bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Aβ 42:40 ratio tracks with changes in brain amyloid PET SUVr in the core and open label extension of the phase 2 proof of concept study ban2401‐g000‐201 following treatment with lecanemab in subjects with early Alzheimer’s disease
Authors: Swanson Chad J , Kanekiyo Michio , Kaplow June , Dhadda Shobha , Irizarry Michael C , Koyama Akihiko , Li David JianJun , Verbel David , Gordon Robert , Heanue‐Travers Helena , Hodgkinson Mark , Kramer Lynn D
Published: December 2021

Background

Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils) and insoluble fibrils. Lecanemab reduced the amyloid PET standard uptake value ratio (SUVr) and slowed clinical decline in an 18‐month Phase 2 proof of concept study in early Alzheimer’s disease (Alz Res Therapy 13; 2021). An Open label extension (OLE) with 10 mg/kg IV biweekly lecanemab dosing was implemented after analysis of the Core study, with an intervening gap period off‐treatment ranging from 9‐54 months (mean 24 months). The present study aimed to evaluate longitudinal plasma Aβ 42:40 ratio (C2N PrecivityAD assay) and the relationship to longitudinal amyloid PET in the Core study, gap period, and OLE.

Method

The amyloid PET sub‐study in the Core study assessed baseline, 12 months and 18 months SUVr with florbetapir, and participants in the OLE amyloid PET sub‐study were imaged at baseline, 3 or 6 months, and 12 months. Plasma samples were collected at the same timepoints and analyzed as described previously (West et al, Mol Neurodegen 2021). Mean changes from Core or OLE baseline and Pearson correlation coefficients were calculated at the group and individual levels for amyloid PET SUVr and plasma Aβ 42:40 ratio, accounting for repeated measures.

Result

OLE subjects with plasma samples (N=121) were evaluated for this analysis. Lecanemab produced dose dependent reductions in PET SUVr, with corresponding increases in plasma Aβ 42:40 ratio in Core and OLE. In the OLE, reductions in PET SUVr were dependent on OLE baseline SUVr; PET reductions in the OLE were inversely correlated with increases in plasma Aβ 42:40 ratio. Changes in plasma Aβ 42:40 ratio were inversely correlated with changes in PET SUVr at the group and individual levels in the Core (group: r=‐0.939, p=0.0056; individual: r=‐0.49; p<0.0001) and OLE (group: r=‐0.907, p=0.0007; individual: r=‐0.31 p=0.0012) studies.

Conclusion

Lecanemab dose‐dependent reduction in brain amyloid PET SUVr correlate with increases in plasma Aβ 42:40 ratio. These data align with the OLE clinical data and suggest that plasma Aβ 42:40 ratio has the potential to track the anti‐amyloid effects of lecanemab in AD patients.
Development and assessment of a brief screening tool for psychosis in dementia
Authors: Cummings Jeffrey L , Atri Alireza , Ismail Zahinoor , Dickerson Brad C , Ballard Clive , Grossberg George T , McEvoy Bradley , Foff Erin
Published: December 2021

Background

Hallucinations and delusions associated with dementia‐related psychosis (DRP) can occur in persons with dementia—however, quickly screening for these symptoms in busy clinical settings can be challenging. We developed the DRP3 Screen, a novel tool to screen for psychosis in clinical settings; performed an Alignment Exercise to determine association of the DRP3 Screen with established psychosis/DRP reference assessments; and retrospectively assessed the ability of the DRP3 Screen to detect patients with DRP enrolled in a clinical trial (HARMONY, NCT03325556).

Methods

The DRP3 Screen comprises 3 yes/no questions and was developed by Acadia Pharmaceuticals Inc. in collaboration with an international team of six subject matter experts (SMEs). Through facilitated discussions, the panel developed questions addressing key aspects of psychosis in dementia. SMEs independently rated level of alignment (Table) of the questions with current reference assessments (SAPS‐H+D, NPI‐Q, IPA Criteria) to determine if the symptoms itemized in those assessments would be captured by ≥1 DRP3 Screen question. Criteria for association with a reference assessment item was mean rating ≥2.0 for at least one DRP3 Screen question (95% CI, lower limit ≥1.3). Inter‐rater reliability of the Alignment Exercise for individual reference assessments was assessed using Fleiss’ kappa statistic. For retrospective application of the DRP3 Screen to HARMONY, patients were considered likely to have been identified by the DRP3 Screen if they were positive (score ≥2) on ≥1 SAPS‐H+D items that were positively associated with the DRP3 Screen.

Results

All items across 3 reference assessments (except SAPS‐H+D D6, somatic delusions) were associated with the DRP3 Screen. Mean level of alignment segregated to none/some (0.3‐1.8) and most/all (2.3‐3.0) with significant inter‐rater agreement of the DRP3 Screen with the SAPS‐H+D, NPI‐Q and IPA Criteria, (kappa values: 0.37, 0.26, and 0.45, respectively; p<.0001). Retrospective application of the DRP3 Screen to HARMONY identified all trial enrollees.

Conclusions

The novel DRP3 Screen is a brief tool designed to assess the presence of hallucinations and delusions in persons with dementia. Potential for its clinical application has been established through association with current reference assessments, with significant agreement among raters; and through successful retrospective application to an existing trial population.
Data‐driven approach for early detection of pathological pathways in middle‐aged adults with family history of sporadic Alzheimer’s disease
Authors: Peña‐Gomez Cleofé , Akinci Muge , Sánchez‐Benavides Gonzalo , Shekari Mahnaz , Grau‐Rivera Oriol , Operto Grégory , Milà‐Alomà Marta , Sala‐Vila Aleix , Salvadó Gemma , Kollmorgen Gwendlyn , Suridjan Ivonne , Blennow Kaj , Zetterberg Henrik , Molinuevo Jose , Gispert Juan Domingo , Suarez‐Calvet Marc , Arenaza‐Urquijo Eider M
Published: December 2021

Background

In a sample of cognitively unimpaired (CU) middle‐aged adults with family history (FH) of sporadic Alzheimer’s disease (AD), we (i) classified participants based on similarity patterns of expression in cerebrospinal fluid (CSF) biomarkers of AD, axonal damage, synaptic dysfunction, neuroinflammation, and glial response, and (ii) characterized the participants expressing these patterns using neuroimaging, demographics, clinical, and FH variables.

Method

254 CU participants with FH of sporadic AD from the ALFA study (Table 1) underwent imaging, lumbar puncture, clinical, and neuropsychological evaluations. CSF‐biomarkers Ab42, Ab40, NfL, neurogranin, sTREM2, YKL40 and GFAP were measured by Roche NeuroToolKit immunoassays; p‐tau181 and p‐tau217 were measured with an in‐house Simoa‐based assay, p‐tau231 with an ADx ELISA, and SYT1 and SNAP25 using immunoprecipitation mass spectrometry. Participants were clustered using an agglomerative clustering algorithm according to their similarity of CSF‐biomarker expression–Subsequently, we performed statistical groups comparisons.

Result

Four clusters were identified. Higher Aβ burden (lower Aβ42/40) was the hallmark of only 1 cluster (C1: “AD‐like”, mean centiloid [CL]: 15), while the other 3 clusters showed lower Aβ burden but higher expression of Glial (C2), Tau (C3, “SNAP‐like”), or synaptic (C4) markers (mean CL: ‐2.6, ‐4.5, ‐2.2, respectively) (Figure 1). The “AD like” cluster comprised the oldest participants with the lowest memory performances (C1<C2<C3C3>C2>C4), participants with the closest age to the parental onset (C1>C2>C4>C3), and low gray matter in the hippocampus and AD‐sensitive regions (C1<C3all) with preserved executive performances and hippocampus (C2>all). The “SNAP‐like” cluster, composed mainly by females (80%), showed the highest proportion of participants with both parents affected with AD and the lowest hippocampus volume (C3<all). The “Synaptic” cluster showed a greater proportion of males, with the best memory performance among the clusters.

Conclusion

In CU middle‐aged adults, we identified differential expressions of CSF‐biomarkers conforming to Aβ‐dependent and independent biological pathways, some of which resemble previously described biomarker conditions such as SNAP. These distinct biomarker expressions were associated with specific imaging and clinical features. Longitudinal studies are warranted to investigate the clinical progression of participants showing these distinct biomarker profiles.
Wisconsin healthcare utilization cost among American Indians/Alaskan Natives with and without ADRD
Authors: Johnson Adrienne L , Norton Derek L , Mundt Marlon P , Seep Elaina , Wyman Mary F , James Taryn T , Zuelsdorff Megan , Lambrou Nickolas H , Umucu Emre , Gleason Carey E
Published: December 2021

Background

The annual cost of Alzheimer’s disease and related dementias (ADRD) in the US is $355 billion; that rate is expected to triple by 2050. Individuals ADRD accrue higher healthcare utilization costs than peers without ADRD, including those with comorbid conditions (e.g., cancer, coronary artery disease, diabetes). Although research examining prevalence of ADRD in American Indians/Alaskan Natives (AI/AN) is limited, recent data suggest the prevalence of ADRD in the AI/AN population is 49% higher than in the Non‐Hispanic White population. Only one study has evaluated the healthcare utilization of AI/ANs, which showed greater utilization rates among those with (versus without) ADRD diagnosis and a rapid increase in utilization following ADRD diagnosis. We have yet to comprehensively analyze the additive cost of ADRD within the US among AI/ANs.

Method

Post‐paid electronic health record data from Wisconsin Department of Health Services were retrospectively analyzed to compare non‐Tribal and Indian Health Service utilization costs among Medicaid enrolled AI/ANs, ages 40 and older, based on the presence or absence of ADRD throughout data review (7/1/2015 through 7/1/2020). Three separate analyses were completed, separated by payer programs: fee‐for‐service, HMO, and long‐term care. In each analysis, controls (individuals without ADRD) were matched to cases (individuals with ADRD) using exact matching across the subclasses defined by crossings of age group, sex, diabetes status, and emphysema status (Tables 1‐3). Weighted Wilcoxon rank sum tests were then used to compare total payable costs per capita. Tests accounted for both the subclass sampling strata and weights produced through the matching process. Weighted Chi‐square tests of association were also employed to confirm balance was achieved across age groups, sex, diabetes status, and emphysema status in the matching process; no weighted imbalances occurred.

Result

Among all three programs, AI/ANs with dementia had significantly higher healthcare utilization costs than those without dementia, after matching for age, gender, diabetes and emphysema status.

Conclusion

AI/ANs with ADRD accrued at $25,000 more over 5 years, on average, compared to those without ADRD. The greatest cost disparity was in long‐term care waiver programs ($50,879). Cost‐effective interventions aimed at ADRD prevention and treatment among AI/ANs are greatly needed.
Brain target occupancy of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme, following administration of single and multiple doses to healthy volunteers
Authors: Kielbasa William , Shcherbinin Sergey , Goldsmith Paul , Phipps Krista M , Biglan Kevin , Mancini Michele , Russell David , Constantinescu Cristian , Gunn Roger N , Nuthall Hugh Norman , Mergott Dustin J. , Lowe Stephen L , Collins Emily C
Published: December 2021

Background

LY3372689, an O‐GlcNAcase (OGA) enzyme inhibitor, is being developed as a potential treatment of tauopathies, including Alzheimer’s disease. OGA inhibition is proposed to delay the progression of tau‐related diseases by slowing the accumulation of hyper‐phosphorylated, insoluble tau filaments. We report on single dose (SD) and multiple dose (MD) clinical studies testing the effect of LY3372689 on brain OGA enzyme occupancy (EO).

Method

A positron emission tomography (PET) radioligand, 18F‐LY3316612, was used to assess brain OGA EO in healthy volunteers (HV). In the SD study [NCT03944031], 0.25, 1 and 5 mg LY3372689 were evaluated across 4 cohorts (N = 4 HV per cohort). Each HV had PET scans at baseline and two post‐dose intervals. Post‐dose scans occurred at 2 and 24 hours at 0.25, 1, and 5 mg, with additional scans for 1 mg at 30 and 54 hours. The MD study [NCT04392271] consisted of 1 cohort (N = 4 HV) given 1 mg LY3372689 once daily for 14 days. Each HV had a baseline PET scan, and PET scans at 24 hours post‐dose after the 1st and 14th administration of LY3372689. Plasma pharmacokinetics was assessed in these studies.

Result

In the SD study, the mean brain OGA EO at 5 mg was 98% at 2 hours and 93% at 24 hours. At 1 mg, the mean EO was 97% at 2 hours, 81% at 24 hours, 68% at 30 hours, and 30% at 54 hours. The EO at 0.25 mg was lower at 2 hours (26%) compared to 24 hours (46%). The Emax and EC50 values were estimated to be 97% and 0.1 ng/mL, respectively. In the MD study, the OGA EO at 24 hours after the 1st and 14th administration of 1 mg LY3372689 was 84%.

Conclusion

PET studies in healthy volunteers demonstrated that LY3372689 can achieve high brain target occupancy of the OGA enzyme. Brain OGA EO was maintained after multiple dosing, supporting the durability of target engagement for longer clinical trials. The human PET data will be used to support LY3372869 dose selection for efficacy trials in tauopathies.
Serious mini‐games for cognitive function assessment
Authors: L'Yvonnet Thibaud , De Maria Elisabetta , Robert Philippe , Rigault Jean‐Paul , Zeghari Radia , Manera Valeria , Moisan Sabine
Published: December 2021

Background

The presence of neurocognitive disorders (NCD) must be detected at an early stage of the disease progression and monitored by clinicians overtime, in order to provide early individualized interventions. Today, a reliable diagnosis requires a heavy set of neuropsychological tests, often coupled with biomarker evidence. There is growing interest in finding objective, fast to administer, and reliable behavioral markers that could complement classical clinical assessment and help detecting early changes in cognitive performance. Serious games have been proposed as promising tools to screen cognitive deficits in people with NCD [1]. In this study, we investigated the interest of employing a battery of mini‐games developed by CoBTeK lab to distinguish elderly patients with mild NCD from patients without cognitive decline.

Methods

In the context of an ongoing project, we recruited 20 subjects with mild NCD (14 females; age: M=75.5, SD=5.7; MMSE, M=26.1; SD=2.2) and 10 subjects with subjective cognitive decline ‐ SCD (9 females; age: M=71.0, SD=7.6; MMSE, M=29.2, SD=1.2) at the Nice Memory Center. Participants played four mini‐games on a tablet, each game assessing a different cognitive function: selective and sustained attention, episodic memory, inhibitory control, and sensitivity to reward. We collected different data including scores, responses, response times, and videos (focused on hand gestures).

Results

Preliminary data analysis focused on one mini‐game (assessing sensitivity to reward) suggests that participants with mild NCD had an almost significantly lower sensitivity to reward. Once the data analysis is complete for the 4 mini‐games, and the final sample size of 50 participants is reached (by the end of June 2021), we plan to integrate all the collected data into a predictive behavior model compliant with model checking techniques.

Conclusions

Converging with previous findings, these very preliminary results suggest that mini‐games could be interesting to differentiate patients with mild NCD from subjects without cognitive impairment. Predictive behavior model based on mini‐games may in the next future help clinicians identify individuals that meet the profile of NCD. Reference: Robert P et al. (2014) Recommendations for the use of Serious Games in people with Alzheimer’s Disease, related disorders and frailty. Front Aging Neurosci. 6:54. doi:10.3389/fnagi.2014.00054
Communication difficulty and application of communication skills under the use of personal protective equipment
Authors: Kanamori Takuya , Uchiyama Masayo
Published: December 2021

Objective

The study aims to investigate the difficulties in communicating and application of communication skills of nurses wearing Personal Protective Equipment (PPE) when interacting with persons with cognitive impairment.

Method

A web‐based questionnaire survey was conducted among 500 registered nurses of the digital researching company in Japan in March 2021. Participants were asked to rate their difficulty in communicating with persons with cognitive impairment while under the use of PPE using a 4‐point Likert scale. Further, they answered the Communication Skill Index (CSI) to evaluate the application of communication skills when interacting with a person with cognitive impairment. The CSI consists of 23 items, each ranging from 1 to 4. A high CSI score suggests frequent application of communication skills. The relationship between these factors were analyzed statistically using the Student’s t‐test and Spearman’s correlation coefficient test.

Results

The study participants’ mean age, proportion of women, and mean length of working experience were 40.0±9.9, 83.2%, and 14.8±9.7 respectively. All participants used facemasks, 31.2% of them used safety glasses, and 13.2% of them used medical gowns while caring for persons with cognitive impairment. The mean score of the communication difficulty was 2.6±0.8, and 55.6% of the participants found it difficult to communicate with persons with cognitive impairment while under the use of PPE. Further, participants using safety glasses and medical gowns had significantly higher communication difficulty than those who only wore facemask (p<0.05). The mean score of total CSI was 72.7±11.3, and the mean score of each item ranged from 2.6 to 3.6. “Use other words to reflect what the person with cognitive impairment has said” was the lowest, while “speak slowly” was the highest. A significant correlation was found between communication difficulty and total CSI score, and a score of 6 on CSI items, such as “use a gesture” and “ask only one question at once” (P<0.05).

Conclusion

Majority of the nurses wearing PPE find it difficult to communicate with persons with cognitive impairment. Thus, they must consciously apply their communication skills.
Association between magnetoencephalography resting‐state brain oscillatory activity in regions with early Alzheimer’s disease neuropathology and global cortical atrophy
Authors: Brinson Zabecca S. , Proskovec Amy L. , Yu Fang F. , Longoria Anthony , Rossetti Heidi , Kelley Brendan J. , Berry Jarett D. , Maldjian Joseph , Davenport Elizabeth M.
Published: December 2021

Background

Previous magnetoencephalography (MEG) studies have shown that individuals with mild cognitive impairment and Alzheimer’s disease (AD) demonstrate increases in δ and θ, decreases in α and β, and lower ratios of relative power between high and low frequency bands compared to controls. This analysis investigates the association between global cortical atrophy, a measure of neurodegeneration, and MEG resting‐state oscillations in cortical regions that show early AD neuropathology.

Method

Eighteen cognitively impaired adults (mean age: 65.2 years, 56% female) and 18 age‐and‐sex‐matched controls (mean age: 65.7 years, 44% female) were included in this analysis. All completed a 6‐minute resting‐state MEG scan and a T1w structural brain MRI scan. Processed MEG data was filtered into canonical frequency bands. Mean relative power (MRP) and α/δ, β/δ, α/θ, (α+β+γ)/(δ+θ) ratios were computed for 6 AAL atlas regions: angular gyrus, anterior cingulum, hippocampus, parahippocampal gyrus, posterior cingulum, and precuneus. Global cortical volumes (GCV) normalized by intracranial volumes were computed using FreeSurfer 6.0. Linear mixed effects modeling was performed for each region, with MRP or spectral ratio as the outcome and normalized GCV as the predictor. Age and sex were covariates and cognitive status was included as a random effect.

Result

Normalized GCV was negatively associated with MRP‐θ in the precuneus (β=‐0.0085, p=0.034), posterior cingulum (β=‐0.0088, p=0.032), and angular gyrus (β=‐0.0077, p=0.043); positively associated with MRP‐α in the precuneus (β=0.0161, p=0.006), posterior cingulum (β=0.0140, p=0.007), and angular gyrus (β=0.0128, p=0.027); positively associated with the α/δ ratio in the precuneus (β=0.1468, p=0.006) and posterior cingulum (β=0.1068, p=0.012); and positively associated with the α/θ ratio in the precuneus (β=0.1398, p=0.044). Higher beta coefficients were found for the cognitively impaired vs. nonimpaired for the α/δ ratio in the precuneus (β=0.1532 vs. 0.1404) and posterior cingulum (β=0.1119 vs. 0.1017) and the α/θ ratio in the precuneus (β=0.1876 vs. 0.0920).

Conclusion

Stronger spontaneous θ activity, weaker spontaneous α activity, and lower spectral ratios are associated with global cortical atrophy, a known pathological process in AD. The precuneus α/θ ratio may be able to distinguish cognitively impaired from nonimpaired subjects and help in determining those at risk for AD.
The effect of plasmalogen precursor supplementation on blood catalase and malondialdehyde levels in cognitively impaired persons
Authors: Goodenowe Dayan B. , Haroon Jonathan , Zielinski Margaret A. , Mahdavi Kennedy D. , Habelhah Barshen , Shtilkind Leah , Kling Mitchel A. , Jordan Sheldon E.
Published: December 2021

Background

Malondialdehyde (MDA) is a metabolic byproduct of lipid peroxidation that is elevated in in the serum of Alzheimer’s patients. Catalase (CAT) enzymatically and plasmalogens (PLS) biochemically react with and neutralize hydrogen peroxide. 1‐O‐alkyl‐2,3‐diacylglycerol (ADG) PLS precursors containing docosahexaenoic acid (DHA) at the sn‐2 position have been shown to increase blood PLS and to be neuroprotective in animal models of neurodegeneration. The goal of this study was to evaluate the effect of dietary DHA‐ADG supplementation on PLS and MDA levels and CAT activity in the serum of cognitively impaired persons.

Method

Twenty‐two persons (11M/11F), aged 37‐84 (average = 69) with mild to moderate cognitive impairment [CDR: 14(0.5); 4(1); 4(2)] were administered DHA‐ADG [1.0ml/day for 30 days; 2.0ml/day for 60 days; 4.0ml for 30 days, followed by a 30‐day wash‐out period]. Serum PLS, MDA, and CAT were measured at baseline and the end of each month.

Result

Blood DHA‐PLS were elevated two‐fold by month 3 (2.06, 95% CI=1.64‐2.48) and remained elevated during treatment. Serum DHA‐PLS levels were positively correlated with CAT activity (R=0.32, p=2.7e‐03) and negatively correlated with MDA levels (r=0.41, p=9.3e‐05). Increased DHA‐PLS levels from baseline correlated with decreased MDA levels (r=0.42, p=6.4e‐05), but not increased CAT (r=0.02, p=0.9e‐01). DHA‐ADG supplementation significantly elevated CAT activity in persons with baseline CAT activity less than the average and significantly decreased MDA levels in persons with baseline MDA levels above the average to levels equivalent to the top and bottom 50%, respectively (p<0.05). MDA levels and CAT activity were negatively correlated (r=0.26, p=1.4e‐02).

Conclusion

DHA‐ADG was effective at elevating blood DHA‐PLS, reducing MDA in persons with high baseline MDA levels and increasing CAT activity in persons with low baseline CAT activity at the dosages studied. Although total serum DHA‐PLS were correlated with both MDA and CAT, DHA‐PLS elevation from baseline was only correlated with decreased MDA levels from baseline suggesting that the increased CAT effect of DHA‐PLS elevation was due to its MDA lowering effect. These observations are consistent with the known biochemical effects of PLS on peroxide neutralization and provide further mechanistic evidence regarding the protective effects of high blood PLS levels.
Feasibility of repeated administration of automated verbal‐paired‐associate memory in older adults
Authors: Kaula Alexander J , Cormack Francesca K , Taptiklis Nick
Published: December 2021

Background

Verbal Paired‐Associates (VPA) has traditionally been administered in the clinic by a trained rater. Automated remote administration and scoring would enable use of this cognitive task at scale, over multiple visits, to allow detection of changes in memory abilities over time. Here, we address several key aspects in a feasibility study: First, the task must have good dynamic range, with performance not at ceiling or floor in older adults. Second, in order to be sensitive to memory changes over time, the test must show good test‐retest reliability. Third, older adults should be willing and able to carry out the task and operate the technology.

Method

41 Participants aged 55‐90 years were enrolled in the study using the Prolific online study tool, agreeing to take part in a repeat‐visits study lasting five days. Five parallel sets of eight word‐pair stimuli were generated based on a model which allowed memorability characteristics to be titrated such that the task difficulty would be suitable for an older‐adult population. On each day of the study, participants were emailed a link to the day’s task. We used the Neurovocalix web‐app to present word‐pairs and to automatically score their responses. A questionnaire was administered to assess the subjective experience of participants. Audio of participant responses was reviewed offline by the researcher.

Result

Scores showed some improvements over time, and the range of scores conformed to our expectations based on prior modelling. Test‐retest reliability was modest between first and second sessions but became much stronger from session two onwards. Participants generally enjoyed the task and were highly motivated to perform to the best of their abilities. Questionnaire responses confirmed that the majority found the task and interaction with the automated system engaging and rewarding.

Conclusion

These preliminary results suggest automatic assessment of memory works for longitudinal measurement in older adults. The change in test‐retest reliability from sessions 1‐2 to sessions 2 and onwards suggests that a familiarisation phase will be important.
Patient experience and satisfaction with remote memory assessment: Responding to clinical need in times of COVID‐19 restrictions
Authors: Raczek Malgorzata , Porter Emma , Daley Stephanie , Farina Nicolas , Velayudhan Latha , Abraham Rajesh
Published: December 2021

Background

The suspension of memory services during the COVID‐19 pandemic delayed dementia diagnosis and access to early intervention. Some services responded to the challenge by developing a remote memory assessment pathway to comply with reduced social contact measures to protect vulnerable patients. The aim of the study was to establish whether remote model is considered a satisfactory experience within the context of the COVID‐19 pandemic and to understand the factors associated with patient and carer satisfaction of remote pathway.

Method

73 participants recruited from patients referred to memory clinic in West Sussex, who were assessed over a video or telephone. Participants completed an 11‐item questionnaire capturing satisfaction across a range of elements, contextual items (the impact of the pandemic, loneliness, previous experience of using teleconference technology and diagnosis), as well as 3 dimensions from Patient Experience Questionnaire. Descriptive statistics are reported at a whole sample level, separated by patient and carer status. A hypothesis driven set of bivariate analyses (Spearman’s rank) was used to understand the association between overall satisfaction and key independent factors across the whole sample.

Results

73 participants were typically older adults (M=68.5, SD=13.3) and female (n=40, 54.8%). The patient was more likely to be older, feel lonely within the past week and to have used video call software when compared to the carer (p> 0.05). Participants were generally satisfied with the remote pathway with 95.8% (n=69) agreeing or strongly agreeing with the statement “Overall, I was satisfied with the assessment”. Patients and carers did not significantly differ on any satisfaction response, apart from the ease of use of technology, in which carers were more likely to find the technology easy to use (U= 432.5; p=0.01). Worry about contracting COVID and communication experience was positively associated with overall satisfaction, whilst perceived communication barriers were significantly negatively associated with overall satisfaction.

Conclusions

Remote memory assessment was a positive and satisfactory experience for most patient and carers. The remote pathway should be considered as an option available during and beyond the pandemic to improve access and patient choice of assessment modality.
Favorable cognitive effects of the BET protein inhibitor apabetalone in patients 70 and older
Authors: Johansson Jan O , Cummings Jeffrey L. , Zetterberg Henrik , Winblad Bengt , Sweeney Mike , Kulikowski Ewelina , Lebioda Kenneth , Khan Aziz , Toth Peter P. , Kalantar‐Zadeh Kam , Ginsburg Henry N. , Nicholls Stephen J. , Ray Kausik K , Schwartz Greg G
Published: December 2021

Background

Cognitive decline in late life including Alzheimer’s disease (AD) and vascular dementia (VaD) may be caused by epigenetic change. Bromodomain and extra‐terminal (BET) proteins are epigenetic transcriptional “readers” found to contribute to chronic disease. Apabetalone, a small molecule BET protein inhibitor for oral administration, was assessed for therapeutic effects on cognitive performance in a randomized trial of patients at high risk for cardiovascular disease (CVD).

Method

In the BETonMACE post‐Acute Coronary Syndrome trial in type 2 diabetes mellitus patients were randomized to apabetalone capsule 100 mg b.i.d. or placebo (n=2425). The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at baseline (n=464) and yearly in the embedded cognition study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score ≥ 26 (normal performance), MoCA score 25 – 22 (mild cognitive impairment), and MoCA score ≤ 21 (dementia).

Result

Apabetalone exposure was equivalent in each of the three MoCA‐score defined groups. Apabetalone treatment over approximately two years was associated with an increased total MoCA score in participants with baseline MoCA score of ≤ 21 (p = 0.02). Onset of cognition benefit appeared after 12 months treatment. There was no significant difference in change from baseline in the treatment groups with higher MoCA scores.

Conclusion

In the BETonMACE trial epigenetic BET protein inhibition by apabetalone capsule 100 mg b.i.d. vs placebo was associated with improved cognition as measured by MoCA in patients with baseline scores of < 21. It is feasible to embed cognition assessment in randomized Phase 3 CVD endpoint studies. BET protein inhibitors warrant further investigation for late life cognitive disorders.
Age and circadian rhythm‐dependent effects of M1 muscarinic acetylcholine receptor positive allosteric modulators and donepezil on sleep‐wake architecture and arousal
Authors: Russell Jason K , Bubser Michael , Newhouse Paul A , Lindsley Craig W , Jones Carrie K
Published: December 2021

Background

Degeneration of basal forebrain cholinergic signaling in aging and Alzheimer's disease (AD) is linked with abnormalities in arousal, sleep/wake architecture, and cognition. While acetylcholinesterase inhibitors (AChEIs) are approved for the treatment of AD, they produce dose‐limiting adverse effects due to nonselective activation of peripheral muscarinic acetylcholine receptors (mAChRs). Selectively targeting the M1 mAChR using M1 positive allosteric modulators (PAMs) has shown promise for boosting cognitive performance and arousal across preclinical species. We evaluate the effects of the M1 PAM VU0453595 on arousal and sleep/wake architecture in aged and young mice across both the active and inactive phases of the circadian cycle. We hypothesize that dosing an M1 PAM during the active phase in aged mice will produce a greater enhancement of arousal and wakefulness, normalizing deficits observed in aged mice.

Method

Utilizing electroencephalography, we examined the effects of the M1 PAM VU0453595 in comparison with the AChEI Donepezil on sleep‐wake architecture and state dependent spectral power in young and aged C57/BL6 mice following dosing in either the active or inactive phases of the circadian cycle.

Result

When compared to young mice, aged mice displayed several alterations in normal sleep‐wake architecture; in the inactive phase, reductions in rapid eye movement (REM) sleep, while in the active phase increases in non‐REM (NREM) sleep and decreases in wakefulness. Aged mice also displayed reductions in slow delta power during NREM sleep and increased delta power during wake. In young mice, dosing with both compounds increased wakefulness and arousal during wake in the inactive phase, with reduced effects in the active phase. In the aged mice VU0453595 increased arousal during wake in the inactive phase, and both wakefulness and arousal during wake when dosed in the active phase. Donepezil in contrast produced increased wakefulness in the inactive period, but reduced wakefulness in the active period and limited effects on arousal during wake.

Conclusion

The M1 PAM VU0453595 produced increases in wakefulness and arousal in aged mice during the active phase, suggesting that selective M1 PAMs may be suitable for dosing during the active phase in aging and AD populations to normalize disruptions in wakefulness and arousal.
Plasma p‐Tau181 and p‐Tau231 offer complementary information to identify Alzheimer's disease pathophysiology
Authors: Ferreira Pamela C.L. , Brum Wagner Scheeren , Ferrari‐Souza João Pedro , Tissot Cécile , Bellaver Bruna , Therriault Joseph , Benedet Andréa Lessa , Ashton Nicholas J. , Servaes Stijn , Lussier Firoza Z. , Chamoun Mira , Stevenson Jenna , Rahmouni Nesrine , Gauthier Serge , Vanmechelen Eugeen , Zetterberg Henrik , Blennow Kaj , Zimmer Eduardo R. , Karikari Thomas K. , Rosa‐Neto Pedro , Pascoal Tharick A.
Published: December 2021

Background

Pathophysiological detection of Alzheimer’s disease (AD) is commonly made using cerebrospinal fluid (CSF) and positron emission tomography (PET). However, these methods are invasive and expensive, limiting their use in clinical settings Blood‐based biomarkers, mainly measuring phosphorylated tau epitopes at threonine 181 (p‐tau181), threonine 217 (p‐tau217), threonine 231 (p‐tau231), have shown promising results in detecting AD. However, it is still unknown whether the use of different plasma p‐Tau epitopes offer overlap or complementary information. Here, we tested the hypothesis that plasma p‐Tau181 and p‐Tau231 markers provide complementary information to each other to identify AD pathophysiology.

Methods

Plasma p‐Tau181, p‐Tau231, [18F]AZD4694 amyloid‐PET, [18F]MK6240 tau‐PET, MRI and cognitive assessment from 284 individuals [30 cognitively unimpaired (CU) young, 155 CU), 54 mild cognitive impairment (MCI) and 38 AD] were obtained from the McGill TRIAD cohort. The individuals with diagnose of AD or MCI was classified as cognitively impaired (CI). Maximum Youden Index were used to determine cut‐offs for plasma p‐Tau181 (11.1 ng/mL) and plasma p‐Tau231 (11.8 ng/mL) considering CU young adults as controls. We classified the individual as positive or negative using plasma for each p‐Tau biomarker. Individuals were divided in the four possible groups (p‐Tau181‐/p‐Tau231‐, p‐Tau181+/p‐Tau231‐, p‐Tau181‐/p‐Tau231+ and p‐Tau181+/p‐Tau231+) and compared to assess differences in cognition and other biomarkers.

