielba , Piriz Angel , Criollo Brian , Dominguez Zoraida , Recio Patricia , Rivera Diones , Medrano Martin , Mayeux Richard 
Published: December 2021

AbstractBackgroundBiomarkers provide earlier and more accurate diagnoses of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) biomarkers have proven highly specific and sensitive in research studies (e.g. ADNI, BIOFINDER), although often including mostly well‐educated, white non‐Hispanics without co‐morbidities. CSF testing also requires lumbar puncture, so blood testing would be of great value. Here we examined a Caribbean Hispanic cohort, with measurements of both plasma and CSF biomarkers of amyloid (Aβ42, Aβ40), tau (p‐tau181), and neurodegeneration (t‐tau, NfL).MethodStudy cohort included individuals of Caribbean Hispanic ancestry (N = 123; 45 [37%] men, 78 [63%] women) enrolled in the Dominican Republic or New York City, who underwent venipuncture, lumbar puncture, and neurological assessments. Average age was 69.5 yr (sd 8.0; range 45‐91); APOE e4 genotypes were 50% without e4, 30.2 % e4 heterozygous, and 19.8% e4 homozygous. Clinical diagnoses included non‐demented (54%), mild cognitive impairment (MCI, 21%), and dementia (25%). No individuals had non‐AD dementias, so MCI and dementia were combined as “AD” (46%). Samples were stored at ‐80C, and assayed in duplicate (average coefficients of variation 4‐7%) on the Simoa SR‐X platform (Quanterix), using Neurology 3‐Plex A kits for Aβ42, Aβ40, and t‐tau, and separate assay kits for p‐tau181 and NfL. Ratios of Aβ42/Aβ40, t‐tau/Aβ42, and p‐tau181/Aβ42 were also calculated. Regression and ROC analyses were performed, including models adjusting for age, gender, and number of APOE e4 alleles, using IBM SPSS 27.ResultOverall, individuals with AD showed elevated levels of both plasma and CSF t‐tau, p‐tau181, and NfL. There was significant correlations between plasma and CSF for p‐tau181 (r=0.45, p<0.0001), for NfL (r=0.62, p<0.0001), and for plasma ratios Aβ42/Aβ40 (r=0.33, P<0.001), t‐tau/Aβ42(r=0.34, p<0.001) and p‐tau181/Aβ42 (r=0.39, p<0.0001) but not for plasma Aβ40, Aβ42, or t‐tau individually. Plasma analytes performed moderately well, especially p‐tau181 and NfL, better than CSF, in classifying persons with cognitive impairment, with ROC areas under the curve (AUC) of 74.4% and 73.2% respectively. Plasma ratios of Aβ42/Aβ40, t‐tau/Aβ42, and p‐tau181/Aβ42 did not perform as well.ConclusionPlasma p‐tau181 and NfL biomarkers performed well in classifying AD, in comparison to CSF biomarkers, in this Caribbean Hispanic cohort.
Connectome‐based predictive modeling of cognitive reserve
Authors: Boyle Rory , Connaughton Michael , McGlinchey Eimear , Knight Silvin P. , De Looze Celine , Carey Daniel , Stern Yaakov , Robertson Ian H. , Kenny Rose Anne , Whelan Robert 
Published: December 2021

AbstractBackgroundCognitive reserve (CR) enables individuals to maintain cognitive function despite the presence of pathology or atrophy. CR may be most directly measured using functional neuroimaging. Connectome‐based predictive modeling can develop measures of cognitive phenotypes using task‐fMRI that can be applied to resting‐state fMRI, which is easier to collect and unaffected by task‐related confounds. We aimed to develop and validate a CR measure that could be applied to resting‐state fMRI data.MethodPaper Folding task‐fMRI scans from 220 participants of the Cognitive Reserve/Reference Ability Neural Network studies formed a training set. Resting‐state fMRI scans from 294 participants from The Irish Longitudinal Study on Ageing formed a test set. fMRI data were preprocessed, motion‐corrected and parcellated into 205 nodes using the Shen atlas, excluding 63 brainstem and cerebellar nodes due to incomplete coverage. Functional connectivity matrices were calculated via Fisher z‐normalised correlations between the mean time series of each node‐pair.Connectome‐based predictive modeling with leave‐one‐out cross‐validation was used to predict a CR residual from task‐based functional connectivity in the training set (Fig. 1). This generated three network‐strength predicted CR measures. We established the validity of these measures via a positive correlation with a CR proxy (NART scores) and global cognition, independent of brain structure. We then applied the model to the test set and assessed the validity of the resulting network‐strength measures.ResultThe three network‐strength measures accurately predicted the CR residuals of unseen participants (Fig. 2) and demonstrated validity as they were positively correlated with NART scores (Fig. 3) and global cognition, independent of brain structure. However, application of the model to the resting‐state data in the test set did not generate accurate predictions of the CR residual (Fig. 4) and the resulting measures did not correlate with NART scores nor global cognition (Fig. 5).ConclusionValidated measures of CR were generated using task‐based fMRI data but these measures did not generalise to resting‐state fMRI from an independent dataset. The inability to generalise may be because CR involves a reorganisation of connectivity in response to task demands or that the data here excluded the cerebellum.
No evidence for amyloid in the retina of Alzheimer's disease patients
Authors: den Haan Jurre , de Ruyter Frederique Jasmine Hart , Lochocki Ben , Kroon Maurice A.G.M. , Kemper Marleen , Scheltens Philip , Verbraak Frank , de Boer Johannes , Bouwman Femke H. 
Published: December 2021

