bluuebunny/crossref_metadata_2025 huggingface dataset:
Liquid biopsy shows differences in cfDNA fragmentation pattern between AD patients and controls
Authors: Santamaria Blanca Acha , Luquin Idoia Blanco , Corroza Jon , Miguel Mikel San , Roldan Miren , Zueco Sara , Beiras Itsaso Elizalde , Cabello Carolina , Agudo Maria Ángeles Garde , Jericó Ivonne , Erro Elena , Mendioroz Maite
Published: December 2020

Background

In the field of precision medicine, liquid biopsy has been developed as a non‐invasive blood test to isolate circulating cell‐free DNA (cfDNA). Although liquid biopsy has gained much attention in oncology as a diagnostic tool, the role of liquid biopsy to aid diagnosis in neurodegenerative diseases remains unclear. Here, we investigated characteristics of plasma cfDNA in AD patients and controls.

Method

Plasma cfDNA was isolated from 2 mL of plasma by using QIAmp Circulating Nucleic Acid Kit (QIAGEN) in a set of 95 subjects (43 Probable AD patients based on the NIA‐AA criteria and 52 controls). Fragment Analyzer system (Agilent formerly Advanced Analytical) was used to (1) check cfDNA purity, (2) measure concentration and (3) assess the fragmentation pattern including cfDNA length and concentration of the “classical” three cfDNA peaks. Statistical significance for intergroup differences was evaluated by Mann‐Whitney test with a significance level of 0.05.

Result

The distribution of age and gender was similar between AD patients and controls. No genomic contamination was identified in cfDNA samples. Global plasma concentration of cfDNA was similar in both groups [median (IQR) 17.8 (31) in AD vs. 13.4 (10) in controls, p‐value=0.129]. However, differences were found in the concentration of the first cfDNA peak (size 166 bp) [0.019 (0.025) in AD vs. 0.033 (0.031) in controls; p‐value< 0.05] and in the concentration of the third cfDNA peak (size 534 bp) [0.099 (0.079) in AD vs. 0.193 (0.196) in controls; p‐value< 0.05]. No significant differences in cfDNA fragment length were detected between AD patients and controls.

Conclusion

This exploratory study provides evidence of significant differences in the fragmentation pattern of cfDNA in AD patients compared to controls. These results suggest that liquid biopsy is a diagnostic tool worthy to be explored in larger AD cohorts.
lncRNAs as a novel source of diagnostic applications for early Alzheimer’s disease and other dementia types
Authors: Firat Hüseyin , Nazi Sami Ait Abbi , Bier Jean‐Christophe , Blanc Frédéric , Boutillier Stéphanie , Danilin Sabrina , David Renaud , Démonet Jean‐François , Dubois Bruno , Frisoni Giovanni B , Gabelle Audrey , Gurvit Hakan , Ivanoiu Adrian , Magnin Eloi , Marizzoni Moira , Moussaoui Saliha , Mutter Catherine , Pasquier Florence , Schordan Eric , Sellal François ,   ADDIA Consortium,   ADKIT Consortium
Published: December 2020

Background

There is an unmet need for an accurate, non‐invasive biomarker test for the diagnosis of early Alzheimer’s disease (AD). To identify new biomarkers, we focused on long non‐coding RNAs (lncRNAs) as they are tissue‐ specific to identify lncRNA panel candidates for diagnostic of early Alzheimer’s disease (AD) and other dementia types.

Method

We performed a screening using NGS RNA‐Sequencing to quantify over 127000 lncRNAs in human postmortem brain tissue and blood samples including whole blood, PBMCs and, plasma samples collected in prospective clinical studies that recruited patients with early AD, patients with late AD, patients with one of the other 5 dementia types and healthy controls.

Result

We identified for the first time several panels (i) a panel of brain‐enriched lncRNAs never described before, (ii) panels of brain‐enriched lncRNAs that are either expressed in whole blood or circulating in plasma. (iii) Interestingly, out of these, we also identified panels of lncRNAs that are differentially expressed in the blood of patients with AD or with other dementia types as compared to healthy control subjects. The most accurate lncRNA panel to detect early AD is selected for use as Research‐Use‐Only test and is being further validated to compile the data dossier for submission to regulatory agencies for approval as an in‐vitro diagnostic (IVD) tool diagnostic of AD. Additional clinical applications are for prognostic or theragnostic purposes.

Conclusion

Our results from studies combining the use of high‐quality samples from well‐designed prospective clinical studies, cutting edge technologies and scientific knowhow enabled to translate novel brain specific lncRNA panels measurable in blood as new non‐invasive and accurate diagnostic approaches using highly specific and low represented sequences specific to neurodegenerative diseases. This project is funded by the Alzheimer's Drug Discovery Foundation (ADDF) Diagnostics Accelerator, a fund set up in collaboration with Bill Gates and other philanthropic partners, By H2020 SMEINST (GA#674474) and by EuroTransBio (ETB‐2014‐63 supported by Region Grand Est).
Combined training of aerobic exercise and 3D video game to improve hippocampal and memory functions in older adults: An RCT trial
Authors: Cui Xiaoyu , Gui Wenjun , Li Juan
Published: December 2020

Background

With the proportion of older adults rising, the progressive cognitive decline and dementia have become one of the most serious public health issues worldwide. As a result, there is a pressing need for developing effective non‐pharmaceutical intervention programs to counteract age‐related cognitive decline. Animal models robustly support that aerobic exercise can effectively improve neurogenesis and memory, whereas most of the current findings from human studies are in contrast. We speculated that two reasons may contribute to these inconsistent findings in human research. One is that hippocampal neurogenesis induced by the aerobic exercise is more likely to survive when simultaneously accompanied by cognitive stimulations, particularly when the cognitive goals are challenging. Another is that the beneficial effects from aerobic exercise are specific to hippocampal dependent memory tasks. Therefore, we designed a training program by combining aerobic cycling with 3D video game.

Method

We conducted a randomized controlled trial with healthy older adults randomly assigned to combined aerobic cycling and 3D video game training group (n=22), aerobic cycling group (n=23), 3D video games group (n=25), or control group (n=28). The effects of combined training on neuroplasticity (including plasma brain‐derived neurotrophic growth factor, hippocampal gray matter volume, and hippocampal‐cortical functional connectivity) and cognitive plasticity (focusing on hippocampal‐dependent memory, tested via Mnemonic Similarity Task) were examined compared with all three other groups. The training lasted four months with a frequency of twice per week, 1hour per session.

Result

The combined and video game training groups reported equivalent game experiences and reached similar game levels. The average and maximum heart rates were being monitored to ensure a medium exercise intensity in both combined and cycling groups. In addition self‐reported fatigue levels were equivalent in these two groups. The preliminary behavioral data analysis revealed that combined group performed better on immediate and delayed memory recall. More importantly, there was a larger effect size in pattern separation task in combined group (Cohen’s d =1.12) than in cycling (Cohen’s d =0.49) and video game (Cohen’s d =0.55) groups.

Conclusion

Combined aerobic exercise ‐ video game training could improve hippocampal‐dependent memory functions, which waits the MRI data analysis to further prove.
Clinical course of early and late mild cognitive impairment
Authors: Lin Szu‐Ying , Lin Po‐Chen , Lin Yi‐Cheng , Lee Yi‐Jung , Wang Pei‐Ning
Published: December 2020

Background

Amnestic mild cognitive impairment can be sorted to early mild cognitive impairment (EMCI) or late mild cognitive impairment (LMCI) according to severity of memory impairment. The aim of present study is to compare the prognosis and clinical course between EMCI and LMCI.

Method

From January 2009 to December, 2017, we recruited 640 participants from memory and dementia clinic at the Neurology Department of Taipei Veteran General Hospital. All patients receive at least two series neuropsychological evaluation annually and were categorized to EMCI or LMCI according to ADNI‐2 criteria.

Result

Total 186 patients with EMCI and 277 patients with LMCI were included. 177 cognitive normal participants were also included as normal control. The mean follow‐up duration was 2.85 ± 2.02 years (minimal: 1, maximum: 9 years). At the secondary year, 58 (31.2%) EMCI and 9 (3.2%) LMCI reversed to normal cognitive status. Annual dementia conversion rates were 1.61, 4.41, 21.98 per person year in NC, EMCI and LMCI groups, respectively. EMCI and LMCI had higher rate of progression to dementia (Log rank test, p<0.001) than normal subjects. Both MCI groups showed significant decline in global function (MMSE) and executive function (digital forward, Trail making test A (time), Trail making test B (line) and verbal fluency) than those in normal subjects. No significant different was found in episodic memory and language function between converters and non‐converters

Conclusion

Both early and late MCI showed higher risk of dementia. Although MCI showed wide variation in neuropsychological tasks and clinical diagnosis during follow‐up periods, there was higher global and executive functional decline.
Restoring dysfunctional regulatory T cells through ex vivo expansion in Alzheimer disease
Authors: Faridar Alireza , Thome Aaron , Zhao Weihua , Thonhoff Jason R , Beers David , Pascual Belen , Masdeu Joseph C. , Appel Stanley
Published: December 2020

Background

Inflammation is a significant component of Alzheimer disease (AD) pathology. Chronically activated microglia release proinflammatory cytokines, mediate synaptic loss and exacerbate tau propagation. Regulatory T cells (Tregs) have been shown to suppress microglia‐mediated inflammation. We have previously found a failure in suppressive activity of Tregs at the clinical Alzheimer dementia stage. In this study we evaluate the potential of ex vivo expansion of AD Tregs to modify their immunophenotype and restore their function.

Method

10 patients with Alzheimer disease, 10 with mild cognitive impairment and 10 healthy controls were studied. Tregs were co‐cultured with responder T cells and proliferation was determined by 3H‐thymidine incorporation. In separate experiments, regulatory T cells were added to induced pluripotent stem cell‐derived pro‐inflammatory macrophages and changes in IL‐6/TNF‐a transcripts and protein levels were measured. Freshly isolated regulatory T cells were also expanded ex vivo in the presence of CD3/CD28 expander beads, interleukin‐2 (IL‐2) and rapamycin to promote their suppressive function. The immunophenotype of baseline and ex vivo expanded regulatory T cells from were also assessed

Result

The suppressive function of regulatory T cells on responder T cell proliferation was compromised at the Alzheimer disease stage, compared with mild cognitive impairment and healthy controls. Tregs did not suppress proinflammatory macrophages at baseline. However, following ex vivo expansion, Treg suppression of responder T cell proliferation and pro‐inflammatory macrophage activation increased in both patients and controls. Ex vivo expanded Tregs expressed higher levels of immunoregulatory markers including CD25, FoxP3, Granzyme B and PD1. In further evaluation of underlying mechanism, these cells exerted their suppressive function on pro‐inflammatory macrophages through a contact‐mediated mode of action.

Conclusion

Our data demonstrates that the ex vivo expansion of dysfunctional Tregs alters their immunophenotype and enhance their suppressive function at the Alzheimer disease stage. Restoration of regulatory T cell function could be explored as a means to modulate the inflammatory status of Alzheimer disease.
Hippocampal subfield deformation shows unique patterns associated with amyloid‐beta, TDP‐43, and PHF‐tau burden
Authors: Heywood Ashley , Schneider Julie A , Bennett David A , Arfanakis Konstantinos , Beg Faisal , Wang Lei
Published: December 2020

Background

Alzheimer's dementia (AD) is the most common form of dementia in adults over the age of 65, however, current diagnostic tools need to be improved. The relationships between clinical syndromes and pathological causes are complex, which makes accurate diagnosis difficult. The goals are to develop an in vivo hippocampal surface atlas from structural MRI that is predictive of postmortem β‐amyloid, paired helical filament (PHF‐tau) neurofibrillary tangles (NFTs) and transactive response DNA‐binding protein‐43 (TDP‐43) neuropathologies.

Method

Using a sample of 101 older adults from two longitudinal cohort studies conducted by the Rush Alzheimer’s Disease Center, we utilized hippocampal shape analysis of ante‐mortem T1‐weighted sMRI to generate surfaces for the whole hippocampus and zones approximating the underlying subfields using a previously developed automated image‐segmentation pipeline (Freesurfer‐Initiated Large Deformation Diffeomorphic Metric Mapping; FSLDDMM). Multivariate linear regression models were constructed to examine the relationship between shape and pathology measures while accounting for covariates which include co‐existing pathologies and other neuropathological variables (hippocampal sclerosis, Lewy bodies, gross infarcts, atherosclerosis, arteriosclerosis, and cerebral amyloid angiopathy). These relationships were mapped onto hippocampal surface locations. In a previous sample of 42 subjects from the same cohort, univariate models were not able to be examined due to low power.

Result

A significant and unique pattern of deformation for each neuropathology when accounting for covariates were seen. Specifically, β‐amyloid was associated with a significant inward deformation in zones approximating the subiculum, where PHF‐tau NFTs were associated with a significant inward deformation along the left hippocampal tail within the subiculum. TDP‐43 inclusions were associated with a significant inward deformation in the body of the hippocampus along the CA1/subiculum border. Results were corrected for multiple comparisons using the random field theory (RFT) with a family‐wise error rate (FWER) < 0.05.

Conclusion

These results indicate a unique pattern of deformation due to individual neuropathology, after accounting for covariates. With the presented increased sample size, a significant TDP‐43 signature arose. Results indicate that hippocampal deformation may be used to represent a biomarker of individual post mortem disease which could allow for the early and accurate diagnosis of disease and aid in the selection for clinical trials.
Dementia in care homes: Using an intergenerational programme to support engagement, community inclusion and positive care environments
Authors: Chandler Rebecca , Gillin Nicola
Published: December 2020

Background

Therapeutic interventions and activities are often used in care homes (CH) to improve the quality of life for residents with dementia. Intergenerational programmes (IPGs) are one form of intervention which may offer benefits to the CH environment and its residents by engaging people with dementia in new relationships and activities with younger people. This study explored the use of an IGP called Up which brings together school children and CH residents for weekly visits.

Aims

To explore the perceived benefits of intergenerational interactions for older adults with dementia living in a CH, and the CH workforce and environment. To explore perceived benefits to school children, and community inclusion and understandings of dementia.

Method

16 semi‐structured interviews and 2 focus groups (relatives of CH residents, CH staff, school teachers, & school children) were analysed using Thematic Analysis. Emergent themes most relating to older adults with dementia are presented.

Results

Meta‐theme 1, Opportunities to Shine, explores how the intergenerational interactions provided unique and new opportunities for residents to demonstrate their individual personalities and skills, irrelevant of their disabilities or illness. Seeing residents in this way transformed how they were seen by CH staff, relatives and others, allowing them to be re‐humanised and recognised beyond their sometimes dependent states. Meta‐theme 2, Evolving Environments, refers to how intergenerational interactions were perceived to bring new life into the CH environment, uplifting residents and challenging monotony and the care home stereotypes of silence. The positive atmosphere created spilled over into the work environment and staffs approach to their work and the residents. Within the evolving environment and changing perspectives, residents with dementia could be seen as ‘normal’ and integrated members of the wider community, a community now felt more understanding of dementia through the presence of younger generations within the CH.

Conclusion

These findings provide insight into how IGPs can be used to positively impact the lives of people with dementia living in CH. They too suggest that IGPs can provide the opportunity for environments, both within and outside the CH communally, which are more conducive to caring and understanding approaches to people with dementia.
The flexibility and reversibility of cognitive frailty
Authors: Lin Yicheng
Published: December 2020

Background

Declining physical and cognitive functioning play critical roles in ageing. Cognitive frailty is a concurrent physical and cognitive decline condition. We defined cognitive frailty as dynapenia concomitant with impairment in any cognitive domain, but without dementia. This definition not only includes a larger population at earlier stages of both physical and cognitive impairments but also highlights the potential reversibility of cognitive frailty. In this study, we tried to validate the flexibility and reversibility of cognitive frailty.

Method

The I‐Lan Longitudinal Aging Study (ILAS) is a population‐based cohort study. There were 551 community‐dwelling people aged beyond fifty years old had received second wave evaluation. The mean follow‐up duration was 2.5 years (2.50 ± 0.38 years). We divided all participants to four groups based on the physical and cognitive evaluations: normal, physical frailty only, cognitive impairment only and cognitive frailty in the first visit and follow‐up after 2.5 years. We aim to investigate the transformation of 4 different groups at two different evaluation time.

Result

More than half (62.7%) of cognitive frailty subjects remained in cognitive frailty condition at the 2nd wave evaluation. The incidences for baseline cognitive frailty group transforming to normal, physical frailty only, and cognitive impairment only were 6.5%, 19.6%, and 11.1%, respectively. The cognitive impairment only group had higher rate of transforming to cognitive frailty than the frailty only group (37.5 % vs. 27.0%). There were 26.2% physical frailty only subjects returned to no frailty state and 29.9% cognitive impairment only subjects returned to no cognitive impairment condition. The incidences of normal group transforming to physical frailty only, cognitive impairment only and cognitive frailty group were 32.7%, 14.5% and 15.7%, respectively.

Conclusion

The clinical transformation of cognitive frailty points out the reversibility of the disease, which indicate that controlling the risk of frailty and physical, cognitive training, and exercise may be therapeutic for cognitive frailty.
Risk factors for dementia progression among community‐dwelling older adults in a longitudinal national survey
Authors: Allen Samuel C. , Pajewski Nicholas M. , Yang Mia
Published: December 2020

Background

The sociodemographic factors that influence the progression to dementia are poorly understood.

Method

To examine dementia progression, we used Rounds 1‐4 (2011‐2014) of the NHATS weighted sample survey of in‐person interviews with adults age 65 and over (N=12,409). We used the NHATS definitions for dementia, possible dementia (MCI), and probable dementia which utilized AD8 Dementia Screening Interviews, self‐reports, and additional cognitive tests to assess dementia categorization for each round. Progression to dementia was defined as either transition from no dementia to possible dementia or possible dementia to probable dementia on consecutive rounds without regression in the opposite direction. We used a cox proportional hazard regression (SAS v. 9.4) to assess how each sociodemographic factor impacts dementia progression.

Result

The average age at the beginning of the study was 77.8 years old, 59% were female, and the largest racial group was White (41.8%). Advancing age (p<0.0001; HR = 1.049) and Hispanic race (p<0.0001; HR = 2.105) increase the chances of dementia progression. Moreover, a participant having one or no people in their social network (a proxy for social isolation) also increases the likelihood of dementia progression (p=0.0378; HR=1.346) as does refusing to answer how many people are in the participant’s social network (p=0.0007; HR=2.686). Using a cane or walker in the past month (a measure of mobility impairment) is also associated with increased dementia progression (p=0.0016; HR=1.525). The protective effect of exercise was not statistically significant (p=0.3523; HR=0.863). Other factors which do not predict dementia progression to a statistically significant degree include: gender, educational status, living alone, depression, hearing/vision impairment, and multimorbidity (≥3 comorbidities).

Conclusion

Advanced age, Hispanic race, social isolation, and using a cane or walker in the past month are all associated with an increased risk of dementia progression. The modifiable risk factors—mobility and social isolation—may be of particular clinical significance for at‐risk populations such as elderly patients with MCI. Further research is needed to determine whether altering these risk factors leads to a decrease in dementia progression.
Twinning program: The Netherlands‐Indonesia
Authors: Utomo Amalia Fonk
Published: December 2020

Background

Alzheimer Indonesia & Alzheimer Netherlands have a strong collaboration under the Twinning Program of Alzheimer's Disease International. This is a 3 years collaboration for 2017‐2019. To exchange information, support & learn from each other and for Alzheimer Indonesia to benefit from the experience from Alzheimer Netherlands to improve quality life of people with dementia & caregivers.

Method

6 work areas: Knowledge transfer from science & practice; Building network of volunteers for Indonesia Netherlands (ALZI – NL); Development of support activities of the Alzheimer's Organization in Indonesia; Organizing a public event in Indonesia; Train the trainer program (Dementia Care Skills training) in Indonesia; Project coordination

Result

• Knowledge transfer & support: ADI Asia Pacific Conference on 2‐5 November 2017, the 1st integrated multidisciplinary gathering on Dementia in Jakarta, Indonesia with 7 expert speakers from the Netherlands. Attended by over 700 participants from 20 countries (healthcare workers, ALZI Chapter leaders, youth community leaders, general public, government officials & volunteers). • Capacity building for Alzheimer Indonesia by extending it's network to 22 chapters/cities, conducted 173 caregivers meetings and 12 intergenerational home visits across Indonesia. • 3 Dementia Care Skills training conducted with participation from 26 caregivers. • Hosted Hope Love Care on Dementia, medical symposium and public event on 19‐21 October 2018 in Malang, East Java. Over 700 participants (healthcare workers, ALZI Chapter leaders, youth community leaders, general public, government officials and volunteers) with 6 international speakers & 8 national speakers. • Chapter Meeting on 22‐24 November in Denpasar Bali Attended by all chapter manager across Indonesia and overseas (through zoom) to have workshop & sharing session. Conducted Alzheimer’s Indonesia Annual Chapters Meeting as part of internal organization strengthening and capacity building. • Support activities for Indonesians in the Netherlands through Stichting Alzheimer Indonesia Nederland. • Knowledge transfer by book adaptation ‘Dementie? en nu?’ ‐ Alzheimer Nederland to Indonesian language and culture ‘Demensia? Lalu Bagaimana’.

Conclusion

Extension for the project is needed. The first 3 years build a good foundation& at least another 3 years to reach sustainable organization. Other countries with related culture and historical should consider of doing this.
Classification accuracy of the English version of the Canadian Indigenous Cognitive Assessment (CICA) in a majority culture memory clinic sample
Authors: O'Connell Megan E. , Walker Jennifer D. , Jacklin Kristen , Bourassa Carrie Ann , Kirk Andrew , Hogan David B. , Morgan Debra G.
Published: December 2020

Background

Most cognitive screening tools are culturally inappropriate for Indigenous peoples. The Kimberly Indigenous Cognitive Assessment (KICA) screening tool was collaboratively developed in Australia with, and for, Indigenous peoples. Using a similar community‐based method, the KICA was adapted to Canadian Indigenous peoples’ culture and translated into other languages, beginning in Ontario on Manitoulin Island, and was re‐named the Canadian Indigenous Cognitive Assessment (CICA). The classification accuracy of the CICA‐Ontario version, English translation, was explored in the current project in a memory clinic setting where the majority of patients were of Eurocentric origin.

Method

Of 79 consecutive cases presenting to an interdisciplinary diagnostic memory clinic, 58 completed the CICA. Inclusion criteria included consent for participation in research and planned administration of the typical 2 hour long neuropsychological battery. CICA data were not used for any clinical process; consequently, diagnosis was independent. Diagnosis was made by consensus of the neurologist and neuropsychologist after patient and collateral informant interviews and nursing, neurological, medical (comprehensive blood work, neuroimaging), neuropsychological, and physical therapy evaluations.

Result

Patients’ ages ranged between 38 and 90 (M= 65.3, SD= 12.3) and 52 percent were male. Diagnoses included no objective cognitive impairment despite cognitive concerns termed subjective cognitive impairment (SCI; n= 23; CICA
M
= 37.09; CICA
SD
= 1.08), mild cognitive impairment (MCI; n= 14; CICA
M
= 34.93; CICA
SD
= 2.46), dementia due to Alzheimer disease (AD; n= 9; CICA
M
= 31.44; CICA
SD
= 3.00), and non‐AD dementias (n= 12; CICA
M
= 32.75; CICA
SD
= 5.07). Classification accuracy as measured by the area under the receiver operating characteristic (ROC) curve (AUC) for groups with diagnoses of dementia (n= 21) vs no dementia (SCI or MCI; n= 37) was .78 (AUC confidence interval (CI) .66‐.92). Accuracy was high for cognitive impairment (dementia and MCI; n= 35) versus SCI (n= 23) (AUC=.84 CI .74‐.94) and lower for MCI (n= 14) vs dementia (n= 14)(AUC=.67; CI .49‐.85).

Conclusion

Although additional validity data from Indigenous peoples is needed, these data support the measurement properties of the CICA‐Ontario English‐version in a majority culture sample.
Improvement of cognitive function after paper‐based cognitive training intervention in early‐stage Alzheimer's disease
Authors: Han Jeong Ho , Kang Min Ju
Published: December 2020

Background

Cognitive training refers to cognitive exercises with inherent challenges that target enhance performance in specific cognitive domain. There has been number of studies reported positive outcome of cognitive training in persons with Alzheimer's disease. In this study, we newly designed set of paper‐based cognitive training program, "Gipum‐seo" which consists of different levels of difficulty using predesigned exercises and evaluated its efficacy of cognitive enhancement on patients with early stage of Alzheimer's disease.

Method

Forty participants who are diagnosed with early stage of Alzheimer’s dementia participated in this study. To test the efficacy of paper‐based cognitive training programs to cognition, all patients were randomly allocated to either an intervention group (n=20) or a control group (n=20). The intervention group regularly received 24 sessions of paper‐based cognitive training, over a 12 week period. Neuropsychological examinations were conducted before and after this training period.

Result

After 12 weeks, the intervention group showed a significant change in Korean version of the Mini‐Mental State Examination (25.90±3.8), compared to the control group (23.7±2.8) (p=0.04). Also, there was significant improvement in language, attention and executive function for the training group, as compared with controls.

Conclusion

Paper‐based cognitive training might have beneficial effects on the general cognitive functions in early stage of Alzheimer’s dementia.
The importance of care partner input in Alzheimer’s disease (AD) drug development
Authors: Majid Tabassum , Paulsen Russ , Callahan Leigh F. , Potashman Michele , Lee Daniel , Hartry Ann , Wunderlich Glen , Hoffman Deborah , Wieberg Dan , Kremer Ian N. , DiBenedetti Dana B.
Published: December 2020

Background

In AD, the role of the care partner (CP) is essential to therapeutic development due to their gradually increasing role over the course of disease progression. Many current trials require CPs to report on patient symptoms later in the disease. Studies have also suggested that the role of the care partner‐patient dyad may be linked to reliable outcomes in drug development. However, there are issues in data collection via patient proxy due to concerns around reliability of information and reporting bias.

Methods

The AD PACE WMM Study assessed needs and priorities of patients and CPs throughout AD through both qualitative and quantitative methods. In both phases of the WMM study, patients in the earlier stages of disease served as their own reporters: those with clinical pathology of AD (Group 1), with MCI (Group 2), and with mild AD (Group 3) served as their own reporters. CPs for those with moderate (Group 4) or severe AD (Group 5) reported what was important to them as CPs. Qualitative results were used to develop patient and CP surveys in which respondents rated the importance of 42 items.

Results

CPs (n=119) were mostly women in their mid‐50s with high SES statuses. The average age of the corresponding care recipients was approximately 80 years and most were women. In general, CPs rated items related to the emotional well‐being of the care recipient (e.g., having a sense of self‐worth; not feeling down, depressed, anxious, anxious, worried, stressed; not feeling like a burden to others) highly. When taken as a whole, mean CP ratings for what is important to them were equal to or lower than mean patient ratings, especially for items with lowest importance ratings (driving, not having difficulty with work, planning and organizing activities).

Conclusion

Understanding and identifying the multiple ways in which CPs can provide critical input in AD therapeutic development needs further investigation. The WMM study identified emotional well‐being as a key priority for CPs for those with moderate or severe AD. Future studies and guidance should examine opportunities for CP input on drug development as CPs provide critical perspectives on the AD patient experience.
Evaluation of what matters most in existing clinical outcomes assessments in Alzheimer's disease
Authors: Hartry Ann , Menne Heather , Wronski Samantha L. , Paulsen Russ , Callahan Leigh F. , Potashman Michele , Lee Daniel , Wunderlich Glen , Hoffman Deborah , Wieberg Dan , Kremer Ian N. , Hauber Brett , DiBenedetti Dana B.
Published: December 2020

Background

The Alzheimer's Disease Patient and Caregiver Engagement (AD PACE) Initiative works to identify and measure treatment‐related needs, preferences, and priorities of individuals with or at risk for Alzheimer’s disease (AD) and care partners across the continuum of AD. First, the What Matters Most (WMM) study assessed needs, preferences and priorities of individuals in these populations. The next work will compare the WMM results to concepts in existing clinical outcome assessments (COAs) used in AD trials. This study identifies the most commonly used measures in AD research throughout the disease continuum.

Method

Targeted literature and ClinicalTrials.gov searches identified COAs used in AD populations. Studies included pharmacological intervention or registry studies with individuals with preclinical or prodromal AD, mild cognitive impairment (MCI), mild, moderate, or severe AD, or caregivers of these individuals, and at least one type of COA.

Results

Over 900 records were retrieved. Records from the literature and Clinicaltrials.gov searches were combined and coded, yielding a total of 109 records for final review. Performance measures were the most common type of COA identified. COAs were most frequently used in MCI, and mild and moderate AD populations; COAs were used less often among prodromal/preclinical and severe AD populations. The six most frequently reported COAs identified were ADAS‐Cog, Mini‐Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Alzheimer's Disease Cooperative Study ‐ Activities of Daily living Inventory (ADCS‐ADL), Clinical Dementia Rating Scale (CDR), and Alzheimer's Disease Cooperative Study ‐ Clinical Global Impression of Change (ADCS‐CGIC).

Conclusion

Performance measures (e.g., MMSE & CDR) were the most common type of COA identified, followed by clinician‐reported and observational measures. Only three COAs were used in all 5 AD populations: MMSE, ADCS‐ADL, NPI. Very few patient‐reported measures were identified; the most frequently being the EQ5D ( used in 4/5 AD populations). The most commonly used clinician‐reported measures included the NPI, ADCS‐CGIC, and Columbia Suicide Severity Rating Scale (C‐SSRS). The next phase of this work will assess the extent to which these existing measures capture the concepts that are most important to individuals with or at risk for AD and their care partners as identified in the WMM study.
Adaptation of the Canadian indigenous cognitive assessment in three provinces and evidence for validity
Authors: Walker Jennifer D , O'Connell Megan E , Crowshoe Lynden , Jacklin Kristen , Boehme Gail , Hogan David B , Pitawanakwat Karen , Blind Melissa J , Warry Wayne , Akan Nicole , Patterson Christopher , Allaby Cheryl
Published: December 2020

Background

The Canadian Indigenous Cognitive Assessment (CICA) tool is an innovative culturally‐grounded dementia case finding tool. Currently, dementia is underdiagnosed and when diagnosis occurs it is at later stages in Indigenous populations in Canada when compared to the general population; a trend documented in Indigenous populations beyond Canada, including Australia and New Zealand. As communities and health systems prepare for rapidly aging Indigenous populations with high rates of multiple chronic conditions, the need for an accurate, reliable dementia case‐finding tool in Canada is critically needed to inform necessary supports and services.

Method

An interdisciplinary, international team composed of researchers and Indigenous community partners led the development of the CICA. The CICA is a community‐based adaptation of the Kimberley Indigenous Cognitive Assessment (KICA) tool, which is a validated dementia screening assessment that was originally developed with Indigenous populations in Western Australia. To adapt the KICA for Canadian contexts, we undertook iterative and community‐specific processes of translation, adaptation, and piloting before we conducted reliability and validity testing in three different sites: Manitoulin Island, Ontario, which is home to seven First Nations communities; an urban Indigenous population in Calgary, Alberta; and File Hills Qu’Appelle Tribal Council, Saskatchewan, which serves 11 First Nations communities. The adaptation process was community‐driven in each site and integrated both Indigenous community knowledge and trauma‐informed approaches to cognitive assessment. The intersections of culture, geography and colonial trauma were explored across these diverse Indigenous communities.

Result

The resulting CICA adaptations were scored out of a possible 39 points and took approximately 15 minutes to administer. The CICA assessed 11 domains of cognition including orientation, recognition and naming, registration, verbal comprehension, verbal fluency, recall, visual naming frontal/executive functioning, free recall, cued recall, and praxis using culturally safe methods in English, Anishinaabemowin, and Nakota. For successful adaptation from the KICA, the orientation, verbal comprehension, verbal fluency, praxis, and naming domains required the most adaptation. Preliminary results indicate that the CICA demonstrated strong inter‐rater reliability, test‐retest reliability, and criterion validity.

Conclusion

The CICA is the first tool of its kind in Canada and offers promising applications in the detection of dementia among Indigenous populations.
Selective knocking out of FynT‐isoform‐attenuated tau pathology, synaptic degeneration and neuroinflammation in P301S mutant human tau transgenic mouse model
Authors: Low Clara Ying Bei , Lee Chingli , Lim Frances Ting Wei , Lee Adrian Kian Long , Lo Juliette Min Huey , Lin Valerie Chun Ling , Tan Michelle Guet Khim
Published: December 2020

Background

Accumulating data demonstrate that Fyn tyrosine kinase is involved in oligomeric amyloid‐β toxicity and tau pathology in Alzheimer's disease (AD). We reported that selective up‐regulation of FynT isoform in post‐mortem AD brains was associated with tau pathology and neuroinflammation (Lee et al., 2016). Furthermore, our preliminary data demonstrated that FynT induction could be recapitulated in aged P301S mutant human tau transgenic mice, which also correlated significantly with tau pathology and neuroinflammation. We thus hypothesize that FynT could be the pathogenic isoform of Fyn in AD. In this study, we generate double transgenic model by knocking out FynT in P301S mice and monitor the possible protective effects on disease progression.

Method

FynT‐knockout (KO) is a transgenic model with specific knockdown of FynT isoform but retains FynB expression. Double transgenic mice (DTg) have been generated by crossing KO with P301S mutant human tau transgenic mice. HTRF technology‐based Cisbio assay kits, real‐time RT‐PCR and immunoblots are used to monitor changes of tau pathology, neuroinflammation and synaptic markers in the brains, respectively.

Result

Subsequent studies were conducted and analyzed in males because we noticed that P301S males significantly manifested more severe tau pathology and neuroinflammation than P301S females. Significant decrease of phosphorylated tau, aggregated tau and GFAP expression were detected in DTg when compared with P301S. Consistently, reduction of synaptic markers in P301S mice can also be rescued by depletion of FynT in DTg.

Conclusion

Selective knocking out of FynT isoform led to the attenuation of tau pathology, neuroinflammation and synaptic degeneration in mice with P301S background. This suggests that FynT could be the pathogenic isoform of Fyn in AD. This study further ascertains the isoform‐specific role of FynT as a therapeutic target for AD.
Stage‐dependent amyloid beta‐ and tau‐associated longitudinal white matter degeneration in early stages of Alzheimer’s disease
Authors: Vipin Ashwati , Ng Kwun Kei , Ji Fang , Shim Hee Youn , Lim Joseph K.W. , Pasternak Ofer , Zhou Juan Helen ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Alzheimer’s disease(AD) is associated with pathological deposition of amyloid‐beta(Aβ) plaques and neurofibrillary tau tangles which have been shown to be related to poorer white‐matter(WM) integrity using diffusion‐MRI(dMRI) [Vipin et al.,2019;Jacobs et al.,2018]. However, possible interactive effects between Aβ and tau on microstructural WM changes remain unclear. Additionally, partial volume artefacts impact dMRI sensitivity but can be corrected through free‐water(FW) correction to provide FW and FW‐corrected tissue measures(FAt)[Pasternak et al.,2009]. Thus, we examined additive and interactive effects of Aβ and tau burden on temporal progression of FW‐corrected WM changes in temporoparietal WM fibres at baseline and over‐time in cognitively normal elderly(CN) and mild cognitive impairment(MCI). We hypothesize that MCI subjects would show more widespread Aβ and tau‐related temporoparietal WM alterations than CN. Additionally, based on prior evidence, Aβ and tau interactive effects would be more prevalent for FW than tissue‐based measures.

Method

We used dMRI data from 72 CN and 82 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative followed over 2‐4 time‐points(55‐90 years). Aβ burden was quantified using AV‐45 PET standardized uptake value and tau burden was quantified using cerebrospinal fluid phosphorylated‐tau(Ptau) levels. We derived subject‐specific FW and FAt fibre maps using the longitudinal TRActs‐Constrained‐by‐UnderLying‐Anatomy method[Yendiki et al.,2016].

Result

CN with higher Aβ burden showed faster decline in RUNC FAt (uncorrected‐p=0.0055; Fig.1). However, in MCI, widespread Ptau effects were found(Fig.2) i.e. higher baseline Ptau burden was associated with lower fibre FAt in left superior longitudinal fasciculus parietal (SLFP; uncorrected‐p=0.039) and left(uncorrected‐p=0.0062) and right(uncorrected‐p=0.026) superior longitudinal fasciculus temporal(SLFT). Synergistic Aβ*Ptau effects were instead observed in right cingulum angular bundle(CAB) FW in CN at baseline and over‐time (FDR‐corrected:p<0.05; Fig.3). This effect was more widespread in MCI‐ higher Aβ combined with higher Ptau associated with higher FW in right CAB, SLFP, SLFT and uncinate fasciculus fibres at baseline(Fig.4).

Conclusion

Our findings provide insights into stage‐dependent differences in additive and synergistic influences of Aβ and Ptau between tissue‐based and FW‐based WM metrics. Thus, together with Aβ and Ptau burden, FW‐corrected WM measures likely provide more detailed insight regarding the regions showing alterations related to the interaction between neuropathological hallmarks of AD to collectively inform regarding disease progression.
Optimization of early‐phase florbetapir as a surrogate of FDG‐PET in ageing and Alzheimer’s clinical syndrome
Authors: Vanhoutte Matthieu , Landeau Brigitte , Sherif Siya , la Sayette Vincent De , Dautricourt Sophie , Abbas Ahmed , Manrique Alain , Chocat Anne , Chetelat Gael ,   the Medit‐Ageing research group
Published: December 2020

Background

FDG‐PET is a validated and widely used sensitive biomarker for neurodegeneration (N) in ageing and Alzheimer’s clinical syndrome as highlighted in the β‐amyloid (A)/tau (T)/N scheme (Jack et al., 2016, 2018). Early‐phase Florbetapir (eAV‐45) appears as a promising proxy for FDG‐PET but needs further validation. Optimization of the time window and preprocessing methods of eAV‐45 are scarce, and no previous study assessed the sensitivity and the reproducibility of this measure in individual cases.

Method

We included 191 participants including young to elderly volunteers and Alzheimer’s clinical syndrome patients, all of whom had both FDG‐PET and dual‐phase Florbetapir acquired on the same scanner, along with structural MRI and neuropsychological examinations. The time window was first optimized at the vertex level by correlation maximization between eAV‐45 and FDG‐PET, and correlation minimization between eAV‐45 and late AV‐45 (lAV‐45). Then, the six reference regions used for PET intensity scaling were compared by computing metrics of: (i) vertex‐wise pattern overlap between eAV‐45 and FDG‐PET (derived from patients versus controls comparisons and correlation with cognitive scores), and (ii) machine learning classification performance reflecting the discriminative power of both eAV‐45 and FDG‐PET at the individual level.

Result

The time interval from 0 to 4 minutes gave optimal vertex‐wise within‐ and inter‐subject correlations of both eAV‐45 versus FDG‐PET (maximal) and eAV‐45 versus lAV‐45 (minimal) (Figure 1). Balanced accuracy of pattern overlap was globally maximal with pons scaling (Figure 2), whereas classification performance between patients’ subgroups and controls were similar across scaling regions for both eAV‐45 and FDG‐PET (Figure 3A). Finally, classification performance was significantly superior for combined early plus late AV‐45 compared to FDG‐PET alone (Figure 3B).

Conclusion

Results show that eAV‐45 from 0 to 4 minutes with pons scaling is an optimal surrogate of FDG‐PET in ageing and Alzheimer’s clinical syndrome. This study highlights the strong potential of optimized dual‐phase AV‐45, allowing to outperform FDG‐PET discriminative power when combining both early plus late AV‐45 information obtained from a single PET‐tracer injection. Interestingly, the use of dual‐phase AV‐45 instead of FDG‐PET plus lAV‐45 will reduce the radiation dose, total time, number of visits and costs.
Validation of an automatic tool for the measurement of brain atrophy and white matter hyperintensity in clinical routine: QyScore®
Authors: Cavedo Enrica , Tran Philippe , Thoprakarn Urielle , Martini Jean‐Baptiste , Movschin Antoine , Delmaire Christine , Gariel Florent , Heidelberg Damien , Pyatigorskaya Nadya , Ströer Sébastian , dos Santos Clarisse Longo , Dormont Didier ,   the Alzheimer’s Disease Neuroimaging Initiative,   the Frontotemporal Lobar Degeneration Neuroimaging Initiative
Published: December 2020

Background

Brain automatic segmentation methods have shown reliable results in measuring brain structure volumes and white matter lesions. Several studies showed that automated segmentation provides greater benefits than risks for patients affected by neurological diseases. However, few automated segmentation software are currently approved by regulatory agencies such as the US Food and Drug Administration (FDA). Here we present the methods and performance of QyScore®, an automated imaging analysis tool certified in Europe (CE marked) and US (FDA cleared) for the automatic volumetry of Grey and White Matter (GM and WM respectively) Hippocampus (HP), Amygdala (AM) and White Matter Hyperintensity (WMH).

Method

A comprehensive database (N = 210) coming from several cohorts of patients with neurodegenerative diseases was established. The reliability measures considered for the validation of QyScore® imaging markers were: Dice Similarity Coefficient (DSC) and the Relative Volume Difference (RVD) for the HP, the AM, the GM and the WM volumes, DSC and the F1 metrics for the WMH. For each reliability index we identified thresholds and we hypothesized that DSC/F1 scores obtained using QyScore® markers were superior to the threshold, while RVD scores were inferior to the threshold. In addition, QyScore® performances were compared with the ones obtained from gold standard methods (manual segmentation) through regression analysis and Bland‐Altman plots.

Result

Comparison with reliability measures are described in Table 1. QyScore® compared with manual segmentation methods provides reliable performances for the segmentation of the grey and white matter volumes, hippocampal and amygdala volumes, as well as white matter hyperintensity volume as described in Figure 1.

Conclusion

QyScore® represents a reliable and user‐friendly tool, supporting the diagnosis made by clinicians for the early detection of neurological diseases such as MCI and AD dementia.