bluuebunny/crossref_metadata_2025 huggingface dataset:
Ten‐minute cognitive screening tool for mild cognitive impairment and prediction of pathological ß‐amyloid
Authors: Butler P. Monroe , Osik Jason , Schwartz Joel , Irzhevsky Victoria , Hansson Oskar , Brown Roland , Gao Feng , Moss Mark
Published: December 2021

Background

Early detection of cognitive decline is critical to improve outcomes for Alzheimer’s disease (AD) and other dementias. Screening for dementia risk during prodromal stages such as mild cognitive impairment (MCI) typically occurs through brief, bedside cognitive measures. While these tests readily detect dementia, the relative sensitivity/specificity for identifying MCI is variable and the ability to predict underlying AD is poor. Herein, we compare traditional cognitive screening tools with a novel ten‐minute battery to test predictive performance to discriminate MCI from normal cognition, and MCI with vs. without ß‐amyloid burden. The ten‐minute battery consisted of the Digit‐Symbol Substitution Test, Trail Making Tests A and B, and a delayed recall task.

Method

Clinical data were assessed from healthy aging and MCI patients from: (i) the AD Neuroimaging Initiative Study (ADNI), (ii) the Swedish Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably Study (BioFINDER), and (iii) the screening phase of aducanumab’s Phase 2 EVOLVE study (NCT03639987) before the trial was prematurely terminated. Datasets were used to build and validate the performance of a statistical model derived from outcome measurements extracted from the ten‐minute battery to predict imaging or fluid biomarker‐based readouts of pathological ß‐amyloid load. Feature selection and model performance evaluations were achieved in two independent ways: stepwise model building and coefficient penalization. Neuropsychological variables were z‐scored against normative data. Additional predictors included age and APOE genotype. Model performance were compared with a standardized screening tool (MMSE) to assess relative ability to differentiate MCI from normal cognition, and MCI with vs. without ß‐amyloid burden based on imaging/fluid biomarkers.

Result

The findings showed greater sensitivity and specificity achieved with the ten‐minute battery relative to the standard cognitive screening tools for MCI detection (AUC‐ROC 0.98 vs. 0.78) and Aß prediction (AUC‐ROC 0.81 vs. 0.58), respectively. Of striking interest, removing APOE as a predictor markedly reduced accuracy in the traditional, but not in the novel ten‐minute battery.

Conclusion

These preliminary data suggest that the novel combination of neuropsychological tests performed in ten‐minutes may serve as a compact, more sensitive and specific screening tool to identify patients with MCI with Aß burden compared to traditional screening batteries.
Cognition differentiates gait speed among older adults
Authors: Paulson Sally , Gray Michelle , Glenn Jordan M. , Madero Erica N. , Myers Jennifer , Gills Joshua L. , Jones Megan , Campitelli Anthony , Vincenzo Jennifer , Walter Christopher
Published: December 2021

Background

The ability to perform a motor and cognitive dual‐task (DT) becomes more challenging as one ages and shows a greater deficit, if one has a cognitive impairment (CI). CI has also been shown to predict a decline in physical functioning. Therefore, the purpose was to examine differences between cognitively healthy (CN) and cognitively impaired (CI) older adults on gait speed (GS) during habitual (HAB) and fast (FAST) walking trials with and without a DT.

Method

83 older adults (80.66±5.36) completed a digital Visual Paired Comparison (VPC) cognitive assessment, which measured working memory, and a Digital Symbol (DS) cognitive assessment, which measured processing speed. Participants were grouped into CN or CI based on their results for each assessment. Subjects performed two trials of each walking test: HAB, FAST, HAB‐DT, and FAST‐DT. The DT trials were performed using a working memory task. GS was calculated using the time to cover 10m. One‐way ANOVA was used to assess for differences in GS between VPC and DS cognitive groups.

Result

While HAB GS (p=.10) was not significantly different between the VPC cognitive groups, the CN group walked significantly faster than the CI group during the FAST, HAB DT, and FAST DT trials (p<.05). There was not a significant difference in HAB GS (p=.10) or HAB DT GS (p=.08) between the CI and CN DS groups. However, the DS CI group walked significantly slower during the FAST (p=.03) and FAST DT (p=.05) assessments.

Conclusion

Individuals with CI showed no statistical difference in habitual walking speed. However, this was clinically meaningful as the individuals with an average or above average working memory and processing speed walked faster than individuals with CI by 8.4% and 6.5%, respectively. While GS declined during the DT trials, individuals with a working memory impairment showed a greater decline, and it was even larger during the fast DT trials and for individuals with a working memory (19.5%) or processing speed (17.6%) impairment. Previous research has suggested DT walking involves activation of the prefrontal cortex, which may partially explain the greater decline in DT GS for those with working memory impairment.
Steeper basal cortisol slopes are associated with elevated risk of pathological amyloid‐beta accumulation
Authors: Saelzler Ursula G. , Moffat Scott D. , Panizzon Matthew S.
Published: December 2021

Background

The accumulation of amyloid‐beta (Aβ) plaques, the hallmark neuropathology of Alzheimer’s disease (AD), begins several decades prior to the onset of cognitive symptoms. The progression of the disease is believed to be driven by this accumulation; therefore, there is interest in identifying factors which trigger or accelerate the aggregation of Aβ. We examined whether changes or elevations in basal cortisol levels predicted the transition to a state of Aβ‐positivity, as determined by Pittsburgh Compound B (PIB) thresholds.

