bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase 2a study evaluating the safety, tolerability, pharmacokinetics, and central nervous system activity of CY6463 when administered to participants with Alzheimer’s disease with vascular pathology
Authors: Glasser Chad , Chickering Jennifer , Wilson Phebe , Florine Emily , Winrow Chris , Wright Chris 
Published: December 2021

AbstractBackgroundThe soluble guanylate cyclase (sGC) stimulator, CY6463, is being developed as a symptomatic and potentially disease‐modifying therapy for serious central nervous system (CNS) diseases, including Alzheimer’s disease (AD). Nitric oxide (NO)‐sGC‐cyclic guanosine monophosphate (cGMP) is a fundamental neurotransmitter system critical to neuronal function. Impaired signaling of this pathway is known to play a role in the pathogenesis of many neurodegenerative diseases. CY6463, a positive allosteric modulator of sGC, amplifies endogenous NO signaling to increase cGMP production. In preclinical models, CY6463 improved neuronal function, cerebral blood flow, neuroinflammation, and cellular bioenergetics.CY6463 has been evaluated in two Phase 1 studies (110 healthy younger adult volunteers and 24 healthy elderly volunteers >65 years of age) assessing the safety, tolerability, pharmacokinetics (PK), and CNS activity of CY6463. Once‐daily CY6463 administration was well tolerated across dose levels, led to target CNS concentrations, achieved predictable/linear food‐independent PK, and had positive impacts on saccadic eye movements as well as brain neurophysiology as measured by electroencephalography (EEG).MethodThis 12‐week, randomized, placebo‐controlled study will evaluate safety, tolerability, PK, and CNS activity of CY6463 in approximately 40 patients with a combination of AD pathology, sub‐cortical vascular disease, and cardiovascular risk factors. This defined subset of the larger AD population, referred to as AD with vascular pathology (ADv), is hypothesized to be more likely to respond to CY6463 treatment due to CY6463’s expected impact on vascular and CNS biology. This study is funded in part by a Translational Research Award from the Alzheimer’s Association Part the Cloud‐Gates Partnership Grant Program.ResultThe primary objective, safety and tolerability, will be evaluated based on adverse event reporting. Exploratory evaluations assessed variously at baseline and weeks 2, 4, 8, and 12, will include plasma and CSF biomarkers of disease; PK; quantitative EEG and event related potentials as biomarkers of neurophysiology; functional magnetic resonance imaging measures of cerebral perfusion and brain connectivity; and cognitive performance tests of attention, executive function, and memory.ConclusionResults from this study in patients with ADv will inform the design of larger, longer studies evaluating the potential for CY6463 to improve cognition in this patient population.
Self‐rated daily language use, more than self‐rated bilingual language competency, moderates the effects of brain on cognition in a Hispanic cohort
Authors: Elliott Meghan R , Rentería Miguel Arce , Mungas Dan M. , Whitmer Rachel A. , DeCarli Charles S. , Fletcher Evan M 
Published: December 2021

AbstractBackgroundSome studies suggest that bilingualism may be associated with better cognition but the impact of bilingualism versus language practice on cognition and brain integrity is not well understood. Here, bilingualism encodes the knowledge of one language or two while language use encodes daily language practice (predominantly English or Spanish, or daily use of both). In a Hispanic cohort, we the assess effects of language variables on cognitive outcomes of baseline and longitudinal executive function and episodic memory, incorporating brain measures, age, gender, and education, and also whether they moderate the relationships between cognition and the MRI markers of brain integrity.MethodA baseline Hispanic cohort (N = 100) with a single MRI scan and a longitudinal subset (N = 73) with serial scans were sampled from the UC Davis Aging and Diversity cohort (Table 1). Linguistic measures were based on self‐reports. They were bilingualism, and among bilingual participants, daily language use. Baseline and longitudinal executive and memory were modeled by regressions incorporating age, education level, brain signature regions, and language variable ‐ first for bilingualism in the entire cohort and then for language use restricted to the bilinguals.ResultBilingualism was not a significant predictor of baseline outcomes and there were no moderations with brain variables (Table 2). Among bilinguals, English‐only speakers showed significantly increased association of gray matter (Table 3) to memory compared to those who daily spoke Spanish or both languages. Longitudinally, bilingualism had no direct or moderating effects on cognitive change (Table 4). Bilinguals speaking primarily English had significantly increased association of atrophy signatures with both cognitive changes compared to Spanish or speakers of both languages (Table 5).ConclusionResults suggest a complex pattern of moderation of brain atrophy effects on cognitive decline in self‐reported bilinguals depending on whether daily language use is predominantly English, Spanish, or both. Bilinguals who spoke predominantly English were more susceptible to brain atrophy effects in comparison with those who used both languages or predominantly Spanish. These results have important implications for understanding how bilingualism relates to cognitive reserve but require replication in larger and different samples.