AbstractBackgroundThe retina is increasingly recognized as a promising target to identify early changes associated with Alzheimer’s disease (AD). Previous studies showed presence of retinal amyloid in AD patients in‐vivo as well as in post‐mortem retinal tissue of AD patients. The objective of this study is to non‐invasively discriminate AD patients from controls with fluorescent retinal imaging, using curcumin as labeling fluorophore.Method26 AD patients (age 66(+9), MMSE≥18) and 14 controls (age 71(+12)) were enrolled from a tertiary memory clinic. Subjects were confirmed amyloid positive or negative based on CSF analysis and/or amyloid PET. We used three curcumin formulations: Longvida (10 days 4000 mg), Theracurmin (5 days 180 mg) and Novasol (4 days 300 mg). Plasma levels of curcumin and its derivatives were determined. Baseline and follow up scans of 2‐6 retinal regions were performed with blue autofluorescence imaging (λ = 486nm). Retinal images were visually assessed in a multidisciplinary setting. In addition a selection of retinal scans of participants receiving Longvida and Novasol were quantitatively analyzed.ResultPlasma analysis yielded mean curcumin levels of 198.7 (±143.4) with Longvida, 576.6 nM, (±211.5) with Theracurmin and 1605.8 nM (±524.6) with Novasol. Visual analysis of baseline images showed no focal hyperfluorescence or other changes in AD‐patients compared to controls. Also, no differences were found when comparing pre‐and post‐curcumin images within AD patients and controls. Quantitative analyses confirmed a similar amount of focal hyperfluorescent spots in AD patients and controls. In addition no difference in increase of focal hyperfluorescence after curcumin intake could discriminate between AD patients and controls.ConclusionWe found no focal retinal hyperfluorescence in AD patients or controls pre‐and post curcumin, even when using curcumin formulations that yielded higher plasma levels than Longvida, a formulation previously successfully used for this purpose. Implication: More and more initiatives are taken to assess retinal amyloid in AD patients and currently even commercial scans are brought to the market. We could not confirm that retinal changes described in previous studies represent retinal amyloid, and we were unable to replicate previous work discriminating AD patients from controls based on retinal amyloid visualization.
Is item response theory superior to classical test theory in scoring A‐IADL?
Authors: Negash Selam , Liu Cong , Randolph Christopher 
Published: December 2021

AbstractBackgroundThe Amsterdam IADL Questionnaire (A‐IADL‐Q) is increasingly being used in Alzheimer disease (AD) trials to assess activities of daily living. The authors of this scale (Sikkes et al., 2012) originally proposed an Item Response Theory (IRT) based scoring. While such an approach has some potential advantages, it requires a complex model, assumptions about population score distributions, and can be difficult to interpret clinically. An alternative to IRT scoring is the Classical Test Theory (CTT) method, which is relatively simple and easier to interpret. The present study compared IRT and CTT for scoring A‐IADL as a function of global cognition in healthy older adults and patients with mild‐to‐moderate AD.MethodAggregated data from three multinational clinical trials including subjects at the preclinical, early symptomatic, and moderate dementia phase of AD were analyzed. A‐IADL and CDR assessments at initial visits were evaluated and participants were classified into three groups based on CDR Global Scores: 0, 0.5, and 1. For IRT scoring, Graded Response Model (GRM) was used to estimate individual’s latent score. For CTT method, scaled average of scored responses were calculated. ROC analysis was conducted to evaluate the utility of each method in distinguishing between CDR groups.ResultThere were a total of 2,694 A‐IADL assessments across the three CDR groups. There was a very high correlation between CTT and IRT estimates of A‐IADL total score (r = 0.996, p < 0.05). As CDR Global Score increased, A‐IADL scores declined for both methods. In IRT scoring, the Item Characteristics Curve showed an overlap for most item responses, and the test information curve was narrow with a peak to the right of theta 0. Importantly, the ROC curve showed slightly better performance for CTT [AUC: 0.829 (0.812‐0.847)] compared to IRT [AUC: 0.809 (0.788‐0.830)].ConclusionThe current study found that CTT scoring of A‐IADL performed slightly better in distinguishing AD populations as a function of global cognition/function. Given the procedural complexities and required assumptions for IRT scoring, the CTT method, which has the advantages of being more straightforward and familiar to clinicians, represents a better choice for most applications of this instrument.
EEG power bifurcation in the transition zone beta to gamma — from motor function to cognition — in Alzheimer and long COVID patients versus healthy controls revealed by quantitative EEG time series analysis of lateral EEG data
Authors: Wirner Frank , Fritsch Thomas , Scheuplein Sebastian , Dazian Dieter 
Published: December 2021

