bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and pilot data for an app‐based cognitive assessment for detecting memory and executive functioning changes in aging and pre‐clinical AD
Authors: Mechanic‐Hamilton Dawn , Lydon Sean , Miller Alex , Halberstadter Kimberly , DiCalogero Michael , Wolk David A.
Published: December 2021

Background

Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility and psychometric properties of app‐based memory and executive functioning tasks included in the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical Alzheimer’s Disease (AD).

Method

The mCAPP includes three gamified tasks: (1) a memory task that includes learning and matching hidden card pairs and incorporates increasing memory load, pattern separation features (lure vs. non‐lure), and spatial memory (2) a stroop‐like task (“brick drop”) with speeded word and color identification and response inhibition components and (3) a digit‐symbol coding‐like task (“space imposters”) with increasing pairs and incidental learning components. The cohort is also assessed with the NACC UDS3 or T‐Cog neuropsychological battery within six months of the mCAPP testing. Participants included nine older adults (44% female; age=73.9±5.4, years of education=16.6±2.3; 77% Caucasian) with normal cognition who are enrolled in the Penn ADRC cohort. In addition to in‐lab testing, a cohort of participants will also use the mCAPP at home for two weeks and remotely collected data will be presented.

Result

On the brick drop task, performance was significantly slower and less accurate on the inhibition task compared to the word and color identification tasks (p<.05). On the space imposters task, increased reaction time and decreased accuracy was observed as the number of digit‐symbol pairs increased, but the difference was not significant. Correlations with UDS 3.0 measures showed significant relationships between the brick drop word/color identification and trail making test A (TMTA) and category fluency (p<.05) as well as between the response inhibition task and category fluency and olfactory function (p<.05). The space imposters task correlated with the TMTA (p<.05). Data will also be presented on home‐based collection of all three mCAPP tasks.

Conclusion

This pilot study shows feasibility and validity of app‐based tests of executive functioning and will also examine detection of subtle cognitive differences associated with preclinical AD through burst testing, home‐based data collection and on all three mCAPP measures.
Associations of smoking and biohazard exposure with Alzheimer’s disease brain and plasma biomarkers in early old age
Authors: Franz Carol E , Whitsell Nathan , Qin Yongmei Amy , Tu Xin M , Kremen William S
Published: December 2021

Background

Cigarette smoking and environmental exposure to other biohazardous chemicals and substances are associated with increased risk of developing cancer, cardiovascular disease, and other diseases that contribute to shorter life expectancy. Their associations with Alzheimer’s Disease (AD)‐related brain indicators of structural integrity and plasma biomarkers are less often examined.

Method

At average age 68 (range 61‐73), 1118 male participants in the Vietnam Era Twin Study of Aging (VETSA) self‐reported on cigarette smoking habits which we used to calculate pack years. Participants also self‐reported on prolonged or severe exposure to herbicides/pesticides, metal dust, Agent Orange, or other biochemical hazards. Using MRI data collected at average age 68 from approximately 470 participants, we examined a published an AD‐Brain signature based on thickness in 7 AD‐related cortical regions and hippocampal volume. We created a novel an AD‐Mean Diffusivity (AD‐MD) signature based on those same regions (higher AD‐MD scores being worse). We also examined a predicted brain age difference score (PBAD), an indicator of global accelerated brain aging. Plasma abeta42, abeta42/40 ratio, and total tau (t‐tau) were assayed using the Quanterix Simoa system. Multivariable analyses controlled for age, ethnicity, education, and the random effect of family (i.e., twin pairs).

Results

Smoking pack years at age 68 were negatively associated with AD‐Brain Signature (p<0.0001) and PBAD (p=0.0013). Pack years (p=0.0001) and Agent Orange (p=0.047) were positively associated with AD‐MD Signature. T‐tau was positively significantly associated with smoking (p=0.0039) and Agent Orange (p=0.004).

Conclusions

Heavier lifetime smokers had brains more similar to brains of adults with AD, showed accelerated brain aging, and had higher levels of t‐tau in early old age. All of these are indicators of higher risk for AD. Exposure to Agent Orange, a toxic herbicide, was also related to poorer structural brain integrity and t‐tau. Smoking had the strongest relationship with overall brain health in late midlife compared with other types of environmental exposures, reinforcing its role in pathological aging and its importance as a public health priority. The results suggest that more attention should be paid to potentially toxic environmental exposures that may increase risk for AD and other health conditions.
Cognitive reserve: Evaluating the relationship between WASI‐II Matrix Reasoning and tau accumulation using [18F]MK6240 in monolingual and bilingual individuals
Authors: Stevenson Alyssa , Rahmouni Nesrine , Stevenson Jenna , Tissot Cécile , Therriault Joseph , Lussier Firoza Z , Bezgin Gleb , Chamoun Mira , Kang Min Su , Benedet Andréa Lessa , Pascoal Tharick A. , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2021

Background

Cognitive reserve (CR), a protective mechanism, allows for sustained cognitive functioning in older adults with greater experiential resources. Bilingualism, an indicator of greater cognitive reserve, has been found to preserve cognitive performance in older adults despite significant disease pathology. While the association with amyloid has been well acknowledged, the effect of tau is still under investigation. In the present study, we aim to evaluate the effect of bilingualism on individuals’ cognition and tau load.

