bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline participant characteristics of GRADUATION: a study to evaluate once‐weekly subcutaneous administration of gantenerumab
Authors: Boess Frank , Lane Christopher , Scelsi Marzia A. , Delmar Paul , Hofmann Carsten , Tonietto Matteo , Klein Gregory , Kerchner Geoffrey A. , Baudler Monika , Doody Rachelle S.
Published: December 2022

Background

Gantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). Exposure‐dependent signals of clinical efficacy were observed with low‐dose gantenerumab in post hoc analyses of the SCarlet RoAD study (NCT01224106) in participants with prodromal AD.1 Open‐label extension studies with uptitration to doses of up to 1,200 mg every 4 weeks (q4w) confirmed substantial Abeta removal without new or unexpected safety findings.2 Two Phase III studies are ongoing to assess efficacy and safety of subcutaneous gantenerumab in early AD, using a target dose of 510 mg q2w (GRADUATE I/GRADUATE II [NCT03444870/NCT03443973]). The GRADUATION trial (NCT04592341) will evaluate the safety, pharmacodynamics (PD), and pharmacokinetics (PK) of once‐weekly (q1w) administration of gantenerumab (255 mg) in participants with early (prodromal‐to‐mild) AD. Subcutaneous q1w administration of gantenerumab may simplify home dosing to meet the individual needs and preferences of people with AD and their caregivers, and to improve their experience by providing additional flexibility and convenience.

Methods

In this open‐label, single arm, Phase II study, participants will receive gantenerumab by subcutaneous injection over a 2‐year period, starting with 120 mg q4w, followed by 255 mg q4w and q2w for 12 weeks each, and a target dose of 255 mg q1w. This target dose is equivalent to the 1,020 mg/month studied in the GRADUATE trials. The primary objective is to evaluate the PD effect of a q1w dosing regimen of gantenerumab on brain amyloid load measured by positron emission tomography. Secondary objectives include assessment of gantenerumab administration by a caregiver at home, safety, and PK/PD relationships. Exploratory objectives will include additional imaging and plasma biomarkers, and cognitive and functional assessments.

Results

Recruitment for GRADUATION is complete. Participants were enrolled from Belgium, France, Germany, Italy, Poland, Spain, UK, and US. Detailed baseline characteristics will be presented.

Conclusion

The GRADUATION study will determine the effect of q1w administration of gantenerumab on brain amyloid load, safety, PK/PD and biomarker endpoints, and assess the feasibility of administration by caregivers at home.

1. Ostrowitzki S, et al. Alzheimers Res Ther 2017;9:95

2. Klein G, et al. Alzheimers Res Ther 2019;11:101
MRI signatures of Brain Age in the Alzheimer’s disease continuum
Authors: Shah Jay , Ghisays Valentina , Chen Yinghua , Luo Ji , Li Baoxin , Reiman Eric M. , Chen Kewei , Wu Teresa , Su Yi
Published: December 2022

Background

Age is the biggest risk factor for Alzheimer’s disease (AD). Substantial efforts to extract age signatures from magnetic resonance imaging (MRI) of the brain have achieved impressive accuracy and demonstrated these signatures were altered by neurological disorders including AD. In this work, we develop a deep learning model to characterize brain age signatures and examine their variation over the AD continuum.

Method

A 3D deep ResNet model was implemented to learn the structural signatures of brain age in predicting the chronological age of the participants. The model was trained on 7372 T1‐weighted MRI scans from a combined lifespan cohort of 5848 cognitively normal participants (age: 8‐ 95 yrs) using a 10‐fold cross validation procedure. The model was then applied to the independent ADNI cohort (N=1175, 50‐98 yrs) to examine MRI derived brain age signatures variation in the AD continuum. The difference (∆age) between model predicted age and chronological age was used as the independent variable for group comparison using univariate ANCOVA tests, controlling for sex, education, and APOE4 gene dose, among five clinical groups: normal control (NC), normal to MCI converters (NC‐MCI), stable MCI (MCIs), MCI to AD converters (MCI‐AD), and AD patients.

Result

The ResNet model achieved an MAE=3.76 yrs and R2=0.93 across 10 folds in the lifespan cohort. In the baseline data of the ADNI cohort, model derived ∆age increased along the AD continuum as expected: NC (‐1.2yrs) < NC‐MCI (‐0.7yrs) < MCIs (‐0.3yrs) < MCI‐AD (0.7yrs) <AD (1.5yrs) (F=11.24, p<0.0001). Post‐hoc pairwise comparison results are summarized in Table 1/Figure 2. Although the difference between NC and NC‐MCI did not reach significance (p=0.24) for the baseline data, comparison between the two groups using data from all visits was significant (p=0.0009), suggesting more subtle differences.

Conclusion

A ResNet model was developed that captures the MRI signatures of brain age with high accuracy in age prediction. The model detected group level differences along the AD continuum in the expected direction. Subtle changes in brain signatures were observable in normal participants who later developed cognitive impairment. Our technique provides a novel approach to investigate the relationship between aging and AD.
Effects of Aging, Sex and Forgetfulness on Mental Rotation Performance
Authors: Schendel Krista , Lwi Sandy J. , Chok Jas M. , Hall Kathleen , Williams Garrett , Blank Michael , Geraci Kristin , Curran Brian , Herron Tim , Woods David L. , Baldo Juliana
Published: December 2022

Background

There is growing interest in the development of screening tests for AD and MCI that focus on non‐amnestic symptoms. Moreover, evidence suggests that declining mental rotation ability can be associated with prodromal Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI). Additional studies in healthy aging adults are therefore needed to determine whether computerized mental rotation tasks may prove useful in predicting cognitive decline.

