bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline characteristics from TANGO: Phase 2 study to evaluate gosuranemab (BIIB092) in patients with early Alzheimer’s disease
Authors: Ratti Elena , Kong Jessica , O'Gorman John , Rajagovindan Raj , Racine Annie , Graham Danielle , Schrempp Daniela Ramirez , Viollet Louis , Jones Stephanie , Mirabile Tracy , Walsh Dominic M. , von Rosenstiel Philipp , Shulman Melanie
Published: December 2020

Background

Gosuranemab is a humanized monoclonal antibody binding tau at the N‐terminal domain. The TANGO study is a randomized, placebo‐controlled, global Phase 2 Study evaluating safety and clinical efficacy of gosuranemab in patients diagnosed with mild cognitive impairment (MCI) due to AD or mild AD dementia. We describe baseline characteristics from the TANGO study, the first evaluation of gosuranemab in AD.

Method

Randomized, double‐blind, placebo‐controlled, parallel‐group Phase 2 study (TANGO) enrolled globally over 600 individuals aged 50‐80 years, diagnosed with MCI due to AD or mild AD, Clinical Dementia Rating (CDR) global score 0.5‐1, CDR Memory Box score of ≥0.5, Mini‐Mental State Examination (MMSE) score 22‐30, objective evidence of cognitive impairment at Screening and elevated brain amyloid as assessed by PET or cerebrospinal fluid (CSF) levels. Participants were randomized 1:1:2:2 to monthly intravenous low, medium, high dose of gosuranemab or placebo during the 76‐week treatment period. After completion of the placebo‐controlled period, patients may enter a long‐term extension during which all patients receive gosuranemab. The primary endpoints included incidences of adverse events, serious adverse events, abnormalities in safety assessments. The secondary endpoints included change from baseline in CDR‐Sum of Boxes score and incidence of anti‐gosuranemab antibodies in serum. Key exploratory endpoints included change from baseline in MMSE, AD Cooperative Study‐Activities of Daily Living, Functional Activities Questionnaire, AD Assessment Scale‐Cognitive Subscale, tau levels in CSF and/or in brain measured by 18F‐MK6240 PET and pharmacokinetic parameters.

Result

TANGO is now fully enrolled and ongoing; over 600 patients were randomized and have received ≥1 dose of study medication. Approximately half of the patients were enrolled in either the CSF or tau PET sub‐studies. Approximately half of the patients are women (50.5%). The percentage of patients diagnosed with Mild AD at baseline is 53%. MMSE mean (standard deviation [SD]) score at baseline was 25 (2.3).

Conclusion

TANGO will assess the safety profile, tolerability and clinical efficacy of gosuranemab in individuals who, per baseline characteristics, are representative of patients with early AD. Study Support: funded by Biogen.
Spatial navigation and verbal memory are influenced by the combined effects of APOE and BDNF Val66Met polymorphisms in mild cognitive impairment
Authors: Laczó Jan , Cechova Katerina , Parizkova Martina , Matoska Vaclav , Kaplan Vojtech , Matuskova Veronika , Markova Hana , Vyhnalek Martin , Hort Jakub
Published: December 2020

Background

The apolipoprotein E (APOE) ɛ4 allele is associated with an increased risk of Alzheimer’s disease (AD), episodic memory deficits and less accurate spatial navigation in non‐demented older adults. The brain‐derived neurotrophic factor (BDNF) Val66Met polymorphism is also related to the increased risk of AD and more pronounced memory impairment but its role in APOE ɛ4‐related spatial navigation deficits has not been established. Our aim was to examine the influence of combination of APOE and BDNF Val66Met polymorphisms on spatial navigation and other cognitive functions in individuals with amnestic mild cognitive impairment (aMCI).

Method

In total, 116 older adults with aMCI from the Czech Brain Aging Study were stratified based on APOE and BDNF Val66Met polymorphisms into four groups: ɛ4–/BDNF
Val/Val (n = 29), ɛ4–/BDNF
Met (n = 11), ɛ4+/BDNF
Val/Val (n = 52), and ɛ4+/BDNF
Met (n = 24). All participants underwent comprehensive neuropsychological examination, brain MRI and spatial navigation testing of egocentric (body‐centred), allocentric (world‐centred), and allocentric delayed navigation in a real‐space human analogue of the Morris water maze.

Result

The ɛ4+/BDNF
Met group although similar to other groups in age, gender, education, depressive symptoms and global cognitive function had less accurate egocentric navigation performance (ps ≤ .045). The differences in allocentric and allocentric delayed navigation performance were not significant (ps ≥ .651). The ɛ4+/BDNFMet group had lower verbal memory performance than the ɛ4–/BDNF
Val/Val group (p = .007) and similar performance to the ɛ4–/BDNF
Met (p = .071) and ɛ4+/BDNF
Val/Val (p = .240) groups. There were no between‐group differences in other cognitive domains including attention and working memory, nonverbal memory, executive function, language and visuospatial function (ps ≥ .268).

Conclusion

The aMCI carriers with the most risky combination of APOE ɛ4 and BDNF
Met polymorphisms had more pronounced egocentric spatial navigation impairment than the other polymorphism groups and more pronounced memory deficits than the carriers with the least risky combination of APOE ɛ3 and BDNF
Val/Val polymorphisms. These findings indicate that aMCI individuals with two risky gene polymorphisms are particularly susceptible to hippocampus‐dependent episodic memory deficits and even more to non‐hippocampus‐dependent egocentric spatial navigation impairment that may reflect more advanced underlying pathological changes.
APOE genotype, brain imaging, and neuropsychological testing markers of Alzheimer’s disease: Data from the Strong Heart Study
Authors: Suchy‐Dicey Astrid M , Nelson Lonnie A , Su Yi , Howard Barbara , Longstreth WT , Buchwald Dedra , Reiman Eric M
Published: December 2020

Background

Carrying an APOE ε4 allele increases risk for Alzheimer’s disease and related dementias. However, risk effects and prevalence of risk alleles are not consistent across races/ethnicities. Prevalence of cognitive impairment or dementia and attributable risk from APOE ε4 genotype are unknown in American Indians (AI). This project evaluated associations of APOE genotype with cranial imaging and cognitive testing markers of vascular and Alzheimer’s dementias in a large, prospective, population‐based cohort of AI.

Method

The Strong Heart Study recruited 4,549 AI aged 45‐75 from 13 tribal communities across 3 major geographic regions in 1989‐1991. In 2010‐2013, all eligible surviving participants, then aged 65‐95, underwent cognitive examination including 3MS, WAIS, COWA, and CVLT‐II long delay free recall and cranial magnetic resonance imaging (MRI). APOE was genotyped from blood using ABI PRISM Linkage Mapping and DNA sequencing.

Result

Most participants carried either 3.3 (73%) or 4.3 genotypes (23%). Clinical risk factors for dementia were prevalent, including high body mass index (mean>30), hypertension (80%), diabetes (48%), high LDL (39‐44%), chronic kidney disease (27%), and prior stroke (8‐9%). APOE ε4 carriers did not differ from non‐carriers in clinical factors, with the exception of serum LDL (103.9 mg/dL vs 96.7 mg/dL, P=0.015). Findings from MRI were also similar between genotypes, including presence of infarcts or hemorrhages, brain volume, and grade (0‐9) for white matter hyperintensities, sulcal widening, and ventricle enlargement. APOE ε4 carriers had marginally more WMH volume than non‐carriers. Cognitive examination scores were also similar, including Modified Mini Mental Status Examination (3MSE), Weschler Adult Intelligence Scale coding test (WAIS), Controlled Oral Word Association test (COWA), California Verbal Learning Test long delay free recall (CVLT).

Conclusion

Despite evidence for higher risk of Alzheimer’s and related dementias from presence of APOE ε4 allele among individuals from other populations, our study found little evidence of such an effect in elderly AIs. These findings raise intriguing questions about the presence of as‐yet‐unknown protective factors. Limitations of this study include cross‐sectional analyses and possibility of selective survival before the MRI examination. Future research should directly examine whether longitudinal changes in cognition and brain structure are associated with APOE genotype.
A novel peripheral biomarker for mild cognitive impairment and Alzheimer’s disease
Authors: Parra Mario A , Schumacher Marcela , Fernández Gerardo
Published: December 2020

Background

Recent evidence suggests that oculomotor behaviours linked to cognitive performance can be a biomarker of Alzheimer’s disease (AD). Short‐Term Memory Binding (STMB) declines in patients with AD dementia and in those at risk of dementia. STMB relies on brain regions relevant to visual processing which are known to support oculomotor behaviours. A combined analysis of oculomotor responses during STMB can enhance the sensitivity of the assessment of patients with AD or at risk of AD such as those with Mild Cognitive Impairment (MCI). We investigated this hypothesis.

Methods

Using eye‐tracking technologies, we measured pupil dilation, fixation, and exploratory eye movement behaviours in patients with AD, MCI and in healthy controls while they performed the STMBT. The STMBT assesses the ability to temporarily hold bicoloured objects whose colours had to be remembered either as individual features (baseline) or integrated within unified representations (binding).

Results

Experiment 1 involved 18 healthy older adults and 18 patients with AD dementia. We observed (1) altered pupil dilation linked to poor STMB performance in AD patients. Experiment 2 involved 42 healthy older adults and 63 patients with MCI. Impaired fixation and exploratory eye movement behaviours accompanied poor STMB abilities in MCI patients.

Conclusion

Taken together, the results above suggest that eye‐tracking measures combined with cognitive markers for AD (STMBT) can (1) enrich the clinical phenotype of this type of dementia, (2) unveil novel features of AD dementia unknown to date, and (2) provide more sensitive tools which can detect and trace aspects of such phenotype in people at risk, thus helping to ascertain the presence of the prodromal stages of the disease.
Working memory training in older adults: COMT Val158Met modulates the transfer of benefits in a virtual reality working memory task
Authors: Boujut Arnaud , Mellah Samira , Verty Lynn Valeyry , Maltezos Samantha , Lussier Maxime , Bherer Louis , Belleville Sylvie
Published: December 2020

Background

Individuals with the Val/Val homozygous variation of the catechol‐O‐methyltransferase (COMT) gene possess lower prefrontal dopaminergic levels than Met/‐carriers and show more pronounced age‐related cognitive impairment (Papenberg et al., 2015). The aim of this study was to examine the impact of the COMT genotype profile on the transfer of working memory (WM) training effect in older adults.

Method

60 older adults were randomly assigned to inhibition or updating WM training conditions which were provided over 12 half‐hour sessions (3 sessions per week). Their COMT genotype was determined from a salivary sample collected using an Oragene OG‐500 collection kit. Transfer was measured with untrained complex WM tasks: Alpha‐span, Reading‐span, and a Virtual Reality dual‐task (VR‐WM) involving the detection of a visual road sign and a concurrent verbal memory task. Testing was done weekly, but to limit the bias of regression to the mean with small samples, the first two and the last two assessments were averaged.

Result

Mixed model analyses showed better performance for COMT Met/‐carriers (n = 43) than Val/Val carriers (n = 11) in the Reading‐Span task and improved performance on the three transfer tasks. There was a COMT x Time interaction on the VR‐WM task. Post‐hoc analyses showed that only the Val/Val group improved their performance following training, allowing them to reach levels similar to that observed in the Met/‐carriers group.

Conclusion

Our results indicate an effect of the COMT status on WM performance and training transfer. The observed pattern is similar to that previously reported in younger adults (Colzato et al., 2014) and emphasizes the role of dopaminergic regulation in WM and WM malleability. Colzato, L. S., van den Wildenberg, W. P. M., & Hommel, B. (2014). Cognitive control and the COMT Val158Met polymorphism: Genetic modulation of videogame training and transfer to task‐switching efficiency. Psychological Research, 78(5), 670–678. https://doi.org/10.1007/s00426‐013‐0514‐8. Papenberg, G., Lindenberger, U., & Bäckman, L. (2015). Aging‐related magnification of genetic effects on cognitive and brain integrity. Trends in Cognitive Sciences. Elsevier Ltd. https://doi.org/10.1016/j.tics.2015.06.008.
CSF phosphorylated tau‐217 is increased in Alzheimer’s and Creutzfeldt‐Jakob diseases and correlates with amyloid pathology
Authors: Emeršič Andreja , Karikari Thomas K , Rodríguez‐Lantero Juan , Ashton Nicholas J , Rot Uros , Kramberger Milica G , Čučnik Saša , Zetterberg Henrik , Blennow Kaj
Published: December 2020

Background

Cerebrospinal fluid (CSF) phospho‐tau181 (p‐tau181) is an established biomarker of tangle pathology in Alzheimer’s disease (AD), but does not detect aberrant tau phosphorylation in other tauopathies. Recently, tau phosphorylation at threonine‐217 (p‐tau217) was suggested to be a superior biomarker for AD pathology. However, it is unclear if p‐tau217 is increased in other neurodegenerative diseases, including Creutzfeldt–Jakob disease (CJD) with concomitant amyloid/tau pathology or in primary tauopathies such as progressive supranuclear palsy (PSP).

Method

We validated an ultrasensitive Single molecule array (Simoa) p‐tau217 immunoassay and tested its diagnostic performance in the CSF of AD (n=110), CJD (n=22), and PSP (n=22) patients as well as age‐matched controls (n=106). Prospectively recruited patients were classified based on clinical presentation and the core CSF biomarker profile (amyloid‐beta‐42[Aβ1‐42 <650 pg/ml], [Aβ1‐42/Aβ1‐40 ratio<0.08], total‐tau <400 pg/ml and p‐tau181 >60 pg/ml) measured by INNOTEST® immunoassays (Fujirebio). Diagnostic performance was compared against INNOTEST® p‐tau181 using area under the curve (AUC).

Result

The in‐house p‐tau217 assay demonstrated a lower limit of quantification of 1.4pg/ml with robust analytical performance, including dilution linearity (mean recovery=104%), spike recovery (mean recovery=97%) and antibody specificity. P‐tau217 correlated strongly with p‐tau181 in all participants (r=0.82, p<0.0001) and showed six‐fold mean increase in both AD and CJD versus either controls or PSP (p<0.0001). In contrast, p‐tau181 was only increased 2.5‐fold in AD patients (p>0.05), but not CJD. P‐tau217 and p‐tau181 had similar performances in separating AD from controls (AUC>97%), and AD from PSP (AUC>95%). P‐tau217 poorly differentiated AD from CJD (AUC=63%, compared with 87% for p‐tau181) due to the highly overlapping p‐tau217 concentrations in both groups. However, p‐tau217 better distinguished CJD from controls (AUC=96%) compared with p‐tau181 (AUC=76%). Cross‐sectionally, p‐tau217 associated with CSF Aβ1‐42 (r= ‐0.76, p<0.0001). In diagnostic group‐stratified analyses, p‐tau217 correlated with Aβ1‐42/Aβ1‐40 only in AD (r= ‐0.31, p<0.05).

Conclusion

Unlike the AD‐specific p‐tau181, p‐tau217 had a very high diagnostic accuracy in distinguishing both AD and CJD from controls. P‐tau217 increases in CJD appear independent of amyloidosis. P‐tau217 identifies tau pathology in both diseases whilst p‐tau181 is useful for confirming AD diagnosis.
Relative contribution of white matter hyperintensity to amyloid and neurodegeneration in cognitive decline over time or clinical diagnoses in a diverse, community‐based cohort of older adults
Authors: Lao Patrick J , Chesebro Anthony G , Beato Juliet M , Amarante Erica , Igwe Kay C , Maas Benjamin , Boehme Amelia , Gu Yian , Stern Yaakov , Schupf Nicole , Manly Jennifer J , Mayeux Richard , Brickman Adam M
Published: December 2020

Background

The 2018 NIA‐AA Alzheimer’s disease (AD) research framework moves towards a multiple biomarker approach to explain AD development and progression more fully. This research framework has the flexibility to incorporate various biomarkers into a full or partial amyloid‐tau‐neurodegeneration (A/T/N) profile. The objective of this study was to determine the relative contribution of white matter hyperintensities (WMH) to amyloid and neurodegeneration on cognition in a diverse, community‐based cohort of older adults.

Method

A subset of cognitively healthy participants (n=155; age=69‐99yrs; 65% women, 30%/44%/26% Non‐Hispanic White/Non‐Hispanic Black/Hispanic) from the Washington Heights‐Inwood Columbia Aging Project underwent baseline Florbetaben PET (amyloid SUVR), T1‐weighted (cortical thickness[mm]) and T2‐weighted FLAIR MRI (WMH volume[cm3]), as well as subsequent neuropsychological assessments and consensus diagnoses every 1.5 years (up to 6 visits). Linear mixed effects models were used to test for change over time in language, memory, executive function, and visuospatial ability, while cox proportional hazard models were used to test for risk of developing MCI or AD. Biomarkers of interest included amyloid, cortical thickness, and WMH, adjusted for demographics (sex/gender, race/ethnicity, education). Interactions between biomarkers and time (e.g., slope differences) were evaluated as significant below 0.1.

Result

In A/N/V models, higher amyloid was associated with faster rates of decline in language (B [95%CI]: ‐0.08 [‐0.13, ‐0.02]), memory (‐0.13 [‐0.21, ‐0.05]), and visuospatial ability (‐0.05 [‐0.12, 0.01]), higher WMH was associated with faster rates of decline in executive function (‐0.05 [‐0.11, 0.009]) and visuospatial ability (‐0.02 [‐0.05, 0.005]), and lower cortical thickness was associated with lower executive function scores (1.6 [0.10, 3.0]). Individuals were more likely to develop MCI or AD with higher amyloid (Hazard Ratio=4.2, [1.1, 15.9]), but not with higher WMH (1.2 [0.83, 1.7]) or lower cortical thickness (0.03 [4E‐4, 2]).

Conclusion

In this imaging subsample of older community‐dwelling adults, cognitive decline is differentially associated by domain with amyloid or vascular burden, while broader, multi‐domain cognitive impairment necessary for MCI or AD diagnoses is associated with amyloid, one of the hallmark AD pathologies. Results support the use of complementary information from biomarker profiles, including traditional AD, vascular, and neurodegenerative biomarkers, to investigate AD and related dementias.
Cognitive performance effects following a single dose of the M1 muscarinic positive allosteric modulator VU319
Authors: Conley Alexander C. , Key Alexandra P. , Blackford Jennifer U. , Rook Jerri M. , Conn Jeffrey , Lindsley Craig W. , Jones Carrie K. , Newhouse Paul A.
Published: December 2020

Background

VU319 is an investigational positive allosteric modulator of the M1 muscarinic acetylcholine receptor developed for cognitive enhancement in Alzheimer’s disease (AD) and other disorders. Cognitive tasks including test of attention, speed, and memory and event‐related potentials (ERPs) were used during the double‐blind, placebo controlled Single Ascending Dose (SAD) study of VU319. The main pharmacodynamic objectives of the SAD were to identify early markers of functional engagement. Following the ascending dose cohorts, a Food Effect substudy was conducted to assess whether there was any change in the cognitive performance if VU319 was dosed with food compared to in a fasted state.

Method

VU319 was given orally to 52 healthy volunteers aged 18‐55 years. The SAD study tested 40 participants in five dose escalating cohorts (60‐600 mg), in which 6 received VU319 and 2 received placebo. The Food Effect substudy consisted of 12 participants, in which ten received oral VU319 and two received placebo. Cognitive and electrophysiological tasks testing attention, memory and psychomotor speed were examined pre‐dosing and at 5 hours post‐dose. The tasks were selected for their sensitivity to cholinergic tone.

Result

Single dose treatment showed improvements in cognitive and ERP performance on the higher doses of VU319 compared to placebo. Participants responded significantly faster to targets on the continuous performance test after 600 mg compared to placebo (p = 0.03, effect size d = 1.2). On the incidental memory task, participants who received 400 and 600 mg VU319 exhibited larger P300 amplitudes compared to placebo, when present with repeated compared to novel images (d > 0.8). Examination of the relationship between plasma levels of VU319 and cognitive performance showed that response time of psychomotor speed measures improved with increasing blood concentration of VU319 across doses (r>0.38).

Conclusion

We conclude that these results demonstrate likely enhancement of the cholinergic system functioning in healthy adults following a single oral dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by M1 allosteric modulators and provide a framework to examine the cognitive impact of multiple doses of VU319 in AD patients.
The locus coeruleus: In‐vivo characterization with advanced MRI methods and associations with memory in older adults at risk for Alzheimer’s disease
Authors: Solders Seraphina K. , Clark Alexandra L. , Weigand Alexandra J. , Sorg Scott F. , Galinsky Vitaly , Frank Lawrence R. , Bondi Mark W.
Published: December 2020

Background

The locus coeruleus (LC) is the brain’s main source of norepinephrine and plays a key role in modulating attention and memory processes. In Alzheimer’s disease (AD), the LC has been identified as an early site of tau accumulation and this tau pathology may spread via its connections to the transentorhinal cortex (TEC). Historically, this region has been nearly impossible to study in vivo. However, recent advances in structural magnetic resonance imaging (MRI) have provided opportunities to capture the integrity of LC neurons and their projections. We utilized a combination of neuromelanin‐sensitive and diffusion tensor MRI to examine LC integrity and its role in memory.

Method

31 older adults (26 cognitively normal; 5 MCI) underwent T1 fast spin echo and diffusion MRI scans as well as neuropsychological testing. Bilateral LC contrast ratios (CRs) were calculated as neuromelanin‐related signal intensities relative to a reference region. In a subset of participants (n=12; 10 cognitively normal, 2 MCI) LC‐TEC white matter pathways were reconstructed using probabilistic tractography in FSL and average fractional anisotropy (FA) was extracted. Logical Memory and CVLT‐2 were used to assess verbal learning and memory.

Result

Results revealed lower bilateral LC‐CRs was associated with poorer performance on measures of story learning (LMI; r=0.425, p=.045) and word‐list recall (CVLT‐2 Short Delay Recall: r=.481, p=.006; CVLT‐2 Long Delay Recall: r=.375, p=.038). Tractography analyses indicated that higher FA of the left LC‐TEC tract was associated with poorer story learning (LM1: r=‐.651, p=.02), whereas higher FA of the right LC‐TEC tract was associated with poorer word‐list recall (CVLT‐2 Short Delay Recall: r=‐.599, p=.039; CVLT‐2 Short Delay Cued Recall, r=‐.705, p=.01).

Conclusion

Preliminary results indicate that neuromelanin and tractography MRI methods can be utilized for in vivo characterization of the human LC. Lower neuromelanin signal, but higher FA is associated with poorer memory performance in a sample of cognitively normal and MCI adults. Greater tau pathology may alter the LC signal and encroaching tau accumulation in the LC‐TEC pathway may initiate neuroinflammatory processes reflected by increased FA. Future work is needed to understand the temporal course and nature of LC changes across the aging‐MCI‐AD continuum.
A biorepository for the in‐depth validation of pre‐analytical sample handling effects on novel blood‐based biomarkers for Alzheimer’s disease: The first results
Authors: Verberk Inge M.W. , Misdorp Els O. , Koelewijn Jannet MW , Shan Dandan , Lambrechts Charlotte , Shaw Leslie M. , Rissman Robert A. , Blennow Kaj , Zetterberg Henrik , Ball Andrew J. , Edelmayer Rebecca M. , Teunissen Charlotte E.
Published: December 2020

Background

Variation in pre‐analytical sample handling can critically affect biomarker concentrations in biofluids. A study on pre‐analytical effects on novel blood‐based biomarkers is therefore of importance to facilitate their swift introduction in clinical settings. Guided by the Alzheimer’s Association, we established a biorepository of systematically “mistreated” blood samples for analysis of various biomarkers using various technologies. Here we present the first results.

Method

Blood samples were collected from 90 volunteers presenting at the hospital for any disease. Blood was mistreated according to 8 pre‐analytical protocols, resulting in n=10 sample sets per protocol with several aliquots per set to be shared among labs for biomarker analysis. The protocols were designed to test the effects of type of collection tube, and the effects on K2‐EDTA plasma of delayed centrifugation (at room temperature (RT) or 4°C), centrifugation temperature (RT or 4°C), delayed freezing after centrifugation (RT or 4°C), two‐week intermittent storage at low temperature (4°C or ‐20°C), freezing‐thawing (up to 4x) and aliquot tube filling (250µl, 500µl or 1000µl in 1.5‐mL tube). Using a novel 4‐plex Simoa assay simultaneously measuring Abeta(1‐42), Abeta(1‐40), GFAP and NfL, we obtained the first results on our sample sets. A decline was regarded relevant when a change of at least a 10% was observed in the biomarker value compared to the reference conditions.

Result

Collection tube type affected the levels of the assessed markers Abeta(1‐42/1‐40), GFAP and NfL (Figure 1). Delayed centrifugation affected only plasma Abeta(1‐42/1‐40), and only when kept at RT for 24h (average ‐18% decline compared to no delay) and not when kept at 4°C (Figure 2). This same pattern was observed for hold time after centrifugation (Abeta(1‐42/1‐40): ‐16% for 24h hold at RT). Two‐week storage at 4°C but not at ‐20°C affected only Abeta(1‐42/1‐40) (average ‐15%). Centrifugation temperature, up to four freeze‐thaw cycles and aliquot tube filling did not affect the biomarker values Abeta(1‐42/1‐40), GFAP and NfL.

Conclusion

These first results of the project on pre‐analytical effects on novel blood‐based biomarker concentrations show that relevant pre‐analytical effects exist and that it is essential to work towards unified standard operating procedures for blood sample collection, handling and storage.
Developing feedback methods for caregivers of persons with cognitive impairment using a home‐based sensing and computing system
Authors: Thomas Neil W , Ault Laura , Goubran Rafik , Wallace Bruce , Knoefel Frank , Kaye Jeffrey
Published: December 2020

Background

Conventional methods assessing activities related to caregiving rely on self‐report with caregivers providing estimations of time and resources directed to these activities, which vary over time and can be difficult to reliably estimate retrospectively. Home‐based assessment platforms using sensors to collect objective information on daily activities represent a novel method to evaluate caregivers.

Method

This pilot study is an observational trial using the Collaborative Aging Research Using Technology (CART) sensor platform to assess cognitive and functional outcome measures. The study is enrolling individuals with cognitive impairment living with a caregiver. All participants’ complete questionnaires on functional status and behavioral symptoms, and undergo cognitive testing at baseline. These conventional measures are compared to the sensor‐based outcome measures. Caregivers complete an additional survey on burden level, the Zarit Burden Inventory (ZBI‐12). Additionally, focus group sessions will be held including caregivers enrolled in the pilot study and caregivers of individuals with cognitive impairment in the community.

Result

Data is currently being collected on daily functional activities in caregivers. Enrollment is ongoing for participant homes installing the sensor system. Three caregivers are enrolled, with an average age of 61.7 years (± 5.0), and 14 (± 3.4) years of education. Baseline mean ZBI‐12 scores were 15 (±4.6). Data has been collected for 9672 hours in total for the 3 participants. Caregivers slept on average 8.8 (±2.3) hrs/night and took 3868 (± 592) steps per day. Sensor data will be compared to ZBI‐12 scores to identify those activities correlated with higher levels of burden. Information from the focus group sessions will be used to guide development of a feedback system to inform caregivers of their activities related to time and effort spent in caregiving.

Conclusion

A home‐based sensing and computing system could provide objective information on activity and effort related to caregiving activities. The design of the feedback system is being developed using input from end‐users. The information provided by this system could help to inform caregivers of changes in their level of caregiving activities associated with higher levels of stress and more promptly identify whether they should seek increased external or community support.
Synonymous variant rs2405442 in PILRA is associated with Alzheimer's disease and affects RNA expression by destroying a ramp sequence
Authors: Miller Justin , McKinnon Lauren , Murcia Josue D Gonzalez , Kauwe John , Ridge Perry G
Published: December 2020

Background

Paired Immunoglobulin‐like Type 2 Receptor Alpha (PILRA) recognizes specific O‐glycosylated proteins on various cell types, including microglia. A common missense mutation in PILRA, rs1859788, that likely causes the confirmed Alzheimer's disease risk locus at 7q21 is in linkage disequilibrium with synonymous variant rs2405442:T>C. This synonymous variant affects a ramp of rare codons at the beginning of PILRA, which may decrease overall transcriptional efficiency. Since reduced inhibitory signaling in microglia has a protective effect on Alzheimer's disease, we propose that destroying a ramp sequence in PILRA will likewise protect against Alzheimer's disease by reducing the amount of PILRA inhibitory receptor.

Methods

We recently developed an algorithm, ExtRamp, to identify ramp sequences within specific gene sequences. Using ExtRamp, we calculated the relative codon adaptiveness of PILRA using all isoforms in GRCh38. We then calculated the relative codon adaptiveness of PILRA with synonymous variant rs2405442:T>C and found that a ramp sequence is present in the reference isoforms but not the mutant isoforms. We predicted that although the mutant has a more common codon, it would have less overall mRNA expression because it lacks a ramp sequence. We performed biological validation using four sets of three qPCR replicates on the longest isoform to determine the transcriptional efficiency of the mutant versus the reference. We normalized the qPCR output by the number of cells.

Results

Figure 1 shows the relative adaptiveness of the longest PILRA reference isoform and the mutant gene averaged over a nine codon window. The mutant gene has a higher codon adaptiveness at the beginning of the gene sequence, which destroys the predicted ramp sequence. Figure 2 shows that our biological validation using qPCR confirms our prediction that the mutant gene has lower mRNA expression (p‐value = 4.45 × 10−9).

Conclusions

Although higher GC content and more common codons generally increase mRNA levels, the ramp sequence appears to play an integral role in transcriptional efficiency in PILRA. Our results show that synonymous variant rs2405442:T>C directly impacts transcriptional efficiency in PILRA and indicates that synonymous variants should be considered in future association analyses for their causal effects on transcriptional efficiency by modifying ramp sequences.
Prediction of amyloid PET status using the LUMIPULSE G β‐amyloid ratio (1‐42/1‐40)
Authors: Willemse Eline A.J. , Tijms Betty M. , Van Berckel Bart N.M. , van Der Flier Wiesje , Gannon Sara , Bastard Nathalie Le , Radwan Rachel R. , Esquivel Rianne N. , Latham Jessica , Benina Natalya , Dickson Diana , Scheltens Philip , Teunissen Charlotte E.
Published: December 2020

Background

Cerebrospinal fluid (CSF) amyloid biomarker concentrations are valuable in the assessment of patients for Alzheimer’s dementia (AD). Automated platforms and the additional measurement of Aβ1‐40(Aβ40) with Aβ1‐42(Aβ42) has decreased preanalytical variability and increased diagnostic accuracy (Delaby, 2019; Hansson, 2019). Notably, the ratio Aβ42/Aβ40 significantly improves concordance with PET when compared to Aβ42 alone (Hansson, 2019). In this study Aβ42/Aβ40 concordance with PET was evaluated on the LUMIPULSE G1200 platform.

Methods

A subset of biobanked individuals from the Amsterdam Dementia Cohort was included based on availability of visual amyloid‐PET reads using an FDA approved tracer (Florbetaben n=156; Flutemetamol n=71; Florbetapir n= 8) and CSF, and an age requirement of ≥50 years old (n=235). Demographics included 58% amyloid‐PET positive; mean age 63 years; 43% female; MMSE range 12‐30; and diagnoses: subjective cognitive decline (n=53), mild cognitive impairment (n=25), AD (n=105), or other dementias (n=52). CSF Aβ42 and Aβ40 were measured using Lumipulse G1200 (Fujirebio Diagnostics Inc., Malvern, PA). A cutoff for Aβ42/Aβ40 was established by maximizing the Youden index subject with constraint for sensitivity and specificity to differ by no more than 10 percentage points.

Results

At a set cutoff of 646 pg/mL CSF Aβ42 sensitivity and specificity was 78.8% (CI 71.3% – 84.8%) and 80.6% (CI 71.7% – 87.2%) with an AUC of 0.854. CSF Aβ40 sensitivity and specificity was 51.8% (CI 43.5% – 60.0%) and 45.9% (CI 36.4% ‐ 55.8%) with an AUC of 0.401. The ratio Aβ42/Aβ40 at a set cutoff of 0.058 had a sensitivity and specificity of 94.2% (CI 88.9% ‐ 97.0%) and 90.8% (CI 83.5% and 95.1%) with an AUC of 0.952. Frequencies of patients within the AT(N) research framework were evaluated. With Aβ42 alone 127 patients were considered amyloid positive while use of the Aβ42/Aβ40 ratio included 138 amyloid positive patients.

Conclusion

The Aβ42/Aβ40 ratio strongly correlates with PET status when measured on the LUMIPULSE G platform. In conjunction with clinical assessment the Aβ42/Aβ40 ratio can serve as a highly sensitive and specific biomarker to assess amyloid status.
Relationship between spectral analysis, SUV and SUV Pons ratio as a measure of cerebral glucose metabolic rate in Alzheimer's disease
Authors: Edison Paul , Raza Sanara , Femminella Grazia Daniela , Blunt Eleanor G , Carver Stefan , Livingston Nicholas R , Nowell Joseph , Holmes Clive , Ritchie Craig W. , Lawrence Robert M , McFarlane Brady , Tadros George , Ridha Basil H , Bannister Carol , Walker Zuzana , Archer Hilary , Coulthard Elizabeth , Underwood Ben , Prasanna Aparna , Koranteng Paul , Karim Salman , Junaid Kehinde , McGuinness Bernadette , Nilforooshan Ramin , Macharouthu Ajayverma , Donaldson Andrew , Thacker Simon , Russell Gregor , Malik Naghma , Mate Vandana , Knight Lucy , Kshemendran Sajeev , Harrison John E , Brooks David J , Passmore Anthony Peter , Ballard Clive
Published: December 2020

Background

Cerebral metabolic rate of glucose (CMRglc) can be measured with fluorodeoxyglucose (FDG) positron emission tomography (PET) using arterial blood sampling. However, blood sampling is an invasive methodology for subjects. Standard uptake value (SUV) is a non‐invasive method to assess the cerebral glucose metabolism. Here we evaluate the relationship between semi‐quantitative measurements such as SUV and Pons ratio with a quantitative measurement such as Spectral analysis (SA) in order to assess their surrogate use in clinical trials.

Methods

To assess cerebral glucose metabolism by a non‐invasive and simplified method, the standardized uptake value (SUV) and used the Pons RATIO (where target region was divided by pons as a reference region, which requires no arterial input function or blood sampling. The SA was performed using blood sampling to create the input function. The study participants included 63 subjects (mean ± SD age, 71 ± 8 years) from the Evaluating Liraglutide in Alzheimer’s Disease (ELAD) trial. Regional CMRglucose (CMRglc) and regional SUV were measured using FDG PET, and the correlation between CMRglc and SUV together with CMRglc and Pons ratio were estimated for the temporal lobe, medial temporal lobe and hippocampus

Results

In this AD population, the SA and SUV in the temporal lobe (r=0.635, p= >0.001), medial temporal lobe (0.533, p= >0.001) and hippocampus (r=0.539, p= >0.001) had a positive correlation and were statistically significant. The correlation coefficient between SA and Pons ratio for the temporal lobe (r=0.166, p= 0.194), medial temporal lobe (r=0.146, p=0.146) and the hippocampus (r=0.193, p=0.129) was positive but not statistically significant.

Conclusion

The SUV correlated better with cerebral glucose metabolic rate using SA than Pons RATIO in AD subjects, while Pons RATIO did not perform well. Therefore, SUV analysis maybe more reliable analysis method compared to Pons RATIO for FDG PET in clinical trials in AD subjects.
Basal forebrain atrophy and tau pathology are correlated in prodromal AD
Authors: Lo Yi‐Wen , Dore Vincent , Xia Ying , Fazlollahi Amir , Bourgeat Pierrick , Villemagne Victor L.L. , Rowe Christopher C. , Fripp Jurgen , Coulson Elizabeth J.
Published: December 2020

Background

Degeneration of cholinergic basal forebrain (BF) neurons play a role in the progression of Alzheimer’s disease (AD), with atrophy of the BF preceding cognitive dysfunction. Here, we investigated whether the presence of Ab and/or Tau PET tracer retention in cognitively normal elderly controls was associated with BF atrophy.

Method

Cognitively healthy participants (N = 134, 49% male) from the AIBL cohort underwent 3T MRI and amyloid (18F‐NAV4694), and Tau (18F‐MK6240) PET scans. PET images were spatially normalised and scaled to the cerebellar cortex using CapAIBL. An amyloid‐positive scan (Aβ+) was defined by cortical retention of ≥20 centiloids. Tau positivity (Tau+) was defined as the average mesial‐temporal lobe SUVR greater than two standard deviations of the Aβ‐ CN subjects for tau. BF volumes were generated from T1w MRIs using an SPM8‐based pipeline and cytoarchitectonic atlas that define BF nuclei Ch1 to 4. Models were corrected for intracranial volume, grey matter, gender and age. Statistical analysis was implemented in Rstudio using general linear models (GLM).

Result

Subjects were placed into 3 groups (age, 75.03 ± 5.22 years, was not different between groups) consisting of 103 Aβ‐/Tau‐ subjects, 19 Aβ+/Tau‐ subjects and 12 Aβ+/Tau+ subjects. Although not cognitively impaired, the Aβ+/Tau+ cohort had lower MMSE and higher CDR scores than the Aβ‐/Tau‐ group. After correction for intracranial volume, gray matter and age, volumes of the entire BF and BF subregions were significantly smaller in the Aβ+/Tau+ group than the Aβ+/Tau‐ group (Figure 1, p < 0.05). BF volumes for NC Aβ‐/Tau‐ and NC Aβ+/Tau‐ groups were not different, indicating that BF atrophy and Tau pathology are strongly related.

Conclusion

These findings are consistent with previous studies of cognitively impaired populations and suggest that in prodromal AD, atrophy in the BF occurs in parallel with the development of tau pathology and cognitive decline. We are investigating longitudinal changes in this population. Figure 1. Box plot representing comparisons between the three groups in terms of volumetry of BF (A) Ch4 sum ( Ch4 posterior and Ch4 anterior compartments) and (B) Ch1‐3 sum after the correction of intracranial volume and age by general linear models.
Colocalization of atrophy and tau improves AI classification of Alzheimer phenotypical variants
Authors: Damasceno Pablo F. , La Joie Renaud , Maia Pedro D. , Visani Adrienne , Iaccarino Leonardo , Strom Amelia , Edwards Lauren , Tempini Maria Luisa Gorno , Jagust William J. , Miller Bruce L. , Rabinovici Gil D. , Raj Ashish
Published: December 2020

Background

The high cognitive and anatomical heterogeneity in phenotypical variants of Alzheimer’s Disease imposes a formidable challenge for biomarker‐based discriminatory models. Motivated by recent findings (La Joie, 2020) suggesting a causal relationship between regional tau accumulation and future atrophy development, we used Machine Learning techniques to test whether colocalization of these two biomarkers could improve clinical differentiation of AD phenotypical variants.

Method

We investigated 85 amyloid‐positive patients with a clinical diagnosis of AD (MCI or dementia stage), including 17 patients with PCA, 16 with lvPPA, and 52 typical cases (tAD, Table 1). Patients received 3‐tesla MRI and PET with [11C]PIB and [18F]Flortaucipir. Thickness measurements were turned into age and sex adjusted z‐scores (Potvin, 2017). Standardized Uptake Value Ratio (SUVR) images were created using reference regions. Mean SUVR or cortical thickness values were extracted from 72 FreeSurfer regions (Figure 1). Random Forest (RF) and Support Vector Machines (SVM) were used for supervised classification of patients into one of the three diagnosis above. Four distinct models were compared: based on amyloid, atrophy, tau, or on the product between atrophy and tau (hence capturing the colocalization of these two biomarkers). Selected ROIs were acquired using SVM feature importance and used in a second SVM method (SVM‐ROIs).

Result

Figure 2a shows the accuracy of the classification models as a function of the used input features. As a general trend: i) amyloid‐based models had the poorest classification accuracy; ii) tau‐based SVM models outperformed atrophy‐based predictions; iii) the product of atrophy and tau significantly improved accuracy; and iv) in SVM models, selection of a subset of regions consistently improved classifications over those models using all brain regions. Figure 2b shows the confusion matrix for the most accurate model (SVM on selected ROIs).

Conclusion

In the cohort used in this study, the product of atrophy and tau provides a better classification feature than each feature considered in isolation. Our results suggest that the colocalization of these two biomarkers represent a valuable instrument for clinical decision‐making in phenotypical variants of AD. References: La Joie, et al. Science Translational Medicine (2020). Potvin, et al. Neuroimage (2017).
Benefits of home‐based dementia care on clinical and quality‐of‐life outcomes for persons living with dementia and their carers
Authors: Samus Quincy M , Amjad Halima , Huang Jin , Leoutsakos Jeannie‐Marie S , Lyketsos Constantine , Johnston Deirdre
Published: December 2020

Background

Scalable, home‐based approaches for the delivery of comprehensive dementia care that bridge medical, social, and supportive care services are needed to improve outcomes and care value for persons living with dementia (PWD) and family carers. We present results from a CMS‐funded Healthcare Innovations Award evaluating the 18‐month impact of a comprehensive home‐based dementia care coordination program, MIND at Home, on clinical and quality of life outcomes in a racially and socioeconomically diverse group of community‐living PWD and family carers.

Methods

This is a prospective, within‐subject, study to evaluate change (baseline to 9‐months, and baseline to 18‐months) in clinical and quality of life outcomes among 342 PWD in Maryland who received MIND at Home. Within‐group changes on dementia‐related unmet care needs (59 items total, 13 domains), neuropsychiatric behaviors (NPI), quality of life (QOL‐AD), carer burden (Zarit Burden Interview), carer depression (PHQ‐9) were assessed using longitudinal mixed effects models. We also tested whether change in outcomes over time was moderated by baseline cognition, living arrangement, or race (Caucasian vs. Non‐Caucasian) in post hoc analyses.

Results

In adjusted linear mixed models, PWD and carers had significantly fewer total percent unmet dementia‐related needs (PWD: β=‐19.95, SE 0.7, p<0.001; CG: β =‐28.30 SE 0.9, p<0.001) and percent unmet in all need subdomains (all p<0.01), fewer behavioral symptoms (NPI) (β = ‐5.16, SE 1.4, p<0.001), reduced caregiver burden (ZBI short) (β = ‐1.69, SE 0.6, p=0.005), and reduced caregiver distress with behavioral symptoms (β = ‐1.63, SE 0.8), p=0.03) from baseline to 18 months. Carer depression trended towards improvement (PHQ‐9, β = ‐0.63, SE 0.37, p=0.086). No statistically significant change in QOL‐AD scores were observed. Most interaction effects were not significant, however non‐Caucasians tended to benefit more on several outcomes compared to Caucasians.

Conclusion

MIND is a scalable home‐based dementia model of care that promotes evidence‐based dementia care strategies addressing range of key medical, social, and environmental determinants of health. This quasi‐experimental analysis provides new evidence of effectiveness for improving outcomes for both PWD and their caregivers over time to and contributes important new longitudinal data to support the program’s value proposition to potential adopters.
The Alzheimer’s disease sequencing project–follow up study (ADSP‐FUS): Increasing ethnic diversity in Alzheimer’s genetics research with addition of potential new cohorts
Authors: Mena Pedro Ramon , Kunkle Brian W. , Faber Kelley , Celis Katrina , Adams Larry D. , Foroud Tatiana M. , Reyes‐Dumeyer Dolly , Kuzma Amanda B. , Naj Adam C. , Martin Eden R , Dalgard Clifton , Schellenberg Gerard D. , Wang Li‐San , Vance Jeffery M. , Cuccaro Michael L. , Mayeux Richard , Vardarajan Badri N. , Pericak‐Vance Margaret A.
Published: December 2020

Background

The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late‐onset Alzheimer Disease (LOAD). A major concern in AD genetic studies is a lack of racial‐ethnic diversity. The ADSP‐FUS collects and sequences existing both ethnically diverse and unique cohorts with extensive clinical data to expand the utility of new discoveries for individuals from all populations. Additional multi‐ethnic cohorts are presently being recruited (e.g. Amerindian, Korean and Indian).

Method

The cohorts consist of participants from studies of AD, dementia, and aging‐related conditions. Clinical classification (i.e., AD, dementia, and non‐affected) is implemented using algorithms based on a minimal set of criteria derived from standard measures (e.g., global cognitive screeners, dementia rating scales, etc.) and pertinent clinical history. Data dictionaries are generated for each cohort by clinical staff at Columbia University and University of Miami (UM). In total, ADSP‐FUS intends to sequence over 40,000 individuals. Existing biospecimens were obtained and processed through the National Centralized Repository for Alzheimer’s (NCRAD), the primary site for preparation and allocation of DNA, which is then delivered to the Uniformed Services University of the Health Sciences (USUHS) for whole genome sequencing (WGS). The resulting raw sequence data is delivered to the Genome Center for Alzheimer’s Disease (GCAD) for processing and harmonization followed by quality control analysis at University of Pennsylvania and University of Miami into analysis‐ready genotype data. The final step is delivery of clinical, genotype and sequence data to the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS), which serves as the ASDP‐FUS data storage, management and sharing center.

Results

Over 30,000 samples have been ascertained and are distributed as follows: 7,896 with African ancestry; 9,475 with Hispanic ancestry; 13,531 with non‐Hispanic white ancestry (1,400 EOAD and 3,745 autopsy) and 89 with Amerindian ancestry.

Conclusion

The ADSP‐FUS is designed to enhance ongoing efforts for the identification of shared and novel genetic risk factors for LOAD among different populations. This project will expand our current knowledge of potential genetic risk and protective variants for LOAD across all populations with the hope of developing new treatments.