Method

This study was conducted in 331 individuals (213 cognitively unimpaired (CU)) and 116 cognitively impaired (CI; 81 MCI and 35 AD) from the TRIAD cohort. 40% of the study participants were monolingual. Wechsler Abbreviated Scale of Intelligence ‐ Second Edition (WASI‐II) was used to measure cognitive ability and reasoning in individuals. Accumulation of tau was assessed with [18F]MK6240 PET and standardized uptake value ratio (SUVRs) were calculated between 90 to 110 min post‐injection, using cerebellum grey matter as the reference region. A voxel‐based regression model evaluated the relationship between the WASI‐II score and the PET markers [18F]MK6240, correcting for age, sex, education, APOE, diagnosis and RFT was used to account for multiple comparisons.

Result

Our data showed that bilingual individuals demonstrated significantly higher scores on the Wechsler Abbreviated Scale of Intelligence ‐ Second Edition (WASI‐II) in comparison to monolingual individuals. A negative association between the cognitive score and tau accumulation was found in both monolingual and bilingual groupings. In the bilingual individuals, the associated regions were precuneus area, medial and lateral lobes. In the monolingual group, the associated regions were right frontal lobe, parietal lobe and cuneus areas.

Conclusion

Our results demonstrate that bilingual individuals are more resilient to the accumulation of tau; shown in higher scores in cognitive ability and reasoning despite having more regions affected than their monolingual counterparts.
Ultrasound‐assisted lumbar puncture in Alzheimer's disease and related disorders research: A pilot study
Authors: Goldfarb Danielle , Viramontes Daniel , Callan Michael , Liebsack Carolyn , Goddard Molly , Reade Marina , Malek‐Ahmadi Michael H. , Weidman David , Tsai Po‐Heng , Wu Teresa , Grimsman Jason , Atri Alireza
Published: December 2021

Background

Lumbar puncture (LP) and collection of cerebrospinal fluid (CSF) are increasingly essential in Alzheimer’s disease and related disorders (ADRD) research. Ultrasound‐assisted lumbar puncture (Us‐LP) has not been studied in ADRD research and could improve LP success rates through more accurate anatomical site selection, precise planning, and individualized intra‐procedure adjustments. This pilot study assessed the feasibility, utility, and tolerability of Us‐LP in ADRD research.

Method

LP clinician‐researchers from ADRD centers completed simulation‐based Us‐LP training using the Philips Lumify system, a portable hand‐held transducer connecting to a tablet. Thereafter, clinician‐researchers had the option to use Us‐LP during research LPs. Participant demographics and attitudes about LP were obtained prior to LP. The clinician‐researchers completed a post‐LP questionnaire assessing procedural details, choices, and LP performance.

Result

Following training, four clinician‐researchers implemented Us‐LP into their practices. Between August 2019‐March 2020, 58 research participants (Table 1) underwent LP. Clinician‐researchers used Us‐LP on 37/58 (64%) participants. Compared to conventional‐LP, Us‐LP choice was associated with higher/highest BMI and older/oldest age categories (Tables 2,3). A U‐shaped relationship between BMI and Age in Us‐LP choice was noted (Figure 1). Us‐LP was also the choice in all who were most obese; in most who were moderately overweight‐to‐obese; and in all who were oldest and moderately overweight‐to‐obese. There were no differences between those receiving conventional‐LP compared to US‐LP with respect to participant history of chronic pain or headache, prior attitudes about LP, success rate, or post‐LP complications.

Conclusion

Training clinician‐researchers in Us‐LP and implementing portable hand‐held Us‐LP for ADRD research studies demonstrated feasibility, utility and tolerability. Pilot data indicated that clinician‐researchers were more likely to use Us‐LP in perceived challenging cases including the most obese, and those oldest and moderately overweight‐to‐obese. More studies are needed to determine if using Us‐LP in ADRD research will improve LP success rates, tolerability, and participant willingness to undergo LP. Improving these factors will accelerate CSF biomarker, aging and ADRD research. Furthermore, with potential availability of AD disease‐modifying treatments in the coming years, LP and CSF collection are likely to play a crucial role in patient selection for treatment.
World Trade Center neurotoxic exposures are associated with elevated plasma amyloid, total‐tau and neurofilament light in responders
Authors: Diminich Erica D. , Clouston Sean A.P. , Vega Irving , Gandy Samuel , Bromet Evelyn , Luft Benjamin J.
Published: December 2021

Background

The collapse of the World Trade Center towers on September 11th 2001 resulted in a 16‐acre environmental toxic disaster. More than 1.2 million tons of construction material and carcinogens including polycyclic aromatic hydrocarbons, gypsum and metals coalesced, resulting in a highly alkaline dust cloud. Police and Law enforcement were among the most highly exposed group.

Method

In this retrospective cohort study, we included a subset of high exposure Responders (n=424) with cross sectional plasma samples of amyloid β40, amyloid β42, total‐tau, neurofilament light and a baseline evaluation of cognitive functioning assessed with the Montreal Cognitive Assessment (MoCA) to examine long‐term associations between WTC neurotoxic exposures (e.g. diesel exhaust, chemicals) with levels of proteins associated with neuropathological characteristics of Alzheimer’s disease and neurodegeneration. Spearman rho p values adjusted for multiple comparisons using the false discovery rate (FDR=0.05) examined associations with participant characteristics and plasma concentrations. Multivariate regressions ascertained independent effects of WTC neurotoxic exposures in predicting plasma biomarker concentrations.