Method

Here, we report findings from a large group of aging adults (n = 276, 42% female, aged 56–89 years, M = 70.5) who were remotely administered a computerized mental rotation task as part of a larger California Cognitive Assessment Battery (CCAB). During the mental rotation task, participants had to decide as quickly as possible whether a presented letter was in its typical (e.g., R) versus mirror‐reversed (Я) orientation. Letters were presented either upright (at 0 degrees) or rotated (+/‐60, or +/‐120 degrees). Participants’ responses on the Cognitive Failures Questionnaire were also collected as part of the assessment battery.

Result

Response times (RT) and accuracy on the mental rotation task were captured and analyzed to determine whether any effects of age, sex, and rotation angle could be observed using this remotely administered mental rotation task. Analysis revealed that both age and sex were significantly associated with performance measures on this task. The expected pattern of longer response times with greater degree of stimulus rotation was also observed. Analysis of sex differences revealed greater accuracy overall by females, while males experienced smaller RT costs based on rotation angle. Finally, a significant relationship between forgetting scores and mental rotation response times was also observed.

Conclusion

Increased age and forgetting scores were both associated with worse mental rotation performance. Continuing longitudinal assessment at 6‐month intervals is ongoing and will further establish trends in mental rotation performance during aging.
Genome‐wide association study on Alzheimer’s disease CSF profiles in the EMIF‐AD MBD and ADNI datasets
Authors: Neumann Alexander , Ohlei Olena , Dobricic Valerija , Vos Stephanie J. B. , Zetterberg Henrik , Visser Pieter Jelle , Tijms Betty , Sleegers Kristel , Bertram Lars ,   collaborators of the EMIF‐AD MBD and ADNI consortium
Published: December 2022

Background

Genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown and disease mechanisms are often unclear. Using CSF biomarkers of AD as outcome may aid in gene discovery and in elucidating disease processes. We previously demonstrated that six CSF biomarkers (β‐amyloid, total/phosphorylated tau, NFL, YKL‐40, and neurogranin) can be robustly clustered into five profiles by principal components (PC) analysis, each representing statistically independent biological processes. Our goals here were: 1. To identify common genetic variants associated with these profiles; 2 To assess the role of associated variants in AD pathophysiology and 3. Explore potential sex differences.

Method

We performed GWAS analyses for each of the five biomarker PCs in two multi‐center studies, i.e.: the EMIF‐AD and ADNI. In total, 931 participants with no, mild cognitive impairment or AD had sufficient genetic and biomarkers information. Overall, we tested the effect of 7,433,949 common SNPs (MAF>1%; incl. X chromosome) and 19,511 protein‐coding genes. Genome‐wide significant variants were followed up with structural equation models to test whether any of the biomarker PCs mediate the effect of the variants on diagnostic status. We further tested sex interactions with a moderated mediation model.

Result

Five loci showed genome‐wide significant association with the PCA‐based CSF profiles, three of which were previously described (APOE, TMEM160B and CHI3L), and two were novel (rs145791381 and GRIN2D). Mediation tests indicated that variants in the APOE region affect AD status via two statistically independent processes: amyloid and tau pathology, but not via neuronal injury/inflammation. Vice versa, TMEM106B, CHI3L, and rs145791381 affected AD only via neuronal injury/inflammation. GRIN2D was associated with synaptic functioning, but was unrelated to AD risk. PCA‐based CSF profiles did not differ between sexes, neither did associations between CSF profiles and diagnosis status. Interestingly, however, genetic effects were stronger in females for most pathways.

Conclusion

The results suggest for the first time an involvement of an intergenic region on chromosome 9p21.3 (rs145791381) in AD‐related disease processes, as well as a role of the glutamate receptor GRIN2D in synaptic functioning. Furthermore, the study highlights the importance of sex differences in the genetics of AD.
NEUROPROTECTIVE POTENTIAL OF FINGOLIMOD AGAINST ALUMINIUM CHLORIDE INDUCED EXPERIMENTAL DEMENTIA IN RATS
Authors: Agrawal Mohit , Chandolia Priyanka
Published: December 2022

Background

Alzheimer’s disease (AD) is an age related neurodegenerative disease mainly characterized by progressive cognitive decline, synaptic loss, extracellular amyloid‐beta (Aβ) deposits and intracellular accumulation of neurofibrillary tangles of tau protein. Multiple etiological factors have been linked with AD pathophysiology, oxidative stress, neuroinflammation, neurotransmitter deficit and foremost are the deregulation of lipid metabolism, consistently involve in AD pathology and cognitive deficit. In the present study, we have explored the neuroprotective potential of Fingolimod (FTY720), against Aluminium Chloride (AlCl3) induced experimental dementia in the rats.

Method

AlCl3 at the dose of (175mg/kg, p.o.) daily on first to 35th day. Spatial and non‐spatial memory was evaluated by using Morris water maze and object recognition test. Fingolimod (0.25 and 0.5 mg/kg, p.o.) was administered at weekly intervals after administered AlCl3 in rats. Administered AlCl3 in rats produced cognitive deficit and caused significant elevation in markers and oxidative stress and degenerative changes in hippocampus and cortical brain region.

Result

On the countatary, fingolimod treatment attenuate AlCl3 induced cognitive decline, reduced oxidative burden and able to preserve neuronal architecture and prevent neuronal loss in hippocampus and cortical brain region of the rats.