Method

Data were utilized from the neuroimaging subset of the Baltimore Longitudinal Study of Aging. One‐hundred and fifteen middle‐aged to older adults (mean age 58.39 at baseline) with at least two 24‐hour urinary free cortisol measures collected prior to reaching the threshold for Aβ‐positivity were included.

Result

A Cox regression model showed that after controlling for age, the slope of basal cortisol levels over time was significantly associated with the risk of becoming Aβ‐positive, such that each standard deviation unit increase in slope was associated with a 38% increase in Aβ‐positivity risk. Conversely, the average cortisol level during this same period was not significantly associated with Aβ‐positivity risk (HR = 1.03, p = 0.14).

Conclusion

These results suggest that increases in basal cortisol levels, regardless of the average level, are associated with increased likelihood of pathological Aβ accumulation. Further investigation is warranted to determine whether basal cortisol increases directly contribute to increased Aβ accumulation and whether this mechanism can be targeted by therapeutic intervention.
Racial‐ethnic differences in baseline and longitudinal change in neuropsychological test scores in the NACC Uniform Data Set 3.0
Authors: Chan Kwun Chuen Gary , Barnes Lisa L. , Saykin Andrew J. , Sano Mary , Au Rhoda , Craft Suzanne , Teylan Merilee A. , Levey Allan I , Weintraub Sandra , Kukull Walter A. , Dodge Hiroko H
Published: December 2021

Background

Racial/ethnic differences in cross‐sectional assessment of cognitive test performance are well known. However, longitudinal studies of differences in cognitive decline have been mixed. The purpose of this study was to examine racial/ethnic differences in baseline and longitudinal change on the Uniform Data Set (UDS) version 3 of the NIA Alzheimer’s Disease Research Centers program.

Method

Longitudinal data from 2,806 participants (2336 non‐Hispanic White, 350 non‐Hispanic Black, 120 Hispanics tested in Spanish) were acquired from the National Alzheimer’s Coordinating Center (NACC), and included baseline and at least two follow‐up visits. We used marginal linear regression models to examine racial/ethnic differences in standardized test scores, by including racial group indicators, time (in years) since initial visit and their interaction, controlling for baseline age, sex, education and changes in global CDR scores during the follow‐up. Additional models examining longitudinal change also controlled for baseline score. The outcome variables included the Montreal Cognitive Assessment (MoCA, Number Span (Forward/Backward), Craft Story 21 Recall (Immediate/Delayed), Multilingual Naming Test (MINT), Category Naming (animals and vegetables), Trail Making A and B, and Benson Figure (Copy/Recall). Estimates were obtained from generalized estimating equations with an exchangeable working correlation, and robust standard errors were used to construct confidence intervals and compute p‐values.

Result

Black and Hispanic participants had lower baseline scores on all tests (difference in standard deviation units: ‐0.029 to ‐0.858 for blacks, and ‐0.014 to ‐1.214 for Hispanics), but showed attenuated decline on all tests (difference in standard deviation units per year: 0.002 to 0.102 for blacks, 0.022 to 0.296 for Hispanics) compared to non‐Hispanic Whites. When baseline test scores were controlled, the differences in longitudinal changes became mostly statistically non‐significant.

Conclusion

Despite large racial/ethnic differences in baseline test scores, there were no racial/ethnic differences in longitudinal change over time once baseline differences were controlled. Further, results suggest that the utility of baseline test scores in UDS version 3 to predict longitudinal change may not be compromised in racially diverse populations.
A phase 1 study of AL002 in healthy volunteers
Authors: Ward Michael , Long Hua , Schwabe Tina , Rhinn Herve , Tassi Ilaria , Salazar Santiago Viveros , Rychkova Anna , Tu GuangHuan , Barner Cheryl , Yeh Felix L , Spencer Madeline , Paul Robert
Published: December 2021

Background

Triggering receptor expressed on myeloid cells ‐2 (TREM2) is a prominent Alzheimer’s disease (AD) risk gene that is expressed by microglia in the brain; reduced function of TREM2 is associated with a 3‐fold increase in AD risk. AL002 is a humanized monoclonal IgG1 antibody. The proposed mechanism of action is that it binds to TREM2 and activates the TREM2 signaling pathway to increase the ability of microglia to clear pathology and protect neurons with the goal of treating patients suffering from AD. INVOKE was a first‐in‐human Phase 1 study designed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenously administered AL002 in healthy volunteers (HV).

Method

INVOKE was a randomized, placebo‐controlled, double‐blind investigation of AL002 in healthy volunteers (HV). The SAD portion of the study, which included a total of 64 HV receiving a single dose of 0.003 to 60 mg/kg AL002 or matching placebo is complete. Blood and CSF biomarkers were measured before dosing and at multiple timepoints after dosing.