Result

Responders were on average 54.3 years at blood draw. Worse performance on the baseline MoCA was associated with higher levels of Aβ40. Plasma Aβ40 and NfL were inversely correlated with dust exposure, Aβ42 and ratio Aβ42‐40 were inversely correlated with total hours on site during 9/11‐9/14 and working in enclosed work areas was associated with higher concentrations of Aβ40 and lower concentrations of ratio Aβ42‐40. Diesel exhaust exposure predicted levels of Aβ40, total tau and NfL whereas early exposure predicted Aβ42 concentrations and dust exposure predicted ratio Aβ42‐40.

Conclusion

Differences across inhaled neurotoxins and time of arrival may have differential long‐term effects on blood‐based protein biomarkers of neuropathology and brain health.
Age‐related ventricular expansion is not spatially concordant with MR‐visible periventricular white matter disease
Authors: Schwartz Daniel L , Hung Caela , Lahna David , Roese Natalie E , Woltjer Randy L , Silbert Lisa C
Published: December 2021

Background

Ventricular expansion (VE) is recognized as one of the earliest predictors of Alzheimer’s disease (AD); however, VE is also ubiquitous in normal aging. VE is reportedly caused by an ex vacuo mechanism, whereby tissue that appears as periventricular white matter hyperintensity visible on FLAIR MRI (PVH) experiences white matter (WM) atrophy and is subsumed by the lateral ventricles. This longitudinal study sought to test the degree to which the locations into which the ventricles expand were previously PVH as opposed to other tissues.

Method

Sixty‐five cognitively intact aged subjects each received 2‐6 T1‐weighted and FLAIR MRIs (Table 1). Each volume was rigidly coregistered to the baseline volume and gray matter (GM), lateral ventricular and PVH masks were generated for each timepoint. Ventricular growth masks (VG) were generated for each subsequent timepoint, each VG voxel was classified into either GM, PVH, or normal appearing white matter (NAWM) per overlap with previous timepoint tissue masks (Figure 1A).

Result

Overall, average VE between visits was 5.1cm3. Over all subjects and visits, 4.2% of VE occurred where tissue had been previously marked as PVH, 16.1% of VE occurred where tissue had previously been marked as GM, including subcortical GM and the hippocampus, and 75.4% of VE occurred in tissue that had been previously marked as NAWM (Figure 1B).

Conclusion

The results support an alternative explanation for VE; that is, that ex vacuo expansion of the lateral ventricles may not be the primary mechanism by which ventriculomegaly occurs in aging. One possible explanation is that unaltered CSF production in the face of dysfunctional CSF egress dynamics causes fluid stasis and reflux which increases pressure in the lateral ventricles.
Transcriptomic profiling in mild cognitive impairment using peripheral blood gene co‐expression networks
Authors: Sanjay Apoorva Bharthur , Correia Rion Brattig , Rocha Luis M. , Apostolova Liana G.
Published: December 2021

Background

In an effort towards AD prodromal risk assessment, precision medicine and biomarker development, we evaluated the efficacy of characterizing and clustering peripheral blood transcriptomic data by constructing gene‐coexpression networks from differentially expressed genes between normal controls and MCI subjects.

Method

Data from the ImaGene study (Imaging and Genetics Biomarkers study of Alzheimer’s Disease, ImaGene) was used. This included 160 subjects clinically diagnosed with amnestic MCI (n=70), non‐amnestic MCI (n=38) and normal controls (n=52) (Table 1). Quantile‐normalized and log‐transformed mRNA levels were obtained from peripheral blood. In a preliminary analysis we selected 2062 genes (out of HOW MANY) which were significantly differentially expressed between normal controls and MCI (two sample t‐test, pfdr<0.05). Gene‐coexpression networks were built by creating correlation matrices of the differentially expressed mRNA values. Network backbones were then built using the shortest path computation to remove redundancy and identify important edges. Hierarchical clustering was performed on the co‐expression matrix to identify important communities or clusters within the network. We identified the strongest cluster associated with amnestic MCI phenotype (pfdr<0.0001) by using the first principal component of the cluster as the eigen gene. The genes within the cluster and edges within the backbone were investigated.

Result

Upon backbone computation, the number of edges compared to original correlation matrix were significantly reduced (Figure 1). Hierarchical clustering yielded 42 clusters of genes. One cluster (eigen gene) had the strongest association with amnestic MCI phenotype (r=0.45, pfdr<0.0001). This cluster consisting of 46 genes warrants further investigation for specific function and interactions with other nodes in the cluster backbone. Two of the driver genes ADRA1A and ARHGAP4 were involved in noradrenergic receptor signaling pathway and PDGF signaling pathway, both of which are dysregulated in AD pathogenesis.

Conclusion

A large noisy transcriptomic data was reduced to a critical number of mRNA measures from peripheral blood. The backbone method pruned the gene coexpression network significantly. The cluster analysis identified a set of genes which had highly significant association with amnestic MCI. This approach can also help build models for risk assessment, gene therapy and help identify novel therapeutic targets/ dysregulated pathways.
Healthcare costs incurred by patients before entering GERAS‐US, a prospective, observational study of early Alzheimer’s disease: Impact of disease severity and amyloid status
Authors: Chandler Julie , Zimmer Jennifer A , Kubisiak Emily , Kubisiak Joanna
Published: December 2021

Background

GERAS‐US (NCT02951598) is a longitudinal, prospective US cohort study assessing healthcare resource use (HCRU) and costs in clinician‐diagnosed, early‐stage Alzheimer’s disease (AD). This study analyzed HCRU and costs incurred by patients before and after cognitive impairment (CI)/AD diagnosis, before entering the GERAS‐US study.