Conclusion

The present study suggests that Fingolimod (FTY 720) show beneficial effects in treating dementia. Our data demonstrated that Fingolimod could be effective in the protection of toxicity induced by Aluminium chloride
Evaluating the DICE method to improve early recognition and treatment of neuropsychiatric symptoms in early Alzheimer’s disease
Authors: Eikelboom Willem S. , van den Berg Esther , Raso Francesco U S Mattace , van Bruchem‐Visser Rozemarijn L. , Goudzwaard Jeannette A , de Jong Frank Jan , den Heijer Tom , Driesen Jan J. M. , Vroegindeweij Lilian J.H.M. , Thomeer Elsbeth C. , Hoogers Susanne E. , Singleton Ellen H. , van Swieten John C , Ossenkoppele Rik , Coesmans Michiel , Papma Janne M.
Published: December 2022

Background

While neuropsychiatric symptoms (NPS) are common in early Alzheimer’s disease (AD), they are currently underdiagnosed and undertreated in the memory clinic. Therefore, we evaluated the effectiveness of the Describe, Investigate, Create, Evaluate (DICE™) approach to structure and standardize the care for NPS in AD in the memory clinic.

Method

A total of 60 community‐dwelling patients with MCI, AD dementia, or AD/VaD dementia were enrolled with their caregivers in two waves (Table‐1). The first wave (n = 36) received care as usual and served as a control group, while the second wave of patients (n = 24, of which n = 20 have currently completed the study) underwent the DICE method. We applied the DICE method during two visits in which NPS were assessed, underlying causes were examined, and patients and caregivers were instructed on management strategies to deal with NPS, which were evaluated after one month. Outcomes were assessed after three and six months. Primary outcomes were quality of life of patients (QoL‐AD) and caregivers (Carerqol‐7D). Secondary outcomes included caregiver burden (Perseverance time), NPS prevalence and severity (NPI‐Q & BEHAVE‐AD), NPS‐related distress (NPI‐Q), competence managing NPS (additional NPI‐Q item), and psychotropic drug use. We used linear mixed models to examine differences in outcomes at group‐level and reliable change index to examine which participants in the intervention group showed reliable improvement in the primary outcomes.

Result

We found no significant differences between the two groups in change in quality of life or any of the secondary outcomes (all p>0.05, Table‐2). A proportion of the intervention group showed reliable improvement in quality of life of patients (n = 6/20) and caregivers (n = 7/20). At baseline, these patients tended to show higher NPS burden and their caregivers reported more NPS‐related distress and lower feelings of competence while managing NPS compared to participants that did no show reliable improvement.

Conclusion

This Stage 2 efficacy study shows no benefits of the DICE method on in early AD at group‐level, but suggest that particular participants might benefit from this approach. Data will be re‐analyzed when all intervention group participants have completed the study and will be extended with qualitative data investigating NPS‐related knowledge and management styles of participants.
Real world clinical perspective on PDE5i utility in dementia.
Authors: Elahi Fanny M
Published: December 2022

Background

There is clearly a large unmet need for more drug treatments in dementia due to Alzheimer pathology (AD) and in VCID. Mechanistic studies in rodents and in vitro support a benefit of PDE5 inhibitors in AD.

Method

A Big data approach recently confirmed this potential benefit with an independent study incorporating multiple levels of biology with in silico network drug discovery for amyloid and tau endophenotypes, data mining from insurance records, as well as in vitro modeling using derived induced pluripotent stem cell (iPSC) neuronal models of AD.

Results

Collectively, this body of work is cause of optimism. However, a real‐world randomized clinical trial (RCT) of the PDE5i tadalafil in older people, incorporating biomarkers, detected no significant effect with respect to cerebral blood flow.

Conclusion

These results raise multiple questions for the dementia clinician‐scientist. Do in vitro and in vivo preclinical paradigms provide non‐translatable findings because these systems are not capturing a key component of AD, such as human aging? Is it still worth pursuing PDE5i as a therapeutic route? What could be some factors that contributed to the negative RCT results and what should be emphasized in the design of a definitive RCT for this class of therapeutics? Finally, what role do biomarkers play in filling critical gaps in knowledge to bridge the path between bench and bedside.
Characteristics and Outcomes of Traumatic Brain Injury among Older Adults with and without Pre‐injury Dementia: an Israel National Trauma Registry Study
Authors: Gardner Raquel C. , Cohen‐Manheim Irit , Givon Adi , Radomislensky Irina , Bodas Moran ,   the Israel Trauma Group (ITG)
Published: December 2022

Background

Older adults have the highest and fastest rising incidence of traumatic brain injury (TBI) compared to all other age groups. Few studies have examined the prevalence of pre‐injury dementia among older adults presenting with TBI. None have examined injury characteristics and outcomes specifically among those with pre‐injury dementia. Our aim was to describe prevalence of pre‐injury dementia among older adults hospitalized with TBI in Israel and to examine features of those with versus without pre‐injury dementia.

Method

We identified all TBIs recorded in the Israel National Trauma Registry from 2015‐2020 among adults age 65 years and older who were admitted to one of 15 trauma centers. We determined the prevalence of a diagnosis of pre‐injury dementia recorded in the registry and compared baseline demographics, injury features, and hospital outcomes among those with versus without pre‐injury dementia.