Result

In the SAD portion of the INVOKE study, AL002 was generally well tolerated in HV. AL002 decreased sTREM2 in cerebral spinal fluid (CSF), in a dose‐dependent manner, demonstrating proof of target engagement in the brain. Microglia biomarkers of TREM2 activation, such as CSF1R, SPP1 and IL1RN, were identified with in vitro and in vivo non‐clinical experiments. Consistent with these findings, treatment of HV with AL002 caused an increase in CSF levels of CSF1R, SPP1 and IL1RN in a dose‐dependent manner, suggesting proof of microglia activity through the TREM2 pathway.

Conclusion

AL002 treatment resulted in TREM2 target engagement and proof of activity in the CSF of HVs. These results have supported progressing AL002 to an ongoing Phase 2 study (INVOKE‐2) to investigate its effects on cognitive decline and neurodegeneration in subjects with early AD.
Smartphone ownership and usage in Chinese‐ and English‐speaking older adults
Authors: Li Clara , Zeng Xiaoyi , Wang Kun , Neugroschl Judith A. , Aloysi Amy , Cai Dongming , Martin Jane , Sewell Margaret , Greenberg Jonathan , Xu Mengfei , Evans Kirsten , Pun Kelly , Tocco Carly , Ardolino Allison , Meuser Caroline , Sheppard Faye , Gamino Juliana , Velasco Nelly , Sano Mary , Loizos Maria , Zhu Carolyn W
Published: December 2021

Background

Data collection by smartphone is becoming more widespread in healthcare research. Previous studies reported racial/ethnical differences in the use of digital health technology. However, cross‐language group comparison (Chinese‐ and English‐speaking older adults) were not performed in these studies. This project will expand to smartphone technology use in diverse older populations with a focus on Chinese American older adults who are monolingual Chinese‐speakers.

Method

The Alzheimer’s Disease Research Center (ADRC) at Icahn School of Medicine at Mount Sinai (ISMMS) evaluates diverse older populations using National Alzheimer’s Coordinating Center’s Uniform Data Set (NACC UDS). The UDS has different language versions, including English and Chinese. The evaluation includes a medical examination, cognitive assessments, and a research blood draw. Smartphone ownership and usage were captured using a local questionnaire developed by our ADRC. The questionnaire, available in English and Chinese, was administered by our ADRC coordinators during the COVID‐19 pandemic. Multivariate analysis of variance (MANOVA) was used to examine differences in technology ownership and usages between the two language groups, while controlling for age, gender, education, and cognitive status (measured by Clinical Dementia Rating).

Result

33 Chinese‐ and 117 English‐speaking older adults who received a diagnosis of normal cognition or mild cognitive impairment at consensus were included in the data analysis. Results reveal a high prevalence of smartphone ownership in our Chinese‐ (100%) and English‐speaking older participants (86.3%). Participants in both language groups use mobile technology for a wide range of purposes, such as getting news and other information (Chinese=90.9%; English=87.2%), sending/receiving text (Chinese=97.0%; English=96.6%), watching videos/TV shows (Chinese=78.8%; English=69.2%), and taking classes (Chinese=57.5%; English=57.3%). However, Chinese‐speaking older adults were less likely than English‐speaking older adults to use mobile technology to post their own reviews or comments online (Chinese=9.1%; English=39.3%, p=0.001), download or purchase an app (Chinese=21.2%; English=70.9%, p<0.001), track health/ fitness via apps/website (Chinese=12.1%; English=47.9%, p<0.001) and manage/receive medical care (Chinese=15.2%; English=67.5%, p<0.001).

Conclusion

Our findings highlight potential barriers to smartphone usage in Chinese American older adults with limited English proficiency. The results have implications for how smartphone technology can be used in clinical practice and aging research.
On the use of saliency maps and convolutional neural networks for improved Alzheimer's disease assessment
Authors: Lopes Marilia Karla Soares , Cassani Raymundo , Falk Tiago H
Published: December 2021

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease accounting for 60–80∖% of dementia cases worldwide[2]. Early diagnosis can decrease the severity of the disorder in addition to improving the quality of life of patients. Biomarkers based on electroencephalography (EEG) have emerged as a promising tool in the study of AD, with the advantage of being non‐invasive, less expensive, and potentially portable when compared to other biomarkers. One such biomarker has been the so‐called "modulation‐spectral‐patch‐feature" proposed in [1]. Such features were found based on visual inspection of modulation spectra from healthy‐controls and age‐matched AD patients. Over the last few years, however, innovations in machine learning, in particular in deep‐neural‐networks, have revolutionized many biomedical image and signal processing applications[4,5,6]. In this paper, we explore their use in building better biomarkers for AD assessment. In particular, we explore the use of saliency‐maps(SM)[3] obtained from classification using convolutional‐neural‐networks(CNN) to extract optimal feature patches in a data‐driven sense.

Method

The study collected data from fifty‐four participants, including 20‐healthy‐controls, 19‐Mild‐Cognitive‐Impairment, and 15‐moderate‐to‐severe‐AD, all age‐matched. Twenty‐channel EEG signals were acquired during eyes‐closed‐resting‐state sessions of eight minutes. The EEG recordings were pre‐processed to remove artifacts. The model performance was evaluated using 5‐fold‐cross‐validation(CV). The average SM was extracted from the validation‐set in order to highlight the relevant modulation "patches" in a data‐driven manner. The CNN model has two convolutional‐layers and three fully‐connected‐layers.