Method

Data of GERAS‐US participants who consented for this addendum study were linked to Medicare claims data, for up to 5 years before baseline study visit (2013–2017). GERAS‐US study classified severity using Mini‐Mental State Examination (MMSE) and Functional Activities Questionnaire (FAQ) scores. Mild cognitive impairment (MCI) was defined as MMSE: 24–30 and FAQ: <6, and mild dementia (MILD) was defined as MMSE: 20–30 and FAQ: ≥6. Amyloid status (positive/negative) was determined by PET scan. Participants selected in this analysis required Medicare fee‐for‐service eligibility (Parts A and B enrollment) for ≥1 month before baseline visit. Mean HCRU and costs before and after CI/AD diagnosis were compared by severity and amyloid status, adjusting for length of fee‐for‐service history before or from the month of first CI/AD diagnosis, respectively. Differences in costs were assessed using general linear model regression analyses and healthcare costs per patient per month (PPPM) were calculated. Descriptive, Chi‐square (categorical variables), and t‐test (continuous variables) analyses were conducted.

Result

Healthcare costs of 174 patients were assessed by severity and amyloid status (Table). Mean total all‐cause healthcare cost incurred PPPM post CI/AD diagnosis was greater for MILD versus MCI cohort (P=.067), and for patients with amyloid‐negative versus ‐positive status (P<.05). Post CI/AD diagnosis, patients in the MILD cohort with amyloid‐negative status incurred greatest mean PPPM total healthcare costs (MILD amyloid‐negative, $1842; MILD amyloid‐positive, $695; P=.014; not shown). Home health cost post CI/AD diagnosis was a significant factor driving differences between MCI and MILD cohorts ($9 vs. $120, P=.014), and between amyloid‐negative and ‐positive cohorts ($124 vs. $19, P=.022) (not shown).

Conclusion

Differences in total healthcare costs were greatest post CI/AD diagnosis, with greater costs being incurred by MILD versus MCI, and amyloid‐negative versus amyloid‐positive cohorts. After diagnosis, home health cost was a major factor significantly driving cost differences.
Interval‐specific likelihood ratios for improving differential diagnosis of Alzheimer’s disease using biomarkers in cerebrospinal fluid
Authors: Poesen Koen , Dubin Jonas , Vandenberghe Rik
Published: December 2021

Background

Single cutoff values are currently applied to interpret Alzheimer biomarker results. Yet these cutoffs are not uniform among centers, nor highly specific to discriminate AD from other disorders. We examined if the likelihood of AD was higher when biomarker levels deviated more from normal levels. For this purpose, we constructed interval‐specific likelihood ratios (LRs) for CSF biomarkers amyloid Aβ1‐42, total Tau protein (tTau) and hyperphosphorylated Tau protein (pTau181).

Method

This retrospective single center study included 208 patients who 1) attended the Neurology Memory Clinic of the University Hospital Leuven in the period of September 2011 till July 2017, 2) underwent CSF AD biomarkers assessment in the diagnostic workup (Innotest, Fujirebio) and 3) had a stable clinical diagnosis for at least three years after diagnosis. For each biomarker, we calculated LRs for AD for different test result intervals, based on 2 methods, including intervals with boundaries equal to limited multiples of previously published cutoff values (method 1), or to generate intervals well distributed over the entire dynamic range of biomarker levels (method 2). In a graphical representation, post‐test probability of AD was related to pre‐test probability and test result interval for each biomarker.

Result

Both methods for constructing intervals showed that for any of the biomarkers the LR increased significantly once deviating from normal values. Further dividing these aberrant levels into additional intervals (method 2) further increased the LR. Further dividing normal levels into more intervals did further decrease the LR, except for Aβ1‐42. No LRs > 10 or < 0.1, suggesting clinically meaningful differences between pre‐test and post‐test probability, were encountered. LRs between 0.1 – 0.2 or 5 – 10, suggestive of modest clinical differences, were seen for normal Aβ1‐42 levels (800 – 1,000 pg/mL; LR = 0.168), and aberrant tTau levels (≥ 1,000 pg/mL; LR = 5.540) and pTau181 levels (≥ 80 pg/mL; LR between 5.936 and 7.420).

Conclusion

The likelihood of AD changed as CSF levels of AD biomarkers deviated more outspoken from normal range, yet related to a modest clinical significance given the partial overlap between AD and non‐AD of biomarker values that deviated from normal values.
The design of Dominantly Inherited Alzheimer Disease Trial of the anti‐tau antibody, E‐2814, on the DIAN‐TU Tau Next Generation Platform
Authors: Schneider Lon S. , Bateman Randall J. , Clifford David B. , McDade Eric , Wang Guoqiao , Llibre‐Guerra Jorge J. , Li Yan , Mills Susan , Santacruz Anna , Sachdev Pallavi , Li David JianJun , O'Sullivan Stacie , Yagi Takuya , Koyama Akihiko , Irizarry Michael C. , Reyderman Larisa
Published: December 2021

Background

Tau pathology is closely associated with the onset and progression of Alzheimer’s disease. Recent advances in drugs that target tau suggest the potential to prevent or attenuate the pathophysiology and pathology of tau. Novel CSF and blood tau species including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, increases 10 years or more before tau tangles are detected by tau‐PET. Two stages of AD are identified and studied using soluble p‐tau and MTBR‐tau forms in the asymptomatic stage and Tau PET in the post‐tangle symptomatic stage. E2814, an anti‐tau monoclonal antibody targets MTBR‐tau and decreases tau pathology in animal models.