Result

Among N = 7,788 identified cases of geriatric TBI, 9.8% (N = 762) had pre‐injury dementia. Compared to those without pre‐injury dementia, those with pre‐injury dementia were significantly older (90% vs. 70% age >75 years), more female (58% vs. 47%), had higher rates of injury location of residential institution (24% vs. 7%) or home (63% vs. 58%), and higher rates of injury mechanism of fall (95% vs. 84%; all p<0.01). No differences were identified in Injury Severity Score (ISS) across groups (p = 0.19). However, those with pre‐injury dementia had lower rates of severe TBI (4% vs. 7% Glasgow Coma Scale <9), lower rates of polytrauma (10% vs. 13%), and lower rates of surgical intervention (9% vs. 13%), yet had higher rates of in‐hospital mortality (10% vs. 8%) and new institutionalization post‐discharge (11% vs. 4%; all p<0.02).

Conclusion

Approximately 10% of older adults admitted to hospitals in Israel with TBI have dementia compared to only 7% of older adults in the general population (per 2019 national health service data), suggesting that dementia is likely a risk factor for TBI in the elderly. Additionally, admission for a TBI resulted in 10% in‐hospital mortality and 11% new institutionalization post‐discharge among those with pre‐injury dementia. Geriatric TBI prevention, primarily through fall‐prevention, is of high public health importance in Israel.
Whole brain MRI‐free tau and amyloid PET quantification
Authors: Ward Tyler J. , Harrison Theresa M. , Murphy Alice , Baker Suzanne L. , Mormino Elizabeth C. , Koeppe Robert A. , Jagust William J. , Landau Susan M.
Published: December 2022

Background

The growing use of PET imaging in Alzheimer’s research and clinical practice has resulted in the need for PET quantification when an MRI is unavailable or contraindicated. The Desikan‐Killiany (DK) atlas in Freesurfer (FS) is often used in conjunction with a native space MRI to define regions of interest for tau and amyloid PET quantification. Here we developed a template‐space DK atlas for use in MRI‐free amyloid & tau quantification, and validated the performance of the template using MRI‐free florbetapir and flortaucipir SUVrs in relation to our gold standard native space SUVrs.

Method

To develop a template‐space atlas made up of 112 DK regions identical to those used in our native‐space, MRI‐dependent pipeline, we segmented T1 MRIs from a subset of 200 cognitively normal ADNI participants using Freesurfer 7.1. Each binary region was nonlinearly warped to template space, smoothed, and averaged across the 200 MRIs to create 112 ROI probability maps (Fig 1A). Each region probability map was normalized between 0 and 1 then merged together into a single template‐space atlas by ranking each voxel in relation to each ROI (Fig 1B). To calculate MRI‐free SUVrs, ADNI baseline flortaucipir (n=768) and florbetapir (n=1290) images were spatially normalized to PET‐only, tracer‐specific templates developed in subsets of ADNI scans. We examined several key amyloid and tau target SUVrs based on the MRI‐free atlas in relation to corresponding MRI‐dependent SUVrs calculated using our gold standard pipeline.

Result

MRI‐free region‐wise cortical SUVRs were highly correlated with their MRI‐dependent counterparts for both florbetapir (average R2 across cortical ROIs = 0.80, cortical summary R2 = 0.84; Fig 2A) and flortaucipir (average R2 across cortical ROIs = 0.87, entorhinal R2 = 0.88, temporal metaROI R2 = 0.97; Fig 2B). Positive/negative status agreement between MRI‐free and MRI‐dependent approaches using previously‐validated MRI‐dependent thresholds was 91% (Aβ) and 92% (temporal metaROI tau).

Conclusion

Amyloid and tau SUVRs and +/− status calculated using a template‐space DK atlas are comparable to those calculated using our gold standard MRI‐dependent approach. This MRI‐free approach will be useful for region‐wise PET quantification when structural scans are unavailable.
Exploring the role of sleep in Alzheimer’s disease: The AlfaSleep project
Authors: Fauria Karine , Minguillon Carolina , Stankeviciute Laura , Hernández Laura , Knezevic Iva , Deulofeu Carme , Fuentes‐Julian Sherezade , Turull Israel , Fusté David , Sánchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , Suárez‐Calvet Marc , Iranzo Álex , Gispert Juan Domingo , Molinuevo Jose Luis , Grau‐Rivera Oriol ,   ALFA Study
Published: December 2022

Background

Sleep disruption is prevalent in the aging population and increasingly recognized as a risk factor and an early sign of Alzheimer’s disease (AD). Emerging data suggest that dysregulated orexin signaling may play a role in this association. The AlfaSleep study aims to characterize sleep patterns with objective measurements, and determine CSF orexin‐A levels in cognitively unimpaired middle‐aged adults at increased risk of AD.

Method

Two‐hundred cognitively unimpaired middle‐aged adults from the prospective observational ALFA+ study have been invited to participate in this study based on their cerebrospinal fluid (CSF) biomarker profile at the ALFA+ study baseline (100 in the AD continuum and 100 control, non‐altered biomarkers). ALFA+ participants are followed‐up every three years (and currently are undergoing the first follow‐up visit) with neuropsychological testing, blood and CSF sampling, and MRI and PET (with FDG, amyloid and tau tracers) acquisition. Participants included in the AlfaSleep study are additionally characterized with actigraphy (Actiwatch2®, Philips Respironics during two weeks), a nasal flow monitoring device (RUSleeping RTS®, Philips Respironics during one night) and CSF orexin‐A measurements. Furthermore, a subset (n = 90) will undergo overnight polysomnography at the Hospital Clinic Sleep Unit (Figure 1). Sleep‐related outcomes include total sleep time, sleep latency, sleep efficiency, sleep fragmentation, apnea‐hypopnea index and sleep microarchitecture measures (e.g. spectral power analyses). These data, as well as CSF orexin‐A levels will be compared across participants with different AD biomarkers profiles and correlated with cognitive performance, neuroimaging and fluid biomarkers data.

Result

To date, 134 participants (mean age 64.4 years, 67% female) have been included in the AlfaSleep study. Of these, 50 (37.9%) reported poor sleep quality (PSQI>5), 45.5% are APOE‐ε4 carriers and 35.8% had abnormal CSF amyloid levels, as measured at the ALFA+ baseline visit (see Table 1 for a detailed description).

Conclusion

Due to its multimodal approach, and the profile of the study population (cognitively unimpaired middle‐aged adults in the AD continuum), the present project will make relevant contributions to understand the role of sleep disruption as a risk factor and early clinical manifestation of AD. Preliminary results will be presented at the conference.
Multiparity and brain‐age interact with amyloid aggregation to determine cognitive performance in cognitively unimpaired middle‐aged women
Authors: Brugulat‐Serrat Anna , Cumplido‐Mayoral Irene , Sánchez‐Benavides Gonzalo , Operto Greg , Falcon Carles , Cacciaglia Raffaele , Shekari Mahnaz , Carmona Susana , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Grau‐Rivera Oriol , Arenaza‐Urquijo Eider M , Suárez‐Calvet Marc , Gispert Juan Domingo ,   for the ALFA study
Published: December 2022

Background

How pregnancy influences women's brain aging later in life remains controversial. Whereas multiparity has been associated with decelerated brain aging, it has been also identified as a risk factor for Alzheimer’s disease (AD). However, the impact of of childbirths on cognitive performance in women at higher risk of developing AD is underresearched. We investigated whether the association between multiparity, brain‐age and amyloid (Aβ) aggregation contributes to cognitive performance in cognitively unimpaired (CU) middle‐aged women.

Method

We included 223 CU parous women from the ALFA+ study (age 49‐74) who underwent cognitive assessment and had valid T1w MRI, and [18F]‐flutemetamol Aβ PET. As controls, 152 men were included. Parity was categorized as 1/≥2 children. The difference between chronological and biological brain age (brain‐age delta) was estimatied by predicting the latter using a pretrained machine learning algorithm on cerebral morphological measurements. Aβ‐positivity was defined as Aβ PET ≥ 30 Centiloids. The Preclinical Alzheimer Cognitive Composite (PACC) was computed. PACC was the dependent variable in linear models using the parity, brain‐age, and Aβ status as predictors. Age, education, age at first birth, and Body Mass Index (BMI) were used as covariates. Interaction term with the parity*brain‐age*Aβ status was modeled.

Result

25.7% of women had one child (n=7 [12.3%] Aβ‐positive), and 74.3% had two or more children (n=25 [15.1%] Aβ‐positive). There were no significant differences in PACC (p=0.701) or Aβ status (p=0.071). Multiparity women showed a significant decelerated brain‐aging (p=0.017) than women with one childbirth. A parity*brain‐age*Aβ status interaction (p=0.021) revealed that among women with one childbirth, an accelerated brain‐aging was associated with a worse PACC performance in those that are Aβ‐positive (p=0.008), while this association was not found in Aβ‐negative (p=0.702) (Figure 1). The same interaction was not found among men (p=0.234).

Conclusion

Our results suggest that the interaction between parity, brain‐age, and Aβ aggregation contributes to cognitive performance in women later in life. Multiparity might exert a neuroprotective effect in cognitive performance in women at higher risk of developing AD. This finding represents an important contribution to the knowledge of female‐specific AD risk factors and women’s brain aging.
Intrusive thoughts and distress following amyloid status disclosure in a preclinical Alzheimer’s disease trial: Comparisons across racial and ethnic groups
Authors: Ritchie Marina , Gillen Daniel L. , Grill Joshua
Published: December 2022

Background

Preclinical Alzheimer’s disease (AD) trials require biomarker testing and disclosure. Efforts are underway to improve the diversity and inclusivity of enrollment in these trials. While previous studies have shown that disclosure can be performed safely, trialists need a more thorough understanding of whether reactions to AD biomarker disclosure differ among racial and ethnic groups.

Methods

Using data from the Anti‐Amyloid treatment in Asymptomatic AD (A4) study, we analyzed participant responses on the Impact of Events Scale (IES), a 15‐item questionnaire that assesses avoidance and intrusive thoughts after disclosure of amyloid imaging results. We fit a linear regression model to test the hypothesis that mean IES scores differed by racial and ethnic group. Confounding factors included age, sex, years of education, study partner type, family history of AD, and amyloid status. We considered potential effect modification by amyloid status by including an interaction term between race and amyloid group.

Results

IES data were available for 4311 participants (3795 = non‐Hispanic [NH] White; 147 = NH Black; 165 = NH Asian; 135 = Hispanic; 69 = Other). Figure 1 illustrates total IES scores for the groups, stratified by amyloid status. NH Asians demonstrated the highest mean IES among those with elevated amyloid. Hispanics demonstrated the lowest mean IES among those with elevated amyloid, but the highest among those with not elevated amyloid. In a regression model, younger age, female sex, and family history of AD were associated with higher IES. Overall, the association between race and ethnicity groups and IES did not significantly differ by amyloid status (p = 0.200). Among not elevated amyloid individuals, Hispanics had a significantly higher mean IES when compared to NH Whites (est: 2.38; 95% CI: 0.57, 4.19; p = 0.10). Among elevated amyloid individuals, this estimate decreased to ‐1.47 (95% CI: ‐4.36, 1.42; p = 0.319).