Result

The tested CNN resulted in the following figures‐of‐merit over the 5‐fold‐CV: 89.4%+/‐2.3% for accuracy and 89.3%+/‐2.3% for f1. From the average SM of each fold, it can be seen that theta‐modulated‐by‐delta and beta‐modulated‐by‐theta were important modulation regions . Others regions such as beta‐modulated‐by‐alpha, alpha‐modulated‐by‐delta, and gamma‐modulated‐by‐beta were also important. While some of these regions match those found visually in[1], other provide more insights into AD assessment.

Conclusion

In this paper, we show the efficacy of EEG modulation‐spectrograms coupled CNNs saliency‐maps to extract data specific features useful for Alzheimer's disease diagnosis. In particular, several main regions of interest were identified, thus building on previous work that relied on visual inspection. As future work, we will also explore the importance of each EEG channel, thus potentially leading to a more low‐cost and portable solution.
MRI and CSF markers of mild behavioural impairment: Findings from the MEMENTO cohort study
Authors: Chen Hung‐Yu , Robert Philippe , Nathan Santhosh , Smith Eric E. , Ismail Zahinoor
Published: December 2021

Background

Mild behavioural impairment (MBI) is characterized by late‐life emergent and persistent neuropsychiatric symptoms (NPS). It is as an at‐risk state for incident cognitive decline and dementia. For some, MBI may be the first observable manifestation of a neurodegenerative process such as Alzheimer’s disease (AD).

Methods

We examined associations between MBI and established dementia imaging and CSF markers, in 789 participants with mild cognitive impairment (MCI). Study data were obtained from the French MEMENTO cohort study.

Neuropsychiatric Inventory (NPI) scores were used to determine MBI scores using a published algorithm. NPI data at baseline and 6‐month visits were used to categorize patients into MBI+ (persistent NPS i.e., NPS at both time points) and MBI‐ (no NPS or NPS at either but not both time points). MRI and CSF measurements were completed at baseline. Linear regressions were fitted to assess if MBI status at 6 months was associated with reduced thickness or volume in each of the a priori selected regions associated with Braak stages 1‐5: entorhinal cortex, hippocampus, fusiform gyrus, inferior temporal cortex and frontal pole. To assess if MBI status was associated with CSF biomarkers (Aβ42, Aβ40, t‐tau, p‐tau, Aβ42/Aβ40, p‐tau/Aβ42 and t‐tau/Aβ42), seven linear regressions were conducted. All models controlled for age, sex, education, and mini‐mental state examination scores. Volume and thickness analysis further controlled for total intracranial volume.

Results

MBI+ (persistent NPS) status was associated with decreased entorhinal thickness and smaller hippocampal volume compared to MBI‐ (Table 1). There were no differences between MBI+ and MBI‐ groups in thickness of the Braak stage 3‐5 regions (Table 1). In the subset of MCI participants with CSF data (n=155), compared to MBI‐, MBI+ had lower CSF Aβ42 levels, higher CSF p‐tau/Aβ42 and t‐tau/Aβ42 ratios (Table 2).

Conclusion

In a memory clinic sample of older adults with MCI, MBI was associated with AD markers and served as a proxy marker to capture AD changes in a non‐demented sample. These findings extend the literature linking MBI with known dementia biomarkers and emphasize the importance of appropriately ascertained NPS, in this case with respect to symptom persistence, in dementia detection and prognostication.
Effects of novel Cognitive Stimulating Activities (CSAs) on cognition and depression: A 5‐year pragmatic and naturalistic study
Authors: Ng Ted Kheng Siang , Chua Rhu Yuan , Feng Lei , Goh Lee Gan , Kua Ee‐Heok , Mahendran Rathi
Published: December 2021

Background

Accumulating epidemiological evidence suggest that cognitive stimulating activities (CSAs) improve cognition in older adults. However, there is a lack of longitudinal naturalistic follow‐up studies supporting the effectiveness of CSAs, particularly in a real‐world setting. Whether baseline cognitive status affects cognitive outcomes, and whether a higher involvement in CSAs elicits greater improvements are unknown. We aimed to investigate a novel multimodal CSA intervention to prevent cognitive decline amongst community‐dwelling older adults.

Method

From the Singapore Longitudinal Diet and Healthy Aging (DaHA) study (n=991, aged ≥60), 264 subjects were assigned to the novel multimodal CSAs controlled trials (mindfulness intervention, horticultural therapy, arts and music reminiscence therapy, and choral singing). The other participants not involved in the CSAs (n=727) served as the control group. At the DaHA cohort’s 5‐year follow‐up, we examined the effects of CSAs on cognitive function. The primary outcomes were changes in global cognition measured by the mini‐mental state examination (MMSE) and its domain scores. Intention‐to‐treat analysis was performed utilizing a linear mixed model. We also conducted sub‐group analyses stratified by baseline cognitive status and the number of CSAs involved.

Result

Compared to the control group, although non‐significant, there was an improvement in the CSA group after five years based on the total MMSE score (β =0.108, 95% CI= ‐0.022 to 0.239, P =0.104). Notably, there was a significant improvement in MMSE‐immediate recall score domain (β = 0.199, 95% CI = 0.048 to 0.351, P = 0.010). Sub‐group analyses showed that older adults with MCI and those involved in more CSAs had greater improvements in total MMSE and selective domain scores after 5 years, with effect sizes of Cohen’s D=0.42.