Results

Plasma p‐tau p‐Tau181 and p‐Tau231 showed moderate correlation with each other (r = 0.64, p <0.0001) (Figure 1). The p‐Tau181+/p‐Tau231+ group presented higher tau PET and amyloid PET uptake compared to groups negative for both or only one p‐tau biomarker (all p<0.01) (Figure 2A, B). Similarly, p‐Tau181+/p‐Tau231+ group showed worse cognitive performance and hippocampal atrophy than individuals with at least one p‐tau biomarker negative (Figure 2C‐E).

Conclusion

These findings highlight ‐ for the first time ‐ that individuals positive for both p‐tau231 and p‐tau181 show worse cognitive performance, higher amyloid and tau burden, and lower hippocampus volume than individuals positive for only one of these markers. Our results have important implications for the use of plasma p‐tau biomarker in clinical trials and practice, suggesting that the quantification of more than one plasma p‐tau epitope may be useful to identify individuals on an AD pathway.
Preliminary analysis of qEEG during a subliminally‐primed task‐switching test in pre‐symptomatic Alzheimer’s disease
Authors: Wu Daw‐An , Adams Sara W. , Hung Shao‐Min , Rossi Iyla P. , Harrington Michael G. , Shimojo Shinsuke , Arakaki Xianghong
Published: December 2021

Background

In testing cognitively healthy (CH) participants with normal vs. pathological amyloid/tau ratios (CH‐NAT vs. CH‐PAT), we previously identified significant differences in alpha‐band markers from quantitative electroencephalography (qEEG) during a Stroop‐based task‐switching test. Using a modified version of the test, we then found that CH‐PATs and CH‐NATs were differentially susceptible to subliminal priming, leading to different effects on reaction time. Here, we applied qEEG to the latter testing paradigm. We have conducted a preliminary analysis, using data from the participants tested prior to interruption of the project by the Covid pandemic.

Method

Participants (CH‐NAT, n=19; CH‐PAT, n=27) viewed a series of Stroop stimuli (e.g. the word “red” written in blue ink), and their task was either to respond to a given stimulus’ color or its word content by pressing buttons. A trial consisted of two stimuli in sequence, and a masked subliminal priming word (“red” or “blue”) was inserted between the two stimuli. The experimental focus was the second stimulus of each trial, which was characterized as having a task which was either switched or non‐switched compared to the first stimulus, and as having a desired response that was congruent or incongruent with the subliminal prime. Event‐related desynchronization (ERD) 250‐750 ms after the second stimulus was measured in the low‐ and high‐alpha bands (αERD).

Result

αERD was observed in both high and low frequency bands following second‐stimulus presentation (both p<<<0.01, in all electrode groups). However there were no significant differences in αERD magnitude between congruent and incongruent prime conditions, nor between the CH‐NAT and CH‐PAT groups (all p>0.05).

Conclusion

Comparisons of prime congruency may be complicated by the fact that the prime can be matched or mismatched along multiple dimensions (prime word, prime location, desired response, stimulus color, stimulus word). Given that behavioral effects have been found for this experimental paradigm, we expect that differences in neural activity may be revealed eventually with more participants, a wider exploratory analysis, and/or a refinement of the experiment task.
Neurochemical signs of astrocytic and neuronal injury in acute COVID‐19 normalizes during long‐term follow‐up
Authors: Kanberg Nelly , Simrén Joel , Éden Arvid , Andersson Lars‐Magnus , Nilsson Staffan , Ashton Nicholas J. , Sundvall Pär‐Daniel , Nellgård Bengt , Blennow Kaj , Zetterberg Henrik , Gisslén Magnus
Published: December 2021

Background

Neurologic manifestations are well‐recognized features of coronavirus disease 2019 (COVID‐19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We wished to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID‐19.

Method

Patients with confirmed acute COVID‐19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow‐up, and blood samples were collected longitudinally. Healthy age‐matched individuals were included as controls. We analyzed plasma concentrations of neurofilament light‐chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF‐15).

Result

We recruited 100 patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID‐19 who were followed for a median of (IQR) 225 (187–262) days. In the acute phase, patients with severe COVID‐19 had higher concentrations of NfL than all other groups (all p < 0.001) and higher GFAp than controls (p < 0.001). GFAp was also significantly increased in moderate disease (p < 0.05) compared with controls. NfL (r = 0.53, p < 0.001) and GFAp (r = 0.39, p < 0.001) correlated with GDF‐15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly included fatigue (n = 40), “brain‐fog” (n = 29), and changes in cognition (n = 25). We found no relation between persistent neurological symptoms and CNS injury biomarkers in the acute phase.

Conclusion

The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicate that post‐acute COVID‐19 neurological sequelae are not accompanied by ongoing CNS injury. Although injury biomarkers commonly increase in severe acute COVID‐19, further investigations into the causes of post‐infectious sequelae are needed.
Plasma biomarkers of neurodegeneration and neuroinflammation in hospitalized COVID‐19 patients with and without new neurological symptoms
Authors: Boutajangout Allal , Frontera Jennifer , Debure Ludovic , Vedvyas Alok , Faustin Arline , Wisniewski Thomas
Published: December 2021

Background

The COVID‐19 pandemic is an unprecedented global health care crisis. Older individuals and those with pre‐existing AD/ADRD or mild cognitive impairment are at increased risk of SARS‐CoV‐2 infection, with a higher mortality. In this study we assessed that the presence of plasma biomarkers associated with AD, neurodegeneration and neuroinflamation in older patients (>60yrs old), who were hospitalized with COVID‐19, who either had or did not have new neurological symptoms associated with infection.

Method

Patients were admitted to New York University Langone Health (NYULH), with sites in Manhattan, Brooklyn and Long Island. All patients were positive for SARS‐CoV‐2 infection. Plasma from 310 patients were analyzed (158 were tested positive for SARS‐CoV‐2 with neurological symptoms and 152 were positive for SARS‐CoV‐2 without neurologic symptoms). Plasma biomarkers assays (total tau [t‐tau], neurofilament light [NfL], glial fibrillary acid protein [GFAP], ubiquitin carboxyl‐terminal hydrolase L1 [UCH‐L1] Aβ40, Aβ42 and pTau‐181) were performed at the Biomarker Core of NYU ADRC using the SIMOA SR‐X

Result

The levels of t‐tau, NfL, GFAP, and UCH‐L1 were measured using the Neurology 4‐plex A and showed a significant elevation in COVID‐19 patients with neurologic symptoms compared to COVID‐19 patients without neurological symptoms: NfL (two tailed t‐test p = 0.0003), GFAP (two tailed t‐test p = 0.0098), UCH‐L1 (two tailed t‐test p = 0.0138) and t‐tau (two tailed t‐test p = 0.04). pTau 181 was also elevated in COVID‐19 subjects with neurological symptoms (two tailed t‐test p = 0.0141). There were no significant differences with Aβ1‐40 (two tailed t‐test p = 0.33). Both Aβ1‐42 and the pTau/ Aβ42 ratio showed a significant differences in patients with neurological symptoms (two tailed t‐test p = 0.049 and p = 0.0017, respectively).

Conclusion

Serum biomarkers of neuronal injury, neuroinflammation and Alzheimer’s disease such as NfL, t‐tau, UCH‐L1, GFAP and pTau‐181 correlate strongly with the presence of neurological symptoms in COVID‐19 patients. These findings indicate that patients who had COVID‐19 may have an acceleration of AD/ADRD symptoms and pathology.
With challenge comes opportunity: Dementia care innovations made in senior living during COVID that will outlast the pandemic
Authors: Doyle Patrick , Smith Nathaniel
Published: December 2021

Background

Senior living communities are designed to foster social engagement and a sense of community between the residents. These settings offer a variety of care services and supports that are at their core relationship‐centered and focused optimizing the health and wellness of the residents. COVID brought major disruptions to this communal environment. Residents accustomed to daily socialization and engagement were physically separated from each other and the broader community. The impact of this isolation was immediate and had a significant impact on residents’ cognitive wellness.

The pressing needs of COVID forced senior living to innovate in relation to the care of people living with dementia in these communities. We will discuss how innovations to process, infection control, technology, and design were used to keep residents safe from COVID and simultaneously maintain residents’ physical and psychosocial well‐being. Finally, we look to how these COVID‐induced innovations can re‐shape the future of dementia care in senior living.
Tactics, teaching and transitioning: Response to the COVID‐19 pandemic in the nursing home sector
Authors: Reda Lillian
Published: December 2021

From leadership to the front‐line our skilled nursing organization leveraged the expertise of all professionals in our various disciplines. A cohesive aligned approach was implemented to provide support, create and standardize guidance, develop systems, education and policies to conquer challenges being posed by COVID‐19 in our settings. In addition to keeping residents safe from the virus, we as operators needed to establish creative ways to respond to the delivery of quality care, caring for residents, families and staff all while adhering to regulatory compliance and the ongoing pandemic and new challenges posed as we venture into a post pandemic world.
DNA damage in brain may lead to cognitive dysfunctions and reduced longevity in WNIN/Ob obese rats
Authors: Sinha Jitendra Kumar , Ghosh Shampa , Raghunath Manchala
Published: December 2021

Background

One of the most common neurodegenerative diseases is Alzheimer’s disease where complex etiological alterations have been observed along with the typical pathology. Specifically, it has been proposed that epigenetic activation of specific genes due to other physiological conditions may also contribute to its pathology.

Method

Ageing being one of the strongest risk factor where accumulation of DNA damage is rampant, we evaluated the extent in the brain of 15 months old WNIN/Ob obese rats. Early accumulation of DNA damage in brain can result in devastating genetic instability and wide array of physiological problems. WNIN obese rats have significantly reduced longevity (average lifespan of 15‐18 months). The extent of DNA damage in brain was studied as a hallmark of senescence in order to establish this rat as a model of aging related studies. DNA damage was assessed at the single cell level in neocortex and hippocampus of WNIN obese rats, WNIN lean littermates and normal WNIN controls at 3 and 15 months of age by Comet Assay. The samples were processed for neutral and alkaline electrophoresis, followed by fluorescent staining and analysis.

Result

The extent of DNA damage in the form of single‐strand breaks (SSBs) as well as double‐strand breaks (DSBs) in cells of neocortex and hippocampus of young WNIN obese rats was comparable with those seen in the 15 months old normal WNIN rats. Interestingly the extent of SSBs and DSBs in young WNIN lean littermates and WNIN controls were comparable.

Conclusion

Onset of significant DNA damage in different brain regions of obese rats at a much younger age is a plausible cause of reduced longevity observed in this novel obese rat model.