Method

We designed an anti‐tau trial to target soluble tau species in two cohorts including pre‐tangle asymptomatic and post‐tangle symptomatic participants in dominantly inherited AD (DIAD). We analyzed longitudinal clinical, cognitive, tau PET and CSF measures of tau species including, multiple p‐tau species (e.g., p‐tau217, 231, 181, 205), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in DIAD cohorts from DIAN and DIAN‐TU. Novel trial design and statistical approaches have been developed to address primary and secondary outcomes, magnitude of effect by stage of disease (pre‐tangle vs. post‐tangle), and potential for prevention.

Result

We designed a trial of two cohorts, each powered, with different biomarker outcomes: in the pre‐tangle, tau‐PET negative cohort, CSF ptau217/tau217 is the endpoint; for the post‐tangle tau‐PET positive cohort, tau‐PET is the endpoint. Further, each cohort will measure target engagement by CSF MTBR‐tau and downstream effects on soluble total tau, p‐tau and MTBR tau with common measures of neurodegeneration by CSF and blood NfL, atrophy by MRI, hypometabolism by FDG‐PET, effects on amyloid by abeta42/40 and amyloid‐PET, and cognitive and clinical measures. This design is facilitated by the predictable pattern of biomarker changes observed in DIAD allowing appropriate powering of the study even in this rare condition.

Conclusion

The Tau Next Generation Platform will address disease progression, before and after tangle formation begins, assessing when an anti‐MTBR tau monoclonal antibody will have the largest effects. It is the first anti‐tau trial for DIAD.
Caring for residents with dementia during a COVID‐19 outbreak in a long‐term care home
Authors: Hung Lillian
Published: December 2021

Background

Although there have been considerable public concerns about the impact of COVID‐19 on residents living in long‐term care homes, much less attention has focused on lessons learned from staff experiences about caring for people with dementia during outbreaks. The outbreaks added significant additional stress to the nursing workforce, which has historically experienced high turnover, chronic staffing shortages, and increased burnout in long‐term care settings. We conducted focus groups (n=20) and individual interviews (n=10) to investigate critical challenges, experiences, and support needed for frontline staff in a long‐term care home in British Columbia, Canada. A total of 30 staff in multiple disciplines participated in the study. They included Registered Nurses, Licenced Practical Nurses, care staff, recreational staff, and unit clerks. We applied qualitative thematic analysis and identified four themes: (a) I am proud, (b) we become stronger, (c) I am nervous (d) the vaccine helps. The frontline staff's voices provided a detailed description of their emotional experiences, creative coping strategies and positive stories about caring for the most vulnerable population in extraordinary situations. In our poster, lessons learned and implications for future research and practice will be explored and discussed.
The screening and enrollment of underrepresented ethnoracial and educational populations in the Alzheimer's Disease Neuroimaging Initiative
Authors: Ashford Miriam T , Miller Garrett , Raman Rema , Donohue Michael C , Okonkwo Ozioma C , Mindt Monica Rivera , Nosheny Rachel L , Petersen Ronald C , Aisen Paul S , Weiner Mike W
Published: December 2021

Background

An analysis of the ethnoracial and educational composition of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, and the relationship between ethnoracial/education and screening, enrollment, dropout, and biomarkers is needed to assess the generalizability of ADNI data to diverse populations, and to inform efforts to increase diversity.

Method

Data from all 4 ADNI phases were used to determine ethnoracial and educational breakdown and differences of the following ADNI participation metrics: screening, screen fails, enrollment, as well as drop‐out within and between ADNI phases. Multivariable logistic regression was used to analyze the association between ethnoracial and educational group and either amyloid positivity or ApoE e4 status, adjusting for age, gender, and diagnostic group.

Result

Across the 4 ADNI phases (screened: n=3,739; enrolled: n=2,286), 11% of screened and enrolled participants identified as Latinx, non‐Latinx Black, or non‐Latinx‐Asian and 16% of the screened and 15% of the enrolled participants reported having =<12 years of education. In contrast, the 2019 US Census American Community Survey for adults 60+ reports 25% non‐White, and 44 % =< 12 years of education. There were no observed differences between participants from historically underrepresented ethnoracial groups and NLW participants in screen fail and dropout rates. We found that individuals with =<12 years of education failed screening at a significantly higher rate (p=.01) and rolled‐over significantly less to subsequent ADNI phases (p<.001) compared to individuals with an education >12 years. Identifying as non‐Latinx Asian was associated with lower odds of being amyloid positive (OR=0.36; p=.014) and an ApoE4 carrier (OR=0.36; p=.008) compared to NLW. Identifying as Latinx was associated with being less likely to be amyloid positive than NLW participants (OR=0.54; p=.031).

Conclusion

Compared to the US Census, ADNI underrepresents enrollment of Latinx, non‐Latinx Black, and non‐Latinx Asian participants and those with low educational attainment. Hence, ADNI reflects the on‐going challenges with recruiting and enrolling underrepresented populations into most AD research. Our findings highlight the need for ADNI to increase enrollment and engagement of underrepresented ethnoracial and educational populations. ADNI is actively undertaking steps to implement improved recruitment approaches aimed at increasing ethnoracial and socioeconomical representation in multi‐center cohort studies.
ACI‐24 in adults with Down syndrome: Results of a phase 1b, randomized, placebo‐controlled study
Authors: Rafii Michael S , Sol Olivier , Mobley William C , Skotko Brian G. , Burke Anna D , Sabbagh Marwan N. , Yuan Shauna , Rissman Robert A. , Delpretti Saskia , Beth Greg , Gray Julian JG , Melo dos Santos Antonio , Hliva Valerie , Vukicevic Marija , Kosco‐Vilbois Marie , Streffer Johannes , Pfeifer Andrea , Feldman Howard
Published: December 2021

Background

The APP gene is located on chromosome 21 and thought to lead to overproduction of beta‐amyloid (Aβ) in persons with trisomy 21 (Down syndrome, DS). As a result, individuals with DS are at high risk for developing Alzheimer’s disease (AD). ACI‐24 is a liposomal, T‐cell independent, anti‐Aβ vaccine which was assessed in a world’s first clinical phase 1b study in adults with DS.