Conclusion

Although global cognition was not significantly improved, the multimodal CSA intervention showed significant improvements in the scores of working memory domain, possibly, highlighting the high malleability of this cognitive domain. Furthermore, moderate effect sizes of improvements observed in the MCI sub‐group and those involved in more CSAs suggesting that these individuals could gain greater long‐term benefits participating in CSAs. From a public health perspective, these sustained improvements in cognitive functions over five years’ time could potentially delay or prevent dementia.
Risk factors of oral health related quality of life: An evidence from Australian Longitudinal Study of Ageing
Authors: Bindal Priyadarshni , Barnett Anthony , Hoang Ha , Mishra Vijay Kumar
Published: December 2021

Background

Oral disease and tooth loss have a significant negative impact on the quality of life and well‐being of older adults. As OHRQoL is a major feature of the daily experiences of older adults, alongside decreased general health and functioning, and shrinking social networks and activities, it is particularly important to examine whether a relationship between OHRQoL and amongst socioeconomic and psychological factors exists. Socioeconomic disparities in oral health have been consistently demonstrated for various indicators, mostly clinical and disease related but also subjective measures of oral health and quality of life. The key risk factors include poor general health, depression, anxiety, loneliness and low social participation and social support.

Method

We utilized secondary data from the seventh wave of Australian longitudinal study of Ageing (ALSA). ALSA was coordinated by the research teams of Flinders University, Australia. The data analysis included a sample of 257 (98‐male, 159‐female) participants from rural Australia. Chi‐square and Wilcoxon’s tests were applied on categorical variables to under the association between outcome and predictors. We created depression scale based on 20 indicators of depression among older people. The multinomial logistic regression model was used to study the strengths of relationships between oral health related quality of life (OHRQoL) and its possible risk factors.

Result

The study found a clear and significant association between OHRQoL and depression, loneliness, anxiety including socio‐economic factors such as age, sex, income and family structure. The older people who faced a little or no difficulty in performing the activities such as eating food, speaking clearly, smiling, laughing and showing teeth without embarrassment are more likely to live better life. Females are less likely to have good oral health related quality of life than men.

Conclusion

This findings of this study would lead future work and will be beneficial to understand healthy ageing through oral health related quality of life (OHRQoL) and its risk factors as well as providing policy and practice recommendations improve overall quality of life in old age, and achieve targets laid out in Sustainable Development Goals for Health (SDG‐3).
Association between patterns of multiple chronic conditions and cognitive impairment in community‐dwelling older adults in Taiwan
Authors: Hsieh Pei‐Iun , Chen Yen‐Ching , Chiou Jeng‐Min , Chen Ta‐Fu , Yeh Su‐Ling , Chen Jen‐Hau
Published: December 2021

Background

Previous studies mainly explored the effect of single chronic disease on cognition. However, limited focuses have been put on the co‐existence of diseases, symptoms, and functional impairments and how their combinations affect older adults. This study aimed to identify sex‐specific patterns of multiple chronic conditions (MCC) and to relate them with cognitive impairment in a six‐year cohort study.

Method

We included 516 non‐demented older adults at baseline (2011‐2013) from the ongoing Taiwan Initiative for Geriatric Epidemiological Research, with three biennially follow‐ups. The global and domain‐specific (memory, attention, executive function, and language) cognition were assessed using the Taiwanese version of Montreal Cognitive Assessment and a battery of neuropsychological tests. Exploratory factor analysis was utilized to identify patterns of 33 self‐reported chronic conditions. For each pattern, the factor score of each participant was calculated by summing up the product of the status of a specific condition and its corresponding factor loadings. The generalized linear mixed model was utilized to examine the association between MCC patterns and cognitive performance adjusted for age, years of education, apolipoprotein E ε4 status, cigarette smoking, alcohol consumption, and years of follow‐up.

Result

Three MCC patterns were identified for each sex, which included (1) Mental‐Exhaustion, (2) Cancer‐Thyroid, and (3) Frailty‐Cardiometabolic patterns in females; and (1) Mental‐Skeletal, (2) Cardiometabolic‐Renal, and (3) Thyroid‐Prostate patterns in males. Among females, higher factor scores of the Mental‐Exhaustion and Frailty‐Cardiometabolic patterns were significantly associated with poor performance of global cognition (β: ‐0.16), logical memory (β:‐0.11 to ‐0.07) and executive function (β:‐0.32). Among males, higher factor scores of the Mental‐Skeletal and Thyroid‐Prostate patterns were significantly associated with poor performance of memory (β:‐0.11) and attention (β:‐0.13). In contrast, a protective effect was observed between Cancer‐Thyroid pattern and memory (β:0.12 to 0.13) or attention (β:0.16), as well as between Cardiometabolic‐Renal pattern and verbal fluency (β:0.15).