The neutral sphingomyelinase 2 inhibitor PDDC reduces tau burden in Alzheimer’s disease mice
Authors: Tallon Carolyn , Bell Benjamin J , Malvankar Medhinee , Hollinger Kristen R , Thomas Ajit G , Yoo Seung Wan , Chaudhuri Amrita Datta , Wu Ying , Rais Rana , Haughey Norman J , Slusher Barbara S 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by worsening cognitive impairment with amyloid and tau deposition spreading throughout the brain in a “prion‐like” manner. Mounting evidence suggests extracellular vesicles (EVs) can act as vectors to propagate these pathogenic proteins along connectivity pathways. Several studies have demonstrated that inhibiting neutral sphingomyelinase 2 (nSMase2) reduces the level of tau and amyloid in the brain. Despite these promising findings, current nSMase2 inhibitors are not suitable for clinical development given their lack of potency, solubility, and/or limited brain penetration. We recently discovered phenyl (R)‐(1‐(3‐(3,4‐dimethoxyphenyl)‐2,6‐dimethylimidazo[1,2‐b] pyridazin‐8‐yl) pyrrolidin‐3‐yl) carbamate (PDDC), the first selective, potent nSMase2 inhibitor (IC50 = 300nM), with excellent oral bioavailability (%F = 88) and brain penetration (AUCbrain/AUCplasma = 0.60). We demonstrated that PDDC was able to inhibit EV release both in vitro and in vivo.MethodTo facilitate chronic oral efficacy studies, PDDC was incorporated into mouse chow which provided consistent brain exposure levels above its nSMase IC50 over a 24h time period. 4‐month old PS19 mice were fed either vehicle or PDDC chow for 5 months and their brains were collected for nSMase2 activity and tau protein level assessments.ResultVehicle treated PS19 mice had elevated nSMase2 activity levels compared to WT controls, which was completely normalized by PDDC treatment. Total tau and Thr181 phosphorylated tau were elevated in PS19 mice and significantly reduced in PDDC treated animals. Decreases in Thr217 and Ser202/Thr205 phosphorylated tau were also observed in PDDC‐treated mice, but the effect did not reach statistical significance. We are currently expanding these studies to evaluate PDDC in a rapid tau propagation model where AAV‐P301LhTau vectors are being unilaterally injected into the brains of WT mice and the propagation of phosphorylated tau to the contralateral side is bring quantified.ConclusionPDDC reduces the levels of total and pTau Thr181 in AD mice supporting its potential use as a novel therapeutic for the treatment of AD.
Efficacy of non‐invasive brain stimulation on global cognition in Alzheimer’s disease and mild cognitive impairment: A meta‐analysis
Authors: Bawa Kritleen Kaur , Teselink Johannes , Koo Grace KY , Sankhe Krushnaa , Liu Celina , Swardfager Walter , Herrmann Nathan , Lanctôt Krista L. 