Conclusions

When stratified by amyloid status, all racial and ethnic groups showed higher mean IES in the elevated compared to the not elevated amyloid group, except for Hispanics. This may suggest that, for Hispanics, having an AD biomarker test at all may lead to avoidance and intrusive thoughts, regardless of the specific test result.
Diversity in Alzheimer’s Disease drug trials: The importance of eligibility criteria
Authors: Franzen Sanne , Smith Jade , van den Berg Esther , Mindt Monica Rivera , van Bruchem‐Visser Rozemarijn L. , Abner Erin L , Schneider Lon S. , Prins Niels D. , Babulal Ganesh M , Papma Janne M.
Published: December 2022

Background

To generalize safety and efficacy findings, it is essential that diverse populations are well represented in global Alzheimer’s disease (AD) drug trials. In this review, we aimed to 1) investigate participant diversity in disease‐modifying AD trials over time, 2) identify which eligibility criteria were used and how they were defined, and 3) how the eligibility criteria may have affected participant diversity levels.

Method

A systematic review of amyloid and tau trials in Alzheimer’s disease was performed using Medline, Embase, the Cochrane Library, and Clinicaltrials.gov, identifying 2247 records.

Result

In the 101 included AD trials, participants were predominantly white (median percentage: 94.7%, IQR: 81.0%‐96.7%); and this percentage showed no significant increase or decrease over time (2001‐2019). Eligibility criteria such as exclusion of persons with psychiatric illness (78.2%), cardiovascular disease (71.3%) and cerebrovascular disease (68.3%), obligated caregiver attendance (80.2%), and specific MMSE‐scores (90.1%; no significant increase/decrease over time, Fig. 1) may have led to a disproportionate exclusion of ethnoracially diverse individuals. Furthermore, many eligibility criteria—such as those describing diabetes, hepatic disease, and renal conditions—often were not well defined, or the cut‐offs varied considerably across studies.

Conclusion

Ethnoracially diverse participants continue to be underrepresented in AD clinical trials. Several recommendations will be provided, such as the use of internationally recognized clinical classifications and cut‐offs, inclusion of participants with specific medical conditions as long as they are medically stable, and flexibility in requirements regarding caregiver attendance. Furthermore, changes need to be considered to 1) the instruments used in trials (e.g. overreliance on MMSE) and 2) requirements regarding education, literacy, and language.
Initial Correlation Analysis of Diffusion Basis Spectrum Imaging of Alzheimer's Brain and Quantitative Histology
Authors: Wu Wenjie , Wang Qing , Sun Zhexian , Flores Shaney , Hobbs Diana A. , Franklin Erin E. , Perrin Richard J. , Benzinger Tammie L.S. , Wang Yong
Published: December 2022

Background

Diffusion Basis Spectrum Imaging (DBSI), a novel MR imaging method, can be utilized as a biomarker in Alzheimer's disease (AD) staging and progression. By distinguishing diffusion effects from other concomitant disorders like axonal injury/loss and demyelination, it is capable of specifically evaluating cellularity and edema in AD brains. To test the hypothesis that DBSI cell fraction and mean cell apparent diffusion coefficient (ADC) correlate with measures of cell density and neuroinflammation, we employed high‐resolution ex vivo DBSI sequences and quantitative digital histology on post‐mortem human AD brain tissue.

Method

A 15 × 20 × 6 mm3 sample of middle frontal gyrus (coronal plane) from a formalin‐fixed post‐mortem human AD brain (Knight ADRC) was incubated in phosphate‐buffered saline for 48 hours and then imaged with a Varian 11.7T MRI, using 2D spin‐echo sequence with 20‐direction diffusion encoding (max b = 3900 s/mm2, voxel = 0.25 × 0.25 × 1 mm). After MRI, it was precisely bisected along the plane of imaging, and processed into paraffin. Slide‐mounted 6 µm histologic sections were stained with H&E and DAB immunohistochemistry (IBA‐1 antibody, hematoxylin counterstain) and digitized (20× magnification, Hamamatsu NanoZoomer). Maps of nuclei and microglia density were computed by segmenting nuclei and microglia respectively using Orbit Image Analysis and in‐house MATLAB programs. These histology maps were registered and downsampled to the corresponding DBSI maps. We generated cell fraction maps and mean cell ADC maps from MR images using in‐house DBSI software by computing the fraction and mean ADC of restricted isotropic diffusion (0 – 0.4 ×10‐3 mm2/s in each image voxel, respectively.

Result

Among 71 evenly spaced regions of interest (ROIs, 2 × 2 mm2) drawn across the entire specimen, the mean DBSI cell fraction correlated with nuclei density (R = 0.74, P < 0.001). Additionally, among 42 ROIs drawn in the white matter region, the mean cell ADC in each ROI correlated with microglia density (R = 0.54, P < 0.001).

Conclusion

Our findings demonstrated the feasibility of DBSI technique in ex vivo AD brain, which could improve our understanding of neuroinflammation in AD pathogenesis, early diagnostics and new disease‐modifying therapies targeting the immune response.
Dementia vs Depression : new methods for differential diagnosis using automatic speech analysis
Authors: Labbé Céline , König Alexandra , Lindsay Hali , Linz Nicklas , Tröger Johannes , Robert Philippe
Published: December 2022

Background

Depression is a very frequent pathology among elderly people. Depressive symptoms are common in neurocognitive disorders which can make it challenging to timely detect and diagnose them. Indeed, there is a high comorbidity of early‐stage dementia and late‐ life depression. There are only a few diagnostic tools that help support differential diagnosis. Speech analysis and the extraction of vocal and linguistic markers could be a non‐invasive new method to support this process.