AbstractBackgroundSimilar EEG abnormalities suggest a nexus from Long COVID (LC) to Alzheimer‘s (AD) and probably to Parkinson‘s disease (PD). Symptoms like memory loss hint to a common cause. Ranasinghe (2020) showed EEG alpha slowing and hyper‐ and hyposynchrony for AD. In LC generalized EEG slowing (Antony, 2020) was reported. There is evidence that switching between brain hemispheres is necessary for scenery and object processing (Brincat, 2021), being disturbed in AD (Maass, 2020). However, explicitly lateral EEG for AD is rarely investigated. We calculate frontal asymmetry index (FAI) for F4/F3 EEG electrodes, which is normally used at alpha frequency for assessing emotional states in major depression (Davidson, 1998), not only for alpha but for further frequencies of AD patients. This possibly yields new biomarkers for AD and LC.MethodFAI := logarithm of quotient between F4/F3 power, calculated for frequencies up to 120Hz of AD data taken from (Valladolid, Abasolo, 2017) and (Naples, Babiloni, 2018). AD and healthy control (HC) resting state EEG data from Valladolid were semi‐automatically artifact‐corrected and subdivided into 5s‐epochs. For AD patients and HCs the average of all 5s‐epochs was used for FAI. We recently determined power spectra and FAI from full‐length 10min resting‐state EEG for an LC patient, suffering from tremor. EEG power was calculated by averaged 5s‐epochs of raw‐data for F4/F3 for frequencies up to 100Hz.ResultIn Fig. 1 (Valladolid) FAI for F4/F3 is shown. A definite bifurcation occurs at 30Hz distinguishing AD group from HC. The power spectrum of an LC patient shows also at 30Hz frequency (Fig. 2) a significant increase, revealing high Beta EEG power conforming with severity of PD‐symptoms (O’Keeffe, 2020). Changing sign of asymmetry (i.e. FAI ∼ 0.3) can be observed at 30Hz (Fig. 3).ConclusionThe application of FAI in the full frequency range shall further be investigated as a new biomarker for AD and LC. The EEG frequency range from 25Hz to 35Hz appears to be an important transition zone from motor function to cognition. Abnormalities in this frequency range might be linked to AD, PD and LC and could open a new diagnostic window.
Development of a site readiness framework to improve health system preparedness for potential new Alzheimer’s disease therapies
Authors: Geldmacher David S. , Christopher Roni , Anderson Misty , Bero Adam W. , Rubino Ivana 
Published: December 2021

