bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative EEG as a translational measure for the assessment of ATH‐1017 neurophysiological changes in mild‐to‐moderate Alzheimer’s disease
Authors: Hua Xue , Church Kevin , Walker William , L'Hostis Philippe , Ereshefsky Larry , Kawas Leen , Moebius Hans J. 
Published: December 2021

AbstractBackgroundAthira Pharma, Inc. is developing a new class of blood‐brain barrier (BBB)‐penetrant small molecule drugs aimed at activating the neurotrophic system HGF/MET to promote multiple neurorestorative processes, with the potential to ultimately improve brain function. ATH‐1017 is the lead clinical candidate for the treatment of Alzheimer’s disease (AD). Electroencephalogram (EEG) plays a growing role in facilitating dose exploration of investigational agents like ATH‐1017 by demonstrating brain penetration and target engagement, helping to accelerate CNS drug development.MethodThe translational measure quantitative electroencephalogram (qEEG) was assessed in preclinical animal models and in human volunteers, including healthy young, healthy elderly, and AD subjects as part of a randomized, double‐blind Phase 1a/b trial assessing the safety and pharmacodynamics of ATH‐1017.ResultAs measured by qEEG, ATH‐1017 induced a fast onset and sustained gamma power induction across a range of active doses in humans and animals based on equivalent PK exposures. Additionally, these exposures directly overlapped with the pharmacodynamic active dose range of behavioral and neuroprotective effects shown in dementia animal models. The translational utility of qEEG across species thus allowed for effective pharmacokinetic/pharmacodynamic (PK/PD) modeling and dose‐optimization across healthy volunteers and AD subjects, defining the dose range for late‐stage randomized, double‐blind studies of ATH‐1017 in AD.ConclusionThe use of qEEG as a translatable tool for PK/PD modeling and dose‐optimization supported brain penetration and pharmacodynamic activity of ATH‐1017, and is indicative of promoting NMDA receptor activities and synaptogenesis across species. The non‐invasive and replicable nature of qEEG measurements provides a direct, quantitative measure of brain activities in response to pharmacological intervention. qEEG facilitates the evaluation of CNS drug candidate early in the drug development process and increases confidence in translation before cognitive assessments in long‐term treatment trials.
Potential utility of longitudinal 123I‐FP‐CIT SPECT imaging in predicting phenoconversion to overt synucleinopathy in isolated REM sleep behavior disorder
Authors: Miyagawa Toji , Przybelski Scott A. , Maltais Daniela D. , Min Hoon‐Ki , Jordan Lennon , Lesnick Timothy G. , St. Louis Erik K. , Silber Michael H. , Graff‐Radford Jonathan , Jones David T. , Savica Rodolfo , Knopman David S. , Petersen Ronald C. , Kremers Walter K. , Forsberg Leah K. , Fields Julie A. , Ferman Tanis J. , Allen Laura A. , Kantarci Kejal , Lowe Val J. , Boeve Bradley F. 
Published: December 2021

AbstractBackgroundIsolated REM Sleep Behavior Disorder (iRBD) patients are known to be at high risk for developing an overt synucleinopathy – particularly Dementia with Lewy Bodies (DLB) and Parkinson’s Disease (PD). Reduced nigrostriatal uptake on 123I‐FP‐CIT SPECT reflects dopamine deficiency, which is common in the overt synucleinopathies. We sought to assess how 123I‐FP‐CIT SPECT imaging in iRBD changes longitudinally and whether an abnormal 123I‐FP‐CIT SPECT scan precedes and predicts future transition to an overt synucleinopathy.MethodParticipants with polysomnography‐confirmed iRBD from the Mayo Clinic Alzheimer’s Disease Research Center database +/‐ North American Prodromal Synucleinopathy (NAPS) Consortium who had two or more longitudinal 123I‐FP‐CIT SPECT scans and been followed prospectively for at least 24 months were included in this analysis. Striatonigral dopamine transporter uptake was evaluated semi‐quantitatively with 123I‐FP‐CIT SPECT using DaTQUANT software (GE Healthcare) to calculate z‐scores of putamen uptake.ResultThirty‐five iRBD participants (86% male) were evaluated prospectively (mean 62.5 ± 19.4 months) and underwent two or more 123I‐FP‐CIT SPECT scans at a minimum of 12 months intervals. Thirteen participants (37%) developed an overt synucleinopathy (11 DLB and 2 PD; phenoconverters) and 22 participants (63%) remained as iRBD (stable iRBD). Phenoconverters were older (mean 70.8 ± 7.0 vs 63.4 ± 6.0 years old) and had more negative DaTQUANT putamen z‐scores (mean ‐1.68 ± 1.42 vs ‐0.33 ± 1.52) than stable iRBD participants at baseline. Among phenoconverters, nine participants (69%) had one or more 123I‐FP‐CIT SPECT scans with DaTQUANT putamen z‐score of <‐2.0 prior to phenoconversion, and mean time from initial DaTQUANT putamen z‐score of <‐2.0 to phenoconversion was 36.8 ± 28.7 months. In stable RBD participants, eight participants (36%) showed a decline in DaTQUANT putamen z‐score of >1 between the most recent and the baseline scan, and four participants (18%) presented DaTQUANT putamen z‐score of <‐2.0 at the most recent scan.ConclusionThese findings suggest that a decline in putamen uptake on 123I‐FP‐CIT SPECT in iRBD serves as a predictor and a surrogate biomarker for progression of iRBD to an overt synucleinopathy.
COVID‐19 pandemic: Quantifying the effects of the first lockdown on behavioral and cognitive measures using TASIC
Authors: Stevenson Jenna , Lussier Firoza Z , Servaes Stijn , Chamoun Mira , Rahmouni Nesrine , Tissot Cécile , Poltronetti Nina Margherita , Pascoal Tharick A. , Benedet Andréa Lessa , Bezgin Gleb , King Suzanne , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2021