Published: December 2021

AbstractBackgroundNon‐invasive brain stimulation (NIBS) is a non‐pharmacological intervention that has shown some promise in improving cognition in people with Alzheimer’s disease (AD), but clinical trials involving NIBS have shown inconsistent results. This meta‐analysis investigated the efficacy of NIBS, particularly repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) compared to sham stimulation on global cognition in people with AD and its prodromal stage, mild cognitive impairment (MCI).MethodMulti‐session randomized sham‐controlled clinical trials were identified though Medline, PsycInfo, and Embase until November 2020. Standardized mean differences (SMD) and 95% confidence intervals (CI) between the two groups were calculated using random‐effects meta‐analyses. Outcome measures for global cognition included scores on the Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS‐cog). Heterogeneity, from different NIBS techniques, disease populations, or tests used to assess global cognition, was measured using chi‐square and I2, and investigated using subgroup analyses.ResultA total of 17 studies (Nactive=233, Nsham=218) were included. NIBS (rTMS [11 studies] + tDCS [6 studies]) significantly improved global cognition in patients with AD and MCI (SMD=1.11; 95% CI=0.42,1.80; p=0.002). Subgroup analyses showed that rTMS (SMD=1.08; CI=0.32,1.84; p=0.005) but not tDCS improved global cognition. Patients with AD [13 studies] (SMD=1.02; 95% CI=0.28,1.76; p=0.007) but not MCI [4 studies] showed significant improvement on global cognition following NIBS as compared to the sham group. Additionally, significant improvement on both the MMSE (SMD=0.67; 95% CI=0.13,1.22, p=0.016) and ADAS‐cog (SMD=1.34; 95% CI=0.30, 2.39; p=0.012) scores were seen in patients with AD following rTMS, when analyzed separately. There was substantial heterogeneity across all analyses (all I2 > 50%) that was not resolved by subgroup analyses. Egger’s test showed no evidence of a publication bias.ConclusionNIBS, particularly rTMS, improved global cognition in those with AD. Further studies with bigger sample sizes in MCI and those using tDCS will help to fully evaluate the specific NIBS techniques and population most likely to benefit on global cognitive measures.
Plasma total bilirubin in patients with Alzheimer’s disease: An observational study
Authors: Ramdane Said , Ramdane Abderraouf 
Published: December 2021

AbstractBackgroundBilirubin, the primary end product of the heme cleavage pathway, is currently regarded as a major physiologic antioxidant with important cytoprotective properties. Oxidative stress is a well established contributing factor in the development of Alzheimer's disease (AD). In the present study, we aimed to compare serum bilirubin levels in patients with AD and healthy elderly controls, and to analyze the potential relationship between serum total bilirubin levels and dementia severity in AD patients.MethodMeasures of fasting serum total bilirubin levels were studied in 68 patients with AD (34 women; mean age 71.4±5.8 years; range 60‐82) (DSM‐IV; NINCDS‐ADRDA criteria) from a private ambulatory of neurology, recruited in a community elderly in Skikda‐Algeria (2017‐2020); and in 68 elderly controls (34 women; mean age 70.4±6.3 years; range 58‐82). Dementia severity was assessed by the clinical dementia rating scale‐CDR global score.ResultThe mean (±SD) plasma total bilirubin level was 0.72±0.13 (Range 0.49–1.08) among AD group and 0.66±0.11 (range 0.48–1.02) mg/dL among control group; (p= 0.0029). By gender, plasma total bilirubin level was higher in cases compared to controls both in men 0.75±0.14 vs. 0.67±0.13 mg/dL respectively, (p= 0.027); and in women 0.70±0.12 vs. 0.64±0.10 mg/dL; (p= 0.040). Patients with mild AD (Mean age 68±3.7 years) showed significantly higher levels of plasma total bilirubin compared with patients with moderate AD (Mean age 77.4±3.6 years): 0.77±0.13 vs. 0.64±0.09 mg/dL respectively (one way ANOVA, p= 0.0001). Plasma total bilirubin level was significantly negatively correlated with dementia severity, r= ‐0.4503; (95% CI for rho: ‐0.621; ‐0.238), p= 0.0001. By gender r= ‐3564; (p= 0.038) for men; and r= ‐0.5481, (p= 0.0007) for women.ConclusionThese data indicate that plasma total bilirubin level is increased in AD compared to controls, and inversely correlates with dementia severity. Patients with mild AD have higher total bilirubin levels (Within clinical normal range) than patients with moderate AD. These results suggest that serum total bilirubin level may provide additional information for predicting development of AD. We speculate that a possible beneficial physiologic antioxidant role for bilirubin could be operating during earlier stages of AD and gradually fades with disease progression.
A retinal deep phenotypingTM platform to predict the cerebral amyloid PET status in older adults
Authors: Soucy Jean‐Paul , Chevrefils Claudia , Osseiran Sam , Sylvestre Jean‐Philippe , Lesage Frédéric , Beaulieu Sylvain , Pascoal Tharick A. , Provost Karine , Arbour Jean Daniel , Rhéaume Marc‐André , Villeneuve Sylvia ,   Prevent‐AD Research Group, Nasreddine Ziad S. , Rosa‐Neto Pedro , Gauthier Serge , Robillard Alain , Chayer Céline , Black Sandra E. , Kertes Peter J. , El Shahawy Hossam , Scott Christopher J.M. , Bhan Aparna , Martins Ralph N. , Shah Tejal M. , Gupta Sunil M. , Calvin Kirsten , Hsu Gregory , Lowe Val J. , Chen John J. , Ritter Aaron 
Published: December 2021

AbstractBackgroundAs the only optically accessible part of the central nervous system, the retina represents an intriguing opportunity for the detection of biomarkers for Alzheimer’s disease (AD). This study evaluated the performance of the Retinal Deep PhenotypingTM platform, a digital biomarker platform comprising a hyperspectral retinal camera and image analysis algorithms, for the detection of likely positron‐emission tomography (PET) amyloid status (negative or positive) in older adults. A set of phenotypic features that correlates with the cerebral amyloid status as determined by amyloid PET scan were identified and used to train a classifying algorithm.MethodHyperspectral retinal images acquired with a Mydriatic Hyperspectral Retinal Camera from 194 participants (age ≥ 50 years), including cognitively normal and cognitively impaired (mild cognitive impairment and dementia) across 5 imaging sites were processed in order to train the model. Of these 194 participants, 73 individuals (38%) were amyloid‐positive, as confirmed by unanimous readings of PET scans by a panel of 3 expert reviewers. The pre‐processed hyperspectral images were segmented into various anatomical sites, and a texture‐based approach was used to extract several thousands of spatial‐spectral features. The most relevant features for the classification task were selected using a minimum redundancy maximum relevance (MRMR) algorithm and used to train a linear support vector machine (SVM) classifier. A nested, cross‐validation technique was used to evaluate the performance of the classifier.ResultThe resulting model based on the 17 most significant features showed high performance to discriminate between amyloid positive and negative subjects with an area under the receiver operating curve (AUCROC) of 0.87 (95% CI: 0.83 – 0.92).ConclusionThe Retinal Deep PhenotypingTM platform shows promise for detecting the likely cerebral amyloid PET status in adults 50 years and older from a simple, non‐invasive retinal scan and could provide an accessible means to identify individuals with abnormal cerebral amyloid in a clinical or drug development context. This phenotyping platform provides a flexible approach that could also be used for the detection of multiple biomarkers involved in cognitive decline from the same hyperspectral images of the retina.
Brain insulin signaling in persons with and without diabetes is associated with cognitive decline
Authors: Gwizdala Kathryn L. , Arvanitakis Zoe , Arnold Steven E. , Ahima Rexford S. , Bennett David A. , Newton Robert L , Carmichael Owen T. 
Published: December 2021

AbstractBackgroundPeripheral insulin resistance is associated with increased risk of AD dementia, and postmortem measures of reduced insulin signaling in the brain have been linked to poorer cognition in AD‐related domains proximal to death. However, the relationship between brain insulin signaling and longitudinal cognitive decline over the years leading up to death is under‐studied. This study assessed the relationship between longitudinal change in domain‐specific cognition and brain insulin signaling in a clinical‐pathologic, community‐based cohort.MethodUsing a subsample of participants in the Religious Orders Study (75 with diabetes matched to 75 without diabetes), we examined data derived from annual cognitive assessments (mean age (years) baseline: 77.25 ± 6.34; final: 86.03 ± 6.14) and postmortem measures of brain insulin signaling. Neuropsychological testing was grouped to form a primary measure of global cognition, and five separate cognitive domains. Brain insulin receptor signaling was quantified via ELISA for the ratio of pS307IRS1 /total IRS1 (insulin receptor substrate‐1) “IRS1 phosphorylation”, ratio of pT308AKT1/total AKT1 (serine/threonine‐protein kinase) “AKT phosphorylation”, and immunohistochemistry for IRS1 cells/mm2, and pIRS1 at S616. Mixed effects regression models assessed per‐person mean level and rate of change (slope) in each cognitive domain, along with effects of brain variables, age at death, sex, and education on mean level, and effects of brain variables on change (the α was set at 0.025).ResultGreater AKT phosphorylation had a trend‐level association with faster decline in global cognition (‐0.02 (0.01) 0.035). Greater AKT phosphorylation was associated with faster declines in working memory (‐0.02 (0.01) 0.015) and visuospatial ability (‐0.01 (0.01) 0.023) and at a trend level with faster episodic memory decline (‐0.03 (0.01) 0.026). Greater IRS1 phosphorylation was associated with slower decline in perceptual speed (0.02 (0.01) 0.023). Greater staining for pS616IRS1 was associated with faster visuospatial ability decline (‐0.02 (0.01) 0.020).ConclusionBrain insulin signaling measures are associated with cognitive decline in the years prior to death. Future work should further characterize these relationships and explore links of peripheral insulin resistance and cognitive decline and dementia.
Amyloid accumulation associated with worse performance of complex task
Authors: Keleman Audrey A. , Bollinger Rebecca M. , Ances Beau M. , Stark Susan L. 
Published: December 2021

AbstractBackgroundThe preclinical stage of Alzheimer disease (AD) is largely considered a clinically silent period that is detectable primarily through neuroimaging and biofluid biomarkers of amyloid and tau. We evaluated whether performance of complex daily activities is associated with amyloid accumulation as measured by positron emission tomography (PET) among cognitively normal (CN) individuals with or without preclinical AD.MethodCN participants (Clinical Dementia Rating 0) from the Knight Alzheimer Disease Research Center performed three activity subtasks (shopping, checkbook balancing, and medication management) from the Performance Assessment of Self‐Care Skills (PASS) at their homes. They also had an amyloid PET scan using Pittsburgh Compound‐B within one year of completing the PASS. PASS subtasks were scored for independence, adequacy, and safety of performance. Nonparametric correlations were used to determine the associations between amyloid accumulation and performance on each subtask.ResultFifty‐six CN participants (mean age 74.8 years, 61% female, 87% white) were included. Median amyloid PET was 1.17 (interquartile range 1.07–1.63; standard cutoff for preclinical AD: 1.42). Amyloid PET accumulation was not associated with performance on the checkbook balancing or medication management subtasks of the PASS. Higher amyloid PET accumulation was associated with worse performance on the shopping subtask of the PASS.ConclusionThis study suggests that a complex task, measured using a performance‐based test, may be associated with higher amyloid deposition. Performance‐based measures could potentially serve as a less expensive method for screening individuals who may likely benefit from further evaluation (plasma amyloid or PET amyloid). They could also lead to a better understanding of functional changes that may be occurring during the preclinical stage of AD.
Speech‐in‐noise perception is a marker of preclinical Alzheimer’s disease
Authors: Waters Sheena , Watson Cameron , Jacobs Benjamin M. , Foote Isabelle F. , Dey Sumit , Noyce Alastair J. , Marshall Charles R. 
Published: December 2021

AbstractBackgroundCentral auditory function is affected early in the course of Alzheimer’s disease, and may be useful as a prodromal disease marker. Speech‐in‐noise perception is a simple test of central auditory function.MethodWe used Speech Reception Threshold (SRT) as a measure of speech‐in‐noise perception in 160,905 healthy subjects in UK Biobank. We assessed odds ratios for incident Alzheimer’s disease by SRT quintile at a mean follow up of 10 years. In a subgroup of 37,082 healthy subjects with contemporaneous cognitive testing and brain imaging we assessed the relationships of SRT with cognitive performance and structural neuroanatomy using voxel‐based morphometry (VBM).ResultPoorer (higher) SRT was associated with greater odds of incident Alzheimer’s disease (odds ratio for quintile 5 relative to quintile 1: 2.91 (95%CI 1.92‐4.57); p=0.000001). Worse SRT was associated with poorer cognitive performance in multiple domains. VBM revealed symmetrical grey matter correlates of SRT in a distributed network of auditory and speech perception areas, as well as medial temporal lobe structures.ConclusionSpeech‐in‐noise perception is a simple non‐invasive assay of cognition, brain structure and risk of incident Alzheimer’s disease, and as such may be readily translatable as a cost‐effective tool for dementia risk stratification at large‐scale.