Conclusion

MCC patterns identified in this Asian population were different from those observed in western countries, and these patterns were associated with poor global or domain‐specific cognition. Further research was required to validate our findings and to clarify the underlying mechanism between MCC and cognitive impairment.
Hal, do I have memory problems? A pilot study investigating a voice recognition cognitive screening tool for detection of neuropsychological changes
Authors: Rosen Jay , Alasantro Lori Haase , Wagner Gabrielle , Sahagian Gregory , Vignisson Vidar
Published: December 2021

Background

The prevalence of mild, age‐advanced changes in cognition, defined as mild cognitive impairment, is spiking as the baby boomer population ages. Early and accurate detection of age‐advanced changes in thinking abilities leads to proper care, efficient use of resources, and promotion of research. Indeed, government based health care systems and insurance programs incentivize routine neurocognitive assessment. Brief, paper and pencil cognitive screeners such as the MMSE and MOCA are widely utilized in clinical settings. Such screeners lack sensitivity to subtle cognitive change and specificity related to the cause of decline. Moreover, administration and interpretation of these screeners is time consuming in a busy, clinical setting. Prior research has determined that electronic‐based testing is effective in detecting cognitive change (Zygouris & Tsolaki, 2014). This pilot study aimed to investigate a convenient, platform agnostic, voice‐recognition screening tool for detection of mild, age‐advanced neurocognitive problems.

Method

Participants (n=16) were recruited from a large community‐based neurology practice, who underwent a comprehensive neuropsychological (NP) evaluation as part of their standard of care. Participants were administered an auditory list learning/recall test and a verbal fluency test (F/A/S and animals) via a voice recognition cognitive screening tool. Pearson correlations were conducted to examine the concurrent validity between the standard NP measures and those obtained using the current screening tool.

Result

Preliminary data suggests a positive correlation between standard NP measures and those obtained using voice recording and speech recognition technologies; language: F/A/S (r = .716, p < .005), animals (r .810, p < .005); memory: delayed recall (r = .515, p < .05).

Conclusion

This pilot study demonstrated concurrent validity between standard NP measures of memory and verbal fluency and those obtained using a novel, voice recording and speech recognition screening tool. These initial data provide support for the efficacy of a computerized based screening tool for older adults. Such a screening too has the potential to maximize utilization across multiple settings (e.g., medical office, hospital, in‐home) and improve early detection of cognitive decline.
Learning vector quantization model for prediction of cerebral Aβ in non‐demented individuals using plasma biomarkers
Authors: Ko Hyunwoong
Published: December 2021

Background

Cerebral Aβ is the hallmark of the AD in the early therapeutic intervention as well as diagnosis of the disease. Detecting in‐vivo Aβ deposition, however, still have limited accessibility. In this respect, the current study aims to identify plasma markers related to cerebral Aβ status via simple machine learning approach.

Methods

Predictability of the candidate plasma markers for cerebral Aβ burden was examined by analyzing 303 non‐demented participants those who had rules based medicine (RMB) and amyloid PET data from the ADNI cohort at baseline visit (83 control and 220 with MCI). Demographic variables (age, gender, education, and APOE status), and 146 of 190 plasma analytes passed quality check were selected as input in learning vector quantization (LVQ) model. The cerebral Aβ burden was measured using PiB PET images. Predictability and importance of variable were calculated using LVQ model.

Results

LVQ model with 10‐cross validation predicted cerebral Aβ status with the 90.67% accuracy (balanced accuracy: 93.14%) in non‐demented people. Based on variable importance analysis, Top‐10 variables above importance ratio above 60 after rescaling were selected: APOE carrier status (100.00), Angiotensin‐Converting Enzyme (ACE, 92.77), Eotaxin‐3 (89.74), Chromogranin A (CgA, 83.61), Brain Natriuretic Peptide (BNP, 79.61), Creatine Kinase‐MB (CK‐MB, 69.61), Monokine Induced by Gamma Interferon (68.26), T Lymphocyte‐Secreted Protein I‐309 (I‐309, 66.89), Matrix Metalloproteinase‐9 (MMP‐9, 64.52), Matrix Metalloproteinase‐9 total (MMP‐9 total, 60.90).

Conclusions

Our findings demonstrated that plasma based analytes can predict the cerebral Aβ positivity in non‐demented people. More specifically, ACE is can be a candidate marker for early detection of Aβ deposition in the asymptomatic stage of dementia. Plus, Eoxatain, and CgA can also play a role in AD pathology. To this end, this research was supported by the MSIT (Ministry of Science and ICT), Korea, under the ITRC (Information Technology Research Center) support program(IITP‐2021‐2017‐0‐01630) supervised by the IITP (Institute for Information & communications Technology Promotion).
The effect of plasmalogen precursor supplementation on blood plasmalogen and C‐reactive protein levels and cognition in cognitively impaired persons
Authors: Goodenowe Dayan B , Haroon Jonathan , Zielinski Margaret A , Mahdavi Kennedy D , Habelhah Barshen , Jordan Sheldon E
Published: December 2021

Background

Decreased blood and brain plasmalogens levels are associated with decreased cognition in humans. 1‐O‐alkyl‐2,3‐diacylglycerol (ADG) plasmalogen precursors containing docosahexaenoic acid (DHA) at the sn‐2 position have been shown to increase blood plasmalogens and to be neuroprotective in animal models of neurodegeneration. The goal of this study was to evaluate the effect of dietary DHA‐ADG supplementation on blood plasmalogen and C‐Reactive Protein (CRP) levels and cognition in cognitively impaired persons.