AbstractBackgroundFollowing the rapid spread of the COVID‐19 virus throughout Quebec, the TRIAD cohort, a longitudinal observational study, evaluated the effects of COVID‐19 on it’s aging and vulnerable population and their caregivers. This study aims at investigating the behavioural and psychological effects of COVID‐19 and social isolation on the aging population. The TRIAD Assessment of Social Isolation and Cognition (TASIC) was developed to assess these effects on participants of observational trials.MethodPre‐pandemic data including, demographical information, Clinical Dementia Rating (CDR), Mini‐Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Montreal Cognitive Assessment (MoCA) and a Social Support Questionnaire, were collected during in‐person visits and take‐home questionnaires. Following the onset of COVID‐19, TASIC was created to include additional COVID‐19 specific scales developed by Dr. Rosa‐Neto and Dr. King that include Knowledge of COVID‐19 scale, the Montreal Assessment of Stress related to COVID‐19 (MASC), as well as the Impact of Events Scale (IESR), the Peritraumatic Distress Inventory (PDI), the Peritraumatic Dissociative Experiences Questionnaire (PDEQ) for COVID‐19. Assessments were conducted via telephone interviews with TRIAD participants (n=292) and their informants (n=243) by eight trained research assistants from April through June 2020. All participants enrolled in previous TRIAD studies, deemed eligible through detailed screening criteria were contacted.ResultAs a result of this study, and previous work done by the cohort, a culmination of information is available, with 90% of TRIAD participants having completed the COVID‐19 study also having plasma collected. 80% of participants from the COVID‐19 study have PET imaging using [18F]AZD4694 and [18F]MK6240 and MRI sequencing.ConclusionThe COVID‐19 study conducted by TRIAD provides a unique opportunity to understand the effects of a global pandemic on our aging population as well as caregiver burden. This data, in conjunction with other measures available in the cohort, can make important strides in finding ways to help, and better understand those most impacted by the crisis.
Candesartan is associated with lower amyloid accumulation in non‐hypertensive prodromal Alzheimer’s disease
Authors: Okafor Maureen , Wan Limeng , Saleh Sabria , Moore Renee' H , Shaw Les M , Goldstein Felicia C , Hajjar Ihab 
Published: December 2021

AbstractBackgroundWe have previously reported that candesartan improves executive function and memory in hypertensives with MCI. It is unclear if this drug has an effect on AD mechanisms or biomarkers.MethodThis randomized double‐blind clinical trial enrolled 77 non‐hypertensive participants (mean age: 68.1 years; n=48, 62% women; n=15, 20% African American) with prodromal AD. Individuals were screened and underwent cognitive and physical assessments, lumbar puncture, and blood collection at baseline, 6 months and 12 months. All participants were randomized to escalating doses of candesartan (up to 32 mg daily) or matching placebo. We investigated the target engagement of 1‐year treatment of candesartan vs placebo in MCI patients neither clinically diagnosed nor taking medication for hypertension, who have evidence of AD pathology. We assessed the effect of candesartan vs placebo on CSF AD biomarkers (amyloid‐β (Aβ)42, Aβ40, total tau, and phospho‐tau181 (p‐tau181)) analyzed on the Fujirebio Lumipulse platform using Fujirebio immunoassay reagents. Outcome analyses were conducted following an intent‐to‐treat approach with linear mixed models adjusted for group*time and cholinesterase inhibitors or memantine use.ResultParticipants randomized to candesartan developed fewer symptoms of hypotension compared to placebo (18% vs 26%) and there was no discontinuation from the trial due to adverse event from candesartan compared to placebo (0% vs 2.6%). After 1 year, the candesartan group had significantly higher CSF Aβ40 (‐1211.95, p‐value=0.009) and Aβ42 (‐49.51, p‐value=0.046) levels (Figure) vs placebo, reflecting lower brain amyloid accumulation. CSF Aβ42/Aβ40 showed a trend with an increased ratio in candesartan vs a decreased ratio in placebo, but did not reach statistical significance. Participants randomized to candesartan also showed a trend for decreases in CSF total tau and p‐tau181 and increases in Aβ42/total tau and Aβ42/p‐tau181 levels. Although the within groups were significant, the between groups did not reach significance for the tau‐based biomarkers.ConclusionIn this first human study in non‐hypertensive prodromal AD, candesartan treatment demonstrates target engagement and a reduction in brain amyloid accumulation compared to placebo. These findings may be useful in the prevention of AD or the slowing of disease progression. A larger trial is urgently needed for candesartan in AD.
Adapting to the COVID‐19 pandemic in cohort studies: Validation of online assessments of cognition and neuropsychiatric symptoms in an aging population
Authors: Lussier Firoza Z , Servaes Stijn , Kang Min Su , Bezgin Gleb , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Stevenson Alyssa , Pascoal Tharick A. , King Suzanne , Bzdok Danilo , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2021

AbstractBackgroundThe occurrence of the COVID‐19 pandemic has had a significant impact on cohort studies, particularly those whose subjects are at higher risk of developing complications from the virus. As such, assessment methods must be adapted to minimize COVID‐19 exposure risk. The TRIAD (Translational Biomarkers of Aging and Dementia) cohort assessed N=292 individuals during initial COVID‐19 lockdown measures by telephone interview to rate cognition, neuropsychiatric symptoms, and impact of the pandemic. To increase speed and efficiency of data collection, we aim to follow these individuals by means of online survey. Here, we present a validation of our online assessment tools by comparing data obtained through both methods (phone interview and online survey) in the same subjects.Methods10 subjects (4 elderly CN/3 MCI/3 AD) and their informants participated in this study. Subjects were varied for assessment language (English/French) and first assessment method (phone/online). 18 instruments were administered (listed in Table 1). Instrument scores were first compared by computing individual differences (phone‐online), then by pooling all scores by assessment type and calculating an effect size. Pearson correlation coefficient between phone and online scores was also computed.ResultsMean interval between assessments was 8.8±4.8 days. Mean length of online assessment (63.7±20.7mins) was comparable to mean phone interview length (72.6±32.4mins). Instrument scores from phone interviews had a total mean of 102.60, while scores from online surveys had a total mean of 103.93, with a pooled SD of 716.09. Effect size was ‐0.00186. Correlation of phone and online scores yielded a Pearson’s R of 0.85 (p<0.05). Pearson’s R was also computed by applying bootstrapping using 1000 resamples without replacement with a sample size of 50. The Pearson R coefficient after bootstrapping was 0.91 (95% CI: [0.7699‐0.998]).ConclusionOur results suggest that instrument scores from phone and online assessments are comparable, and not significantly different from each other. The observed variance in scores between phone and online assessments may be due in part to the normal test‐retest variability associated with re‐administering instruments. This validation of online assessment tools in an aging population is of significant importance to human studies in the context of COVID‐19.
Associations of neuropsychiatric symptoms with cognitive impairment: The utility of the mild behavioral impairment checklist and the neuropsychiatric interview questionnaire in a cognitive neurology clinic population
Authors: Hu Sophie , Patten Scott B , Charlton Anna , Fischer Karyn , Fick Gordon , Smith Eric E. , Ismail Zahinoor 
Published: December 2021

AbstractBackgroundMild Behavioral Impairment is characterized by later life emergent and persistent neuropsychiatric symptoms (NPS). MBI domains include impaired drive/motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and psychosis. We aimed to compare the relationship between NPS and cognition in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and dementia, using the Mild Behavioral Impairment‐Checklist (MBI‐C) and Neuropsychiatric Inventory Questionnaire (NPI‐Q). MBI domains were derived from the NPI‐Q using a published algorithm.MethodData was examined from 1238 patients in the PROMPT Cognitive Neurology Clinic registry at the University of Calgary. NPS were characterized at baseline using the MBI‐C (n=474) and NPI‐Q (n=1040). Forward stepwise linear regression models were conducted to compare MBI‐C and NPI‐Q total and domain scores with cognition as assessed using the Montreal Cognitive Assessment (MoCA). Age, diagnosis, sex and education were included as covariates.ResultOverall, 90% of patients had an MBI‐C total score>0 and 55.91% of patients scored above cutoff (>7). MBI prevalence (based on cutoff) was 37% in patients with SCD, 54% in MCI, and 62% of dementia patients scored above the cutoff. By domain, over half had impaired drive/motivation (59.57%), affective dysregulation (68.66%) or impulse dyscontrol (64.11%), while relatively fewer had social inappropriateness (33.97%) or psychotic symptoms (22.25%). For the NPI‐Q, 67.98% of patients had a total score>0 including 60.36% of SCD, 60.00% of MCI and 74.95% of dementia. By domain, over half had affective dysregulation (61%) or impulse dyscontrol (58.50%) while less than half had impaired drive/motivation (44.31%), social inappropriateness (23.19%) or psychosis (10.18%). With increasing diagnostic severity, age, MBI‐C and NPI‐Q scores increased, while MoCA scores decreased. Greater MBI‐C and NPI‐Q total and domain scores were significantly associated with lower MoCA score. Of all domains, psychosis had the strongest association with impaired cognition using both measures. Age, sex and diagnosis were modifiers for the MBI‐C.ConclusionNPS are associated with poorer cognition regardless of diagnostic status. MBI domain scores are more strongly associated with impaired cognition than total scores. These findings suggest that the MBI‐C has utility in capturing NPS in this specialty clinic population, as a complement to the NPI‐Q.
Blood pressure trajectories from early life and their association with cognitive function changes in midlife
Authors: De Anda‐Duran Ileana , Fernandez‐Alonso Camilo , Carmichael Owen T , Au Rhoda , Bazzano Lydia , Kolachalama Vijaya B 
Published: December 2021

AbstractBackgroundHypertension (HTN) is a well‐established risk factor for cognitive impairment and dementia. HTN‐induced vascular endothelium and smooth muscle damage have been described as pivotal components of the pathophysiological cascade over the life‐course. While the impact on cognitive function (CF) changes has been studied from midlife‐ to old age, the impact from childhood to middle age exposure remains poorly understood. We aimed to explore this relationship in a community‐based cohort of middle‐age adults.MethodsThe analysis included a total of 342 adult participants (67.3% Woman, 38.9% African American) from the Bogalusa Heart Study, with CF assessments at two time points, baseline (age 48.8 ± 4.9 years) and follow‐up (age 51.7 ± 5.2 years), and at least 3 observations of BP since childhood. CF change was assessed by computing the difference of the two timepoints standardized global cognitive score (GCS) obtained from a battery of tests covering major neuropsychological domains. Systolic BP (SBP) trajectories were created using latent class trajectory modeling. Mixed linear models with unstructured covariance were used to determine the association between SBP trajectories and CF changes in midlife.ResultsMean CF assessment follow‐up was 2.9 ± 0.6 years, and mean follow‐up for BP and other traditional cardiovascular (CV) risk factors was 41.8 ± 3.4 years. Three distinct trajectory classes of SBP were identified: increasing to plateau (n=226 [66.1%]), moderate‐ (n=54 [15.8%]) and high‐ (n=62 [18.1%]) increasing (see Figure 1). With the increasing to plateau SBP trajectory as reference, and after adjustment for modifiable dementia risk factors and traditional CV risk factors, the high‐increasing SBP trajectory was associated with greater decrease in GCS (β= ‐1.22 [95%CI ‐2.39, ‐0.07]; p=0.038). The moderate‐increasing SBP trajectory showed no statistically significant association with GCS change (β= ‐1.00 [95%CI ‐2.23, ‐ 0.22]; p=0.109). (see Table 1)ConclusionsThese findings suggest that highly‐increasing SBP trajectories over time, particularly from childhood to mid‐ life, may adversely affect cognitive performance in midlife, independent of modifiable dementia risk factors. This underscores the importance of addressing CV risk factors during childhood and adolescence through primary prevention, as their cumulative burden could have a detrimental impact on brain health.
Association of tau pathology and vascular risk factor burden with longitudinal measures of plasma neurofilament light
Authors: Ferrari‐Souza João Pedro , Brum Wagner Scheeren , Hauschild Lucas Augusto , das Ros Lucas U. , Bieger Andrei , Ferreira Pamela C.L. , Bellaver Bruna , Benedet Andréa Lessa , Therriault Joseph , Rosa‐Neto Pedro , Karikari Thomas K , Pascoal Tharick A. , Zimmer Eduardo R. 
Published: December 2021

AbstractBackgroundIn the context of Alzheimer’s disease (AD), tau pathology is a major driver of the neurodegenerative cascade that ultimately leads to loss of neurons and synapses. In fact, studies have shown that neurodegeneration is more strongly associated with tau pathology than amyloid‐β (Aβ) accumulation. Although plasma neurofilament light (NfL) is a neuroaxonal damage biomarker that currently is in the research spotlight, the factors influencing the association between its longitudinal trajectory and tau pathology remains unclear. Since vascular risk factors (VRFs) present an important role in AD etiology and progression, here we aimed to determine whether tau pathology, in combination with or independently of VRF burden, is associated with longitudinal plasma NfL trajectory.MethodWe assessed 901 participants [276 CU, 455 MCI and 170 AD] from ADNI with baseline plasma p‐tau181 and [18F]AV45 Aβ‐PET, as well as longitudinal plasma NfL measurements (up to 4 years). Baseline VRF burden was calculated considering the history for cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, stroke or transient ischemic attack, smoking, atrial fibrillation and left ventricular hypertrophy. Individuals were dichotomized as following: elevated VRF burden if ≥2 VRFs (V+), tau positive if plasma p‐tau181 ≥ 17.7 pg/mL (T+) and amyloid positive if global Aβ‐PET SUVR ≥ 1.11 (A+). Subjects who were A‐T+ were excluded. Linear mixed‐effects models (LMMs) were performed to evaluate plasma NfL’s longitudinal trajectories.ResultThe LMMs demonstrated that tau positivity (T+) was significantly associated with a higher rate of longitudinal increase in plasma NfL levels in comparison to the tau‐negative group (Fig. 1). However, analysis dividing the groups both by tau and VRF burden status demonstrated that the rates of increase in plasma NfL were greater only in the presence of both VRF burden and tau positivity (T+V+; t‐value=2.54, p<0.05), when compared to the reference group (T‐V‐; Fig. 2). Moreover, specific slope‐contrast analyses confirmed that only the T+V+ group presented a clearly separate trajectory.ConclusionOur findings suggest that an elevated VRF burden influences the relation between tau pathology and neurodegeneration in AD.Therefore, tau‐mediated neurodegeneration seems to be most relevant in combination with vascular‐mediated neuroaxonal injury. These findings reinforce the pivotal contribution of vascular pathology to AD development.
Difference in allostatic interoceptive network connectivity by cognitive status
Authors: Bateman James R. , Kawas Mohammad I , Craft Suzanne , Lockhart Samuel N. , Kim Jeongchul , Sai Kiran K Solingapuram , Lindquist Kristen A , Whitlow Christopher T. 
Published: December 2021

AbstractBackgroundThe allostatic interoceptive network (AIN) has been proposed as central to linking interoceptive processing and autonomic regulation and involved in emotional experience. Early pathologic changes in AD occur in hubs of the AIN, and changes in emotional reactivity have been identified at both the MCI and dementia stages of Alzheimer’s disease. Interoception has been proposed as a core feature in psychiatric disease, though relatively little attention has been paid to altered interoception in neuropsychiatric symptoms in dementia. We conducted a pilot analysis in cognitively normal (CN) participants and those with mild cognitive impairment (MCI) to identify alterations in functional connectivity of the AIN, default mode, and salience networks.MethodTwenty‐two participants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort including CN participants (n = 11, mean age = 67 ± 7) and MCI (n = 11, mean age = 72 ± 7) received 3T brain MRI using T1 for gray/white matter segmentation and BOLD for resting‐state functional connectivity. BOLD time series data were pre‐processed and de‐noised using standard techniques. Connectivity analyses were performed using the CONN functional connectivity toolbox. Briefly, we performed a comparison of within‐network connectivity of the allostasis and interoception system (comprised of the DMN, SN, and AIN seed regions) between MCI and NC participants while adjusting for age (p < 0.05 uncorrected).Result
Table lists the baseline demographic and clinical characteristics for CN and MCI groups. Participants with MCI had greater connectivity between limbic regions of the AIN and salience network compared with the CN group, and decreased connectivity between the left lateral parietal cortex and multiple hubs of the salience network. Within the AIN seed regions, the amygdala and dorsal posterior and mid insula had increased connectivity (Figure; p < 0.05 uncorrected).ConclusionWe find differences in functional connectivity between CN adults and persons with MCI for three brain networks. Our analyses provide preliminary support that changes in an integrated allostasis and interoceptive system, integrating components of the DMN and SN, may have implications for emotional dysregulation in ADRD.