AbstractBackgroundThe growing Alzheimer’s disease (AD) population, the continued emergence of AD biomarkers, and the potential approval of therapies that target the underlying pathophysiology of AD have the potential to transform the diagnosis, treatment, and monitoring of AD within health systems. Transformation of the AD patient care pathway will present significant challenges, and resources are needed to help health systems prepare to integrate potential new AD therapies into patient care.MethodsPremier Applied Sciences developed a “Site Readiness Framework” for a new paradigm of AD care, with input from key medical experts in AD and select U.S. health systems, as well as financial support and input from Biogen. The development process involved interprofessional contributions from neurology, geriatrics, neuropsychology, psychiatry, radiology, infusion, memory disorders program coordination, and formulary management. Stakeholder interviews were conducted to illuminate the myriad challenges that potential new AD therapies may pose for health systems and guide the development of resources aimed to address those challenges.ResultsKey components of the Site Readiness Framework for AD include a program self‐assessment to help health systems identify gaps in preparedness for new AD therapies, and tools for mapping key considerations, such as purposeful referral of patients from primary care to a specialist, biomarker assessment, preparing for infusion therapy, and care coordination. An overview of the resources available within the Site Readiness Framework for AD, as well as a description of their potential application within a large academic health system, will be reported.ConclusionsThe approval of a disease‐modifying therapy for AD will require a transformation of the AD patient care pathway. The Site Readiness Framework for AD may help health systems prepare to integrate potential new therapies.
On gaps of clinical diagnosis of dementia subtypes: A study of Alzheimer's disease and Lewy body disease
Authors: Wei Hui , Masurkar Arjun V , Razavian Narges 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) and Lewy body disease (LBD) are most common dementias, and can occur concurrently (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation could be difficult. Yet it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectrums and demographic variables. We aimed to compare clinical diagnosis and post‐mortem autopsy‐confirmed pathological results to assess the clinical subtype diagnosis quality across these factors.MethodParticipants were selected from the National Alzheimer’s Coordinating Center dataset, with autopsy‐confirmed AD and/or LBD results, and initial visits with Clinical Dementia Rating (CDR) of 0, 0.5, or 1.0. We analyzed the clinical AD and/or LBD diagnosis in first visits at each CDR stage. This analysis included precision (PPV), sensitivity and specificity of the clinical diagnosis, and disparities in these metrics by sex, race/ethnicity, age and education. If autopsy‐confirmed AD, LBD, or AD+LBD was missed in the clinic, the alternative clinical diagnosis was analyzed.Result1887 qualified participants (Table 1) from September 1, 2005 to August 20, 2019 were included. Clinical AD+LBD diagnosis had poor sensitivity from 3% (CDR 0.5) to 6% (CDR 2.0). Over 60% of participants with autopsy‐confirmed AD+LBD were diagnosed clinically as AD (Table 2). Clinical AD diagnosis had low sensitivities at early dementia stage (57%) and low specificities at all stages (Table 3). Among participants clinically diagnosed as AD, over 33% had autopsy‐confirmed concurrent LBD neuropathology. Clinical LBD diagnosis had poor PPVs from mild cognitive impairment (22%) to severe dementia (20%). Within participants clinically diagnosed as LBD, 32% to 54% revealed autopsy‐confirmed AD+LBD pathology. When clinicians missed these three subtypes, “No cognitive impairment”, “Undecided” and “Primary progressive aphasia or behavioral variant frontotemporal dementia” were the leading alternative clinical diagnosis. With increasing dementia stages, the difference in clinical diagnosis accuracy significantly increased between White and Black/African‐American participants, and diagnosis quality significantly improved for males but not for females.ConclusionOur findings demonstrates that the clinical diagnosis of AD, LBD and AD+LBD are inaccurate and harbor significant disparities based on race and sex at all dementia stages.
ACD856: A novel positive allosteric modulator of Trk‐signaling in clinical development for the treatment of Alzheimer’s disease
Authors: Nordvall Gunnar , Madjid Nather , Backlund Maria , Halldin Magnus , Rother Matthias , Nilsson Boel , Sandin Johan , Forsell Pontus 
Published: December 2021

AbstractBackgroundNeurotrophin pathways, such as those mediated by NGF and BDNF, have in numerous studies been shown to be important for neuronal cell function, communication and cell survival in brain areas vital for cognitive function. Therefore, enhancers of NGF and BDNF signaling through positive allosteric modulation of the TrkA and TrkB receptors may be a valuable new option for the treatment of cognitive decline in various disease states. The aim of this study was to identify and characterize compounds that potently stimulate neurotrophin signaling by binding to the Trk‐receptors and to investigate the effects of such a compound in various preclinical model. Moreover, the aim was also to assess its safety and tolerability in both animals and man.MethodAll binding studies were performed using a Biacore instrument. The effects of ACD856 were investigated in different preclinical in vivo behavioural models to assess its effect on cognitive function. Safety and toxicology studies were subsequently conducted in line with regulatory requirements before a microdosing study in humans was performed to evaluate the pharmacokinetics, safety and tolerability in man.ResultA binding site on the intracellular domain of TrkA was observed for the compound ACD856 using surface plasmon resonance experiments. In an in vitro kinase assay using human full‐length TrkA, ACD856 could significantly increase the apparent maximal velocity (Vmax(app)) of TrkA. ACD856 also demonstrated potent pro‐cognitive effects in vivo, with a favorable PK profile. The compound was shown to be safe and well tolerated in the preclinical toxicological studies. Micodosing results in man showed that ACD856 had a profile suitable for further clinical develoment.ConclusionThe in vitro results suggests that ACD856 binds directly to the TrkA receptor to increase the number of catalytic cycles per timepoint. This mechanism of action is a probably a likely cause for the observed in vivo effects with respect to improved cognitive performance. These data suggest that ACD856 may have a beneficial effect on cognition in patients with cognitive dysfunction and the compound is currently in clinical development for the treatment of cognitive dysfunction in Alzheimer’s disease.