Method

Twenty persons (9M/11F), aged 37‐81 (average = 68) with mild to moderate cognitive impairment [CDR: 13(0.5); 3(1); 4(2)] were administered an escalating dose of DHA‐ADG [1.0ml/day for 30 days; 2.0ml/day for 60 days; 4.0ml for 30 days]. Blood plasmalogen and CRP levels and cognitive status were measured at baseline and the end of each month. Cognitive status was determined using the Quick Dementia Rating System (QDRS), which was used to derive the participant’s Clinical Dementia Rating (CDR).

Result

Overall, maximum average DHA ethanolamine plasmalogen levels were achieved by the end of the 2nd month [224% of baseline, 95%CI = 173‐273%] and this level of elevation was sustained for the duration of the study. Of the 20 participants, 14 (70%) exhibited robust and sustained plasmalogen elevations (>150%, >2 months, ADG Responder). Of the 14 ADG responders, 10 exhibited improvements on QDRS and 6 of these 10 exhibited improvements of at least one CDR level. Of the 14 ADG responders, 4 had baseline CRP levels >1.0. In each of these 4 subjects, CRP levels decreased by >0.5 by the end of the 4th month. DHA‐ADG was well tolerated at all dosages and no adverse reactions were observed. No cognitive improvement was observed in any of the ADG non‐responders.

Conclusion

DHA‐ADG was effective at elevating blood plasmalogen levels at the dosages studied. 10/14 (71%) of cognitively impaired persons experienced improved levels of cognition when blood DHA‐plasmalogens were elevated by >150%. In all persons with elevated baseline CRP levels, DHA‐plasmalogen elevation was associated with a decrease in blood CRP. This analysis suggests that DHA‐ADG supplementation may be beneficial for patients with mild to moderate cognitive impairment.
Plasma complement C3 levels in Alzheimer's disease
Authors: Wang Lijun , Liu Jun
Published: December 2021

Background

Alzheimer's disease (AD) is closely related to the loss of synapses. It has been shown that the complement system is involved in the process of synaptic elimination. We investigated whether the levels of plasma complement C3 could be a probable biomarker for the prodromal and demented AD.

Method

Participants included 58 cognitively normal (CN) subjects, 395 patients with late mild cognitive impairment (LMCI), and 112 AD patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database in the current study.

Result

The results showed that plasma complement C3 levels were significantly increased in AD patients compared to LMCI and CN subjects. Negative correlations between plasma complement C3 and education, MMSE were observed in all subjects.

Conclusion

Our findings indicate that plasma complement C3 levels may not be a valuable biomarker for the diagnosis of AD in the prodromal and dementia stages. Further studies are needed to explore the diagnostic value of plasma complement C3 based on longitudinal population.
Lithium chloride inhibits phosphorylation of tau protein
Authors: Asano Rei , Hamano Tadanori , Yen Shu‐Hui , Sasaki Hirohito , Yamaguchi Tomohisa , Endo Yoshinori , Enomoto Soichi , Shirafuji Norimichi , Ikawa Masamichi , Yamamura Osamu , Nakamoto Yasunari
Published: December 2021

Background

Pathological hallmarks of Alzheimer's disease (AD) are senile plaques (SPs) and neurofibrillary tangles (NFTs), which are formed from highly phosphorylated tau. Lithium chloride (LiCl) has been shown to inhibit phosphorylated tau by inhibiting glycogen synthase kinase‐3β (GSK‐3β). In addition, autophagy lysosome system (Hamano et al., Eur J Neurosci 27; 1119, 2008) and proteasome (J Neurochem 2000) are known to play an important role as tau degradation pathways. We investigated the decrease of phosphorylated tau by LiCl by using cell culture model expressing wild‐type tau via TetOff induction system.

Methods

Ten to 50mM of LiCl treatment (24 hours) was performed to neuroblastoma cells (M1C) expressing wild‐type tau protein (4R0N) via TetOff induction. Total and phosphorylated tau (PHF‐1) levels and autophagy activation were examined by Western blot (WB) analysis.

Results

Reduction of total tau (Tau5) and phosphorylated tau (PHF‐1, and CP13) with LiCl treatment was detected by WB analysis. C‐terminal truncated tau species detected by TauC3 was decreased by LiCl, too. In addition, increase of LC3Ⅱ/I, and decrease of P62 suggesting autophagy activation was observed. Major Tau kinase GSK3β was inactivated by LiCl.

Conclusions

These results imply that LiCl may decrease the phosphorylated tau through suppression of tau phosphokinase and activation of autophagy.
A structured brain‐wide and genome‐wide association study using ADNI PET images
Authors: Li Yanming , Nan Bin , Zhu Ji
Published: December 2021

Background

Detecting association signals between the brain and the genome using ultrahigh‐dimensional PET neuroimaging scans and GWAS SNP data

Method

A multi‐stage variable selection method is introduced for detecting association signals in structured brain‐wide and genome‐wide association studies (brain‐GWAS). Validity of the proposed approach is demonstrated by both theoretical investigation and numerical simulations. We apply our proposed method to a brain‐GWAS using ADNI PET imaging and genomic data.