Method

The primary objectives of this randomized, double‐blind, placebo‐controlled, dose‐escalation, phase Ib multi‐center study were to assess the safety and tolerability of ACI‐24 in adults aged 25‐45 years with DS and its effect on the induction of serum anti‐Aβ antibody titers. The secondary objectives were to explore the effect of ACI‐24 on cognition, behavior, AD biomarkers, T‐cell activation, and brain volumes assessed by MRI. Participants received subcutaneous injections of ACI‐24 (300 µg or 1000 µg) or placebo (3:1 ratio) at different timepoints up to week 48 before entering a 48‐week safety follow‐up period.

Result

Sixteen participants (9F/7M; mean age 32.9 [25‐41]) were randomized into 2 dose‐level cohorts (n=8 each; 6 ACI‐24 and 2 placebo). Treatment compliance was 100%. The safety and tolerability were very good with no serious adverse events reported and no withdrawals due to adverse events. Most adverse events were mild in intensity and unrelated or unlikely related to ACI‐24. No amyloid‐related imaging abnormalities (ARIA) or changes in markers of CNS inflammation were observed. Increases in anti‐Aβ antibody titers were observed in selected participants in both treatment arms receiving ACI‐24 as compared to placebo. In addition, an increase in plasma Aβ1‐40 and Aβ1‐42 levels compared to placebo was observed in active groups. As expected, no consistent changes between treatment and placebo groups were observed in other biomarkers or clinical measures in this small study.

Conclusion

ACI‐24 was safe and well‐tolerated in adults with DS. Evidence of immunogenicity was observed with this T‐cell independent vaccine along with pharmacodynamic and target engagement effects as measured by an increase in plasma Aβ 1‐40 and Aβ 1‐42 levels in treated groups as compared to placebo. These results support the pursuance of an accelerated clinical development with an optimized formulation of ACI‐24.
Rationale for an anti‐inflammatory insulin sensitizer in a phase 3 Alzheimer's disease trial
Authors: Reading Chris L , Ahlem Clarence N , Parameswaran Narayanan
Published: December 2021

Background

NE3107 (3α‐ethynyl‐androst‐5‐ene‐3β,7β,17β‐triol), shows safety, antiinflammatory and insulin‐sensitizing activities in vitro, in animals, and humans. NE3107 binds ERK1/2 and inhibits inflammatory, but not homeostatic NFkB/ERK signaling in vitro, in animals and in humans. NE3107 is blood‐brain permeable, and does not affect neurotransmitter receptors. NE3107 inhibits TNFα‐stimulated NFκB transcription in human macrophages. It also inhibits NFκB nuclear translocation and LPS‐stimulated inflammatory signal transduction. NE3107 prevented IκBα proteolysis in murine macrophages. NE3107 decreased EAE optic nerve microglia, and increased nuclear NFκB in collicular and retinal neurons (homeostatic), but decreased optic nerve head glial nuclear NFκB (inflammatory) in a glaucoma model. NE3107 preserved dopaminergic neurons in MPTP‐treated mice and marmosets. In obese impaired glucose tolerance (IGT) humans, NE3107 decreased CRP, which is involved in AD inflammation and tissue damage, and increased antiinflammatory HDL, which decreases risk of AD pathogenesis. NE3107 increased adiponectin, which suppresses insulin resistance, inflammation, and AD pathology. In obese, inflamed IGT and type 2 diabetes (T2D) subjects, NE3107 decreased insulin resistance, which drives neurodegeneration and AD. Importantly, in obese inflamed T2D subjects, NE3107 decreased inflammation‐driven systems deregulation, known to contribute to AD progression.

Method

Safety and activity data from preclinical, toxicology, human clinical trials, and a protocol synopsis for a pivotal trial in AD were submitted, and the FDA allowed NeurMedix to proceed with the NM101 trial.

Result

A Phase 3, Double Blind, Randomized, Placebo Controlled, Parallel Group, Multicenter Study of NE3107 in Subjects Who Have Mild to Moderate Alzheimer's Disease (NCT04669028) will evaluate safety and efficacy of oral 20 mg BID NE3107 vs. placebo in 316 subjects with mild to moderate AD. Two coprimary outcome measures ADAS Cog12 and ADCS CGIC will be evaluated as the change from Baseline to Week 30. Secondary endpoints include measures of neuropsychological deficits, functional performance, glycemic control and resource utilization. A subset of patients may volunteer for exploratory vMRI and FDG‐PET scans at baseline and week 30.

Conclusion

Inflammation and insulin resistance drive AD. NE3107 decreases these insults that drive systems dysregulation in AD. This trial is well‐positioned to examine the effects of NE3107 on progression of AD dementia, affecting more than 40 million people globally.
Subgroup analyses of the amyloid PET substudies from EMERGE and ENGAGE, phase 3 clinical trials evaluating aducanumab in patients with early Alzheimer’s disease
Authors: Rajagovindan Raj , Chen Tianle , Wu Hao , Tian Ying , Nisenbaum Laura , Castrillo‐Viguera Carmen , He Ping , Haeberlein Samantha Budd
Published: December 2021

Background

Aducanumab, a human monoclonal antibody that selectively targets aggregated forms of beta amyloid (Aβ), is under investigation for the treatment of Alzheimer’s disease (AD). EMERGE and ENGAGE were 2 identically‐designed, randomized, double‐blind, placebo‐controlled Phase 3 trials that evaluated the efficacy and safety of aducanumab in participants with mild cognitive impairment (MCI) due to AD or mild AD dementia and confirmed amyloid pathology. These studies were initiated following the Phase 1b PRIME study in which aducanumab reduced amyloid burden and slowed decline on exploratory clinical endpoints. In both EMERGE and ENGAGE, dose‐ and time‐dependent reductions in amyloid positron emission tomography (PET) composite standard uptake value ratio (SUVR) were observed at Week 78 in the amyloid PET biomarker substudies.

Method

Participants were randomized (1:1:1) to receive high‐dose aducanumab, low‐dose aducanumab, or placebo via intravenous injection every 4 weeks for 18 months. Longitudinal amyloid PET imaging using 18F‐florbetapir was performed in a subset of patients (n=488 in EMERGE; n=585 in ENGAGE) at screening, Week 26, and Week 78.

Subgroup analysis of amyloid PET SUVR for 6 prespecified factors including age (≤64, 65 to 74, or ≥75 years), sex (male or female), ApoE ε4 status (carrier or noncarrier), baseline clinical stage (MCI due to AD or mild AD dementia), baseline Mini‐Mental State Exam (≤26 or ≥27) and use of AD symptomatic medications at baseline (yes or no) for a total of 13 subgroups was conducted for each study.

Result

An advantage of high‐dose and low‐dose aducanumab over placebo was observed in the 13 subgroups, with time‐ and dose‐dependent Aβ reduction observed in each subgroup. These results were consistent with the overall results of the amyloid PET biomarker substudies in which aducanumab treatment was associated with robust dose‐dependent reduction in brain Aβ levels.

Conclusion

Amyloid PET SUVR subgroup analysis revealed a consistent dose‐ and time‐dependent advantage of high‐dose and low‐dose aducanumab over placebo in the prespecified subgroups.
Classification of amyloid β42 aggregation modulators from natural product library identifies promising scaffolds that suppress nuclei‐driven neurotoxicity
Authors: Murakami Kazuma
Published: December 2021

Background

The mechanism of Aβ42 aggregation mainly consists of two phases, nucleation and elongation (including a plateau region). During the nucleation phase, the monomer gradually forms toxic oligomers. During the elongation phase, each nucleus acts as a template and associates with monomers to initiate less‐toxic fibrillization. We previously proposed a method of classifying compounds into 9 groups based on their ability to modulate the nucleation and/or elongation phases. An orcein derivative (O4), which is a phenoxazine dye isolated from the lichen Roccella tinctoria and containing a 2,5‐cyclohexadienone moiety, was reported to convert oligomers into relatively inert fibrils, resulting in the reduction of the neurotoxicity of Aβ42 (Bieschke, J., et al. Nat. Chem. Biol.
2011, 8, 93‐101). Focusing on O4 in the pursuit of anti‐AD drugs, we herein screened 480 natural products including NPDepo (RIKEN).

Method

The ability of Aβ42 to aggregate or oligomerize was evaluated by thioflavin‐T fluorescence assay, transmission electron microscopy, and dot blotting. The neurotoxicity of Aβ42 was tested by MTT assay on mouse neuroblastoma Neuro2a cells.

Result

The 15 compounds that met the criteria of both delaying the nucleation phase and promoting the elongation phase were selected, and the signal intensities for Aβ42 oligomer treated with each of these compounds were lowered in dot blotting using anti‐oligomer antibody. On the other hand, the fibril formation of Aβ42 in the presence of these compounds was observed. Moreover, among the 15 compounds, 12 compounds (80%) reduced Aβ42‐induced toxicity.

Conclusion

Given that some of these anti‐cytotoxic compounds such as warfarin contain 2‐pyrone or 4‐pyrone moiety as does O4, the current data suggest that hit compounds can shift the equilibrium of Aβ42 from toxic oligomer into less‐toxic fibrils by forming Michael adduct with Aβ42.
The effect of prolonged lockdown due to COVID‐19 on demented patients of different stages and on their caregivers
Authors: Tsapanou Angeliki , Zoi Panagiota , Kalligerou Faidra , Blekou Patra , Sakka Paraskevi
Published: December 2021

Background

The impact of the new coronavirus disease (COVID‐19) is deteriorating as time passes and the virus keeps spreading. The aim of this study was to examine the effect of prolonged isolation because of the COVID‐19 pandemic on people with dementia and their caregivers.

Method

Caregivers answered online questions regarding their own physical and psychological burden, and of the person they take care of. The study took place in Athens, Greece, from November 2020 to April 2021. Participants were mostly members of online seminars of the Athens Alzheimer’s Association. Questions referred to their own burden, the overall decline of the persons they take care of, and changes in specific domains as well (i.e., mood, mobility, compliance with the new measures). Further, we also asked about any changes between the two major lockdown periods. Possible answers were: “not at all”, “moderately”, “a lot”. Statistical analysis included descriptive (mean, standard deviation, frequency, and percent) and inferential statistics (chi‐square test). Analysis was performed including the total sample and then, by three different stages of dementia (early, middle, late).

Result

A total of 339 caregivers took part in the study. People suffering from dementia that were referred at, were mostly women, with a mean age of 81 (S.D.: 7.5) years old, mostly being in the middle stage of dementia. Results indicated significant decline, both in an overall aspect of the people with dementia, and in specific domains (mostly communication and mood). Regarding the caregivers, they reported having significantly increased physical and psychological burden, and also, noticing an overall change between the two lockdowns in their own burden. Analysis by dementia‐stage group indicated that significant decline occurred both in the middle‐stage and the late‐stage group.

Conclusion

An urgency for further support of both the people with neurodegenerations and their caregivers is needed. Collaboration among care workers, online programs, governmental support, and day‐care centers should be planned to ensure continuity of care for those in need during the pandemic.
The association between plasma biomarkers, p‐tau181, glial fibrillary acidic protein, and neurofilament light and clinical AD risk: Results from prospective cohort study followed over 17 years
Authors: Stocker Hannah , Beyer Léon , Perna Laura , Schöttker Ben , Gerwert Klaus Bernhard , Brenner Hermann
Published: December 2021

Background

Plasma biomarkers for Alzheimer’s disease (AD) have emerged as the future of AD prescreening measures and/or clinical risk assessment. In order to confirm clinical utility of plasma biomarkers, further validation in longitudinal cohort studies is necessary. Therefore, the aim of this study was to investigate the relationship between plasma biomarkers, phosphorylated tau (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) and incident clinical Alzheimer’s disease diagnosis in a community‐based cohort study prospectively followed over 17 years. Secondarily, disease specificity of these biomarkers was assessed with comparison to vascular (VD) and mixed dementia (MD), and the impact of fatal CVD risk on plasma biomarker prediction was explored.

Method

P‐tau181, GFAP, and NfL concentration in plasma taken at baseline was measured using the SimoaTM HD‐X Analyzer and the 10‐year risk of fatal CVD using the Systematic Coronary Risk Evaluation (SCORE) was determined in 145 participants diagnosed with AD, 66 participants with VD, and 50 participants with MD during 17 years of follow‐up and 507 participants without dementia diagnosis. Cox regression models adjusted for age, sex, and education were used to assess the association between the plasma biomarker levels and risk of incident dementia subtypes.

Result

Higher plasma levels of p‐tau181 and NfL were significantly associated to higher risk of AD development within the first nine years of follow‐up (p‐tau181, p=.02; NfL, p=.01) and were most elevated in AD cases in the first five years of follow‐up, however lacked associations between 9‐17 years. Contrastingly, GFAP levels were consistently elevated in AD cases and significant associations to higher AD risk were evident throughout the 17‐year follow‐up. NfL and GFAP levels additionally exhibited associations to a higher risk of VD and MD; while p‐tau181 did not. Significant interactions between fatal CVD risk and biomarker levels were evident for AD (p‐tau181, p=.03; NfL, p=.01).

Conclusion

Higher plasma p‐tau181 and NfL levels were associated with higher AD risk within nine years, while higher GFAP levels with higher AD risk consistently throughout 17 years. Plasma levels of p‐tau181 and NfL may be more suited to short‐term AD risk stratification; while GFAP may add important long‐term disease risk information.
Machine learning of transcripts and audio recordings of spontaneous speech for diagnosis of Alzheimer’s disease
Authors: Liu Ziming , Proctor Lauren , Collier Parker , Casenhiser Devin , Paek Eun Jin , Yoon Si On , Zhao Xiaopeng
Published: December 2021

Background

Language deficits may occur in early stages of Alzheimer’s disease (AD). Analysis of individuals’ language changes has been shown to predict the diagnosis and severity of AD. This work explored machine learning methods to detect AD using voice recordings of the Cookie Theft picture description tasks.

Method

An open‐source dataset from Dementia Bank, which included manual transcripts and audio recordings of the Cookie Theft picture description task from 309 individuals with AD and 243 cognitively healthy older adults, was employed in the classification analysis. We analyzed transcripts generated using three different approaches (Figure 1), including a) automatically generated transcripts based on denoised voice recording; b) automatically generated transcripts without the denoising process; and c) manuscript transcripts. Denoising was implemented using noisereduce, a Python library to minimize background noise (CITATION). Automatic transcripts were produced using two toolkits: CMUSpinx pocketsphinx interpreter (PS) and Mozilla DeepSpeech (DS). The Small‐Bidirectional Encoder Representations from Transformers (BERT) model was implemented to extract high dimensional feature vectors to provide contextual representation of transcripts for classification analysis. The experiment was designed to compare the performance of transcript type (manual vs. automatic), recording quality (noise vs. denoise), as well as speech recognition methods (DS vs. PS). A neural network model was constructed to classify between those with AD and healthy controls. The classification analysis was conducted using 10‐fold cross validation. The classification was repeated 20 times and the averaged results were reported (see Table 1).

Result

The performance of each approach is shown as Table 1. Overall, the model that used the features extracted from DS transcripts with denoised speech recordings achieved the best performance which had 92.72% accuracy for AD diagnosis validation results. The comparison between raw and denoised speech recordings showed conflicting performances. Using features from PS transcripts with noisy speech recordings obtained better performance than the denoised one, which was different with features from DS transcripts.

Conclusion

The analysis approach which combined transcription driven recognition and transfer learning indicated the potential of better performance in AD diagnosis. Further investigation is needed to understand the reason for its superior performance.