Methods

In this pilot study, we included 12 female patients aged over 60 diagnosed with depression without a neurodegenerative disease or other psychiatric disorders. Clinical assessments include the MMSE, MADRS, EGF and ADC. They were asked to perform two short cognitive vocal tasks: a verbal semantic fluency (SVF) and a short narrative task (positive/negative storytelling) which were recorded. Then, in a second step, vocal and prosodic features were extracted from the audio files using machine learning methods. In a final step, we compared these features to those from a cohort of 9 matched patients with Mild Cognitive Impairment (MCI) diagnosis without any mood disorder and 21 matched controls.

Results

A non‐parametric kruskal‐wallis and BH‐adjusted post‐hoc wilcox test analysis revealed a statistically significant (p<0.05) lower word and semantic switch count for MCI compared to depression in the SVF. Linear mixed effects models were used to evaluate 18 prosodic features from the narrative speech task. Four features were significant between diagnoses; sound to noise ratio, delta deltas and deltas were significantly different for the depressed group in comparison to HC and MCI; total phonation time was longer for depressed patients than MCI patients in the negative story.

Conclusion

Automatic analysis of vocal tasks such as semantic verbal fluency and storytelling could be a fast solution for supporting early characterization of patients. Certain types of extracted speech features show different patterns and namely prosodic features should be further explored. To conclude, this new method could serve as an objective assessment tool for differentiating depression from mild cognitive impairment.
Functional eigenvector centrality dynamics are related to amyloid deposition in preclinical Alzheimer’s Disease
Authors: Lorenzini Luigi , Ingala Silvia , Collij Lyduine E. , Wottschel Viktor , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Chetelat Gael , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Waldman Adam , Wardlaw Joanna M , Ritchie Craig W. , Gispert Juan Domingo , Mutsaerts Henk‐Jan , Visser Pieter Jelle , Scheltens Philip , Tijms Betty M. , Barkhof Frederik , Wink Alle Meije
Published: December 2022

Background

In preclinical Alzheimer’s disease (AD), amyloid accumulates in highly‐functionally connected brain regions. This selective vulnerability is related to the high neuronal fluctuations, typical of these regions. Dynamic functional connectivity (FC) was introduced to investigate network organization over time, with high network variations indicating regional flexibility, hence promoting functional integration. The relation of early amyloid deposition with FC dynamics remains unclear. Eigenvector centrality (EC) evaluates a node's importance in functional networks, both for the whole functional MRI time series (“static” EC) or within sliding‐windows (“dynamic” EC). We studied the association of cerebrospinal fluid (CSF) amyloid load with static and dynamic EC in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.

Methods

Data for 701 non‐demented participants were available. CSF Aβ1‐42 levels <1000 pg/mL were defined as amyloid positive (A+) (Elecsys assay). Both static and dynamic voxel‐wise EC were computed from rs‐fMRI time series. Static EC differences between A+ and A‐ participants were assessed using linear models. Standard deviation and range of dynamic EC were compared between A+ and A‐ participants within significant clusters of static EC differences, and within 10 resting‐state networks (RSN). Linear models were used to determine interaction between amyloid and cognitive performance on dynamic EC variability (Figure 1).

Results

Demographics and clinical characteristics are shown in Table 1. A+ participants showed lower static EC values in parietal and occipital clusters, and higher static EC values in a medio‐frontal cluster (Figure 2). The medio‐frontal cluster had also lower dynamic EC variability in A+ (Figure 3). The default mode (Figure 4) and the visual networks of A+ participants also showed lower dynamic EC variability (p < 0.001). Dynamic properties in the DMN and visual networks were differentially associated with cognitive domains in the A‐ and A+ groups, with lower variability found in A+ participants with higher cognitive scores (Figure 5).

Conclusion

We demonstrate that early amyloid deposition affects static and dynamic EC, possibly by reducing involvement of functional hubs in different network dynamics and functional integration, thus relating to cognitive dysfunctions. Our data suggest dynamic EC as an early biomarker of the interplay between early amyloid deposition and cognitive decline.
Alzheimer’s Disease and Related Dementias Referral Outcomes among Diverse Rural Residents
Authors: Wiese Lisa Ann Kirk , Holt Janet , Williams Ishan Canty , Group Research
Published: December 2022

Background

This study to increase dementia detection in rural settings was conducted in a medically underserved area of southcentral Florida referred to as “the Glades.” Residents face multiple disparities related to Alzheimer’s disease and related dementias, including less than a 60% high school graduation rate, diabetes and hypertension as the primary health diagnosis, and increased exposure to ambient air particles from sugar cane burning.

Method

Locations for testing included eight churches and a virtual “location,” for a total of ten sites. Individuals (N = 217) were cluster sampled within these sites. Participants were administered a brief educational intervention and brain health was screened using Nasreddine’s telephone “Mini‐MoCA” (2019), in which a score < 12 indicates cognitive risk. Referrals were determined for 133 participants.

Results

The sample consisted of 59 virtual and 74 in‐person participants, with a range of 1 to 14 participants per church. Seventy percent were female, 57% lived alone, 13% had a previous memory test, and less than 1% had been previously diagnosed with dementia. The sample consisted primarily of four ethnicities, n = 44 (33%) African Americans, n = 21 (16%) Afro‐Caribbeans, n = 19 (14%) Hispanics, and n = 45 (34%) Whites.

There was substantial variance in outcomes across sites, with an ICC = .179 (n = 133), indicating that 17.9% of the variance in referrals was between sites. Therefore, a mixed linear model approach was used for analysis with participants nested within sites (Feaster et al., 2011) The covariate of whether they had a previous memory test was not statistically significant and only reduced the ICC by .002. Neither gender, nor whether the person lived alone were statistically significant predictors of referrals, (p > .05), however adding ethnic group reduced the ICC to .102, a 47% reduction in intercept variance (N = 131). In particular, African American participants were significantly more likely to have referrals than White participants, g20 = 1.29, p<.001, OR = 3.66. Hispanic and Afro‐Caribbean participants were not significantly more likely to have referrals than White participants, p = .52 and p = .06 respectively.

Conclusion

Further investigation is needed to determine place‐based factors that uniquely increase risk for African Americans in an 89% racially/ethnically diverse community.
The relationship between study partner type and rate of AE reporting in mild‐to‐moderate AD clinical trials
Authors: Lu Thuy Vu Dieu , Gillen Daniel L. , Grill Joshua
Published: December 2022

Background

In randomized clinical trials (RCTs), monitoring adverse events (AE) and serious AE (SAE) is critical to maximize patient safety and trial integrity. There are, however, instances where the propensity to report AEs may differ by participant characteristics, thereby altering the observed safety profile of interventions and the generalizability of safety results. All Alzheimer’s disease (AD) clinical trials require participants to enroll with a study partner (SP), who ensures trial compliance and serves as a source of study data, including data on AEs. We examined AE reporting patterns among AD trial participants by SP type with the hypothesis that the rates of reported AEs and SAEs differ by SP type.

Method

We conducted a retrospective analysis of combined placebo data from seven independent RCTs conducted by the AD Cooperative Study (ADCS) (Docosahexaenoic Acid, Vitamin B, Huperzine A, Rofecoxib or Naproxen, Resveratrol, Simvastatin, and Valproate). Together, these seven trials provide data on 934 patients with mild‐to‐moderate AD. SP of each participant was categorized as spouse, adult child, or other. The total number of AEs by severity and SAEs were recorded for all individuals in the trial (Table 1). We also considered subject‐level reporting rates where we computed the number of unique participants reporting such events (Table 2). Chi‐squared tests were performed to determine if the rate of reporting AEs and SAEs by participants varied across SP type.

Result

A total of 608 (65%) participants enrolled with spousal, 254 (27%) enrolled with adult child, and 72 (8%) enrolled with other SP. Overall, 854 (91%) participants reported at least one AE. There were 5430 AEs (66% grade 1, 28% grade 2, 6% grade 3, and 0% of grade 4 or 5) recorded. Chi‐squared tests comparing the rate of reporting by SP type yielded p‐values of 0.16 and 0.13 for AEs and SAEs, respectively.

Conclusion

We observed that the reporting rate of AEs and SAEs did not substantially vary by SP type. This relationship was consistent across AE severity grades. Our results indicate little evidence that the reported safety profile in mild‐to‐moderate AD trials differs by SP type.
Reducing MRI Inter‐Scanner Variability Using 3D Superpixel ComBat
Authors: Chen Chang‐Le , Torbati Mahbaneh Eshaghzadeh , Wilson James D , Minhas Davneet S , Laymon Charles M , Hwang Seong Jae , Maillard Pauline , Fletcher Evan , DeCarli Charles S. , Tudorascu Dana L
Published: December 2022

Background

Inter‐scanner variability hinders the direct comparability of multi‐site/scanner MRI data for clinical research. The ComBat method is commonly used to reduce the variability based on an empirical Bayes framework1,2, harmonizing the data at the feature level (e.g., region‐of‐interest measures). However, directly harmonizing the scans at the voxel‐level using ComBat has been relatively less explored. In this study, we investigated the performance of the voxel‐wise ComBat. Also, going beyond voxels, we proposed a new ComBat approach which operates on a small group of voxels called superpixels3.

Method

Eighteen subjects (10 patients with Alzheimer's disease and 8 controls; age: 68.0 [9.3] years; 10 females) participated in this study. For each subject, T1‐weighted images were acquired on each of four 3T scanners with different manufacturers or models (i.e., GE, Philips, Siemens‐Prisma, Siemens‐Trio). After the standard image preprocessing including two‐step registration by using the Statistical Parametric Mapping (SPM12)4, the unharmonized scans (Raw data) were aligned in the standard template space. To reduce the computational load for ComBat at the voxel level (Voxel‐ComBat), we used a three‐dimensional superpixel algorithm3 to parcellate the images into hundreds of superpixels based on the study‐specific template, and then the ComBat was applied at the superpixel level (Figure 1). Compared to Voxel‐Combat operating on about half million voxels (computation time >>10,000 seconds), this superpixel ComBat (SP‐ComBat) operates on only a few hundred superpixels, significantly improving the computation efficiency (computation time < 5 seconds) while maintaining the harmonization performance. The harmonized scans were used to estimate cortical thickness by employing surface‐based morphometry5, and the coefficients of variation of thickness measures were calculated to evaluate the harmonization performance.

Result

The harmonized data provided similar contrasts across scanners compared to the Raw images in visual inspection (Figure 2) and had comparable distributions of the tissue‐specific signal intensity between scanners for both Voxel‐ComBat and SP‐ComBat (Figure 3). Also, these two methods significantly reduced the inter‐scanner variation (both p‐values < 0.001) in terms of cortical thickness measures (Figure 4).

Conclusion

This study evaluated the feasibility and effectiveness of Voxel‐ComBat and proposed a new approach, SP‐ComBat, to optimize the efficiency of ComBat harmonization at the voxel level.