Result

We confirm previously reported association signals (e.g. IL8RB and COLEC12 genes) and also uncover several novel SNPs and genes (e.g. GALNT4 and RIN2 genes) that either are associated with brain glucose metabolism or have their association significantly modified by Alzheimer's disease status.

Conclusion

Compared to conventional single‐voxel‐to‐single‐SNP methods, our approach is more efficient and powerful in selecting the important signals by integrating anatomic and gene grouping structures in the brain and the genome, respectively. It avoids resorting to large number of multiple comparisons while effectively controlling the false discoveries.
Development and analytical performance testing of a novel sTREM2 ELISA method to support drug development
Authors: Stoops Erik , Demeyer Leentje , Francois Cindy , Engelborghs Sebastiaan , Bjerke Maria , Dage Jeffrey L. , Wang Hong
Published: December 2021

Background

The triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface receptor of microglia cells in the central nerve system and is associated with neuroinflammation. sTREM2 can be used as pharmacodynamic biomarker for inflammation or microglial activation in therapeutic development programs. There is a need for well characterized assays that are suitable for measurement of neuroinflammatory biomarkers in pre‐clinical and clinical drug development. This abstract describes the characterization of a new robust sTREM2 prototype immunoassay based on monoclonal recombinant rabbit antibodies(mAbs).

Method

A colorimetric sandwich ELISA was developed using capture mAb B02 (code ADx601) and detector mAb C10 (code ADx602) reactive towards the sTREM2 extracellular ectodomain (aa 19‐172). The analytical assay performance will be reported: the repeatability and reproducibility was determined using a neat CSF based QC panel (n=3; 6 test runs; duplicate testing). Accuracy was assessed by testing parallelism and calibrator point back calculated concentrations. Passing Bablok regression analysis was used to demonstrate consistency of sample testing results (43 samples; duplicate testing; 3 test runs). Finally clinical routine CSF samples were analysed (19 patients diagnosed with AD and 20 controls based upon biomarker profile).

Result

A prototype sTREM2 ELISA assay was used to generate the assay characterization data: The %CV for repeatability respectively reproducibility were <12.2% and 15.4%. Accuracy: a slope value of 0.992 was obtained after Deming regression between the theoretical and experimentally obtained levels of 8 samples diluted over the measuring range (25‐3500 pg/mL) while the accuracy of the calibrator points was between 0 and 12.6% difference in back calculated concentration over 6 runs. Testing of the lot consistency (Figure 1) resulted in a slope and intercept value of respectively 1.07 (95%CI: 0.90‐1.17) and ‐80.9 (95%CI: ‐294.70‐154.30).Testing of clinical samples showed an increased sTREM2 concentration in AD versus controls (p<0.01).

Conclusion

A novel CSF prototype ELISA for sTREM2 was developed and characterized including lot consistency, precision, accuracy and others. The generated data indicate a robust sTREM2 immunoassay for use in drug development programs. The next step is the transfer to a manufacturing environment to make the assay available as a commercial test kit (RUO).
Clinical relevance of three‐range cutpoints in Alzheimer’s disease CSF biomarkers
Authors: Brum Wagner Scheeren , Bastiani Marco Antônio , Therriault Joseph , Bieger Andrei , Ferrari‐Souza João Pedro , Benedet Andréa Lessa , Pascoal Tharick A. , Saha‐Chaudhuri Paramita , Rosa‐Neto Pedro , Zimmer Eduardo R.
Published: December 2021

Background

Alzheimer’s disease (AD) was biologically defined by the 2018 NIA‐AA Research Framework (RF), which recommends dichotomously categorizing biomarker status as normal or abnormal using single cutpoints. Nevertheless, the RF also states a three‐range approach might be useful in AD research. However, this potentially relevant strategy remains mostly unexplored in the field. We hereby propose a three‐range cutpoint system to interpret CSF biomarker measurements. We hypothesized the intermediate group would have a different cognitive trajectory than negative/positive groups and that three‐range models would prognostically outperform binary models.

Method

We included 1278 non‐demented individuals (CU: n=575; MCI: n=703) from the ADNI with baseline CSF Elecsys® biomarkers. 20% of these individuals (who had baseline [18F]AV45 Aβ‐PET) were randomly allocated to a “training set” to define three‐range cutpoints – which were later evaluated in a “test set” comprising the remainder 80% participants. Three‐range cutpoints were defined with two‐graph receiver operating characteristics (TGROC) for each CSF biomarker (Aβ1‐42, p‐tau, t‐tau, p‐tau/Aβ1‐42, t‐tau/Aβ1‐42). Cutpoints were generated with 100,000 bootstraps, combining conventional or earlier‐centiloid [18F]AV45 thresholds to cognition in five different schemes for each biomarker. Linear mixed‐effects models (LMM) were employed to choose the best three‐range scheme and also to main analyses. The primary outcome of LMMs was the mPACC composite and participants were followed for up to 6 years. Three‐range models were compared within themselves, to binary and to continuous models based on AIC, BIC, log‐likelihood and R2.

Result

LMMs indicated all three‐range approaches outperformed models with binarized or linear‐continuous form of biomarkers and, interestingly, were closer in information metrics to more sophisticate spline‐continuous models, with p‐tau/Aβ1‐42 being the best three‐range predictor (Table 1). For the latter model (Figure 1), slope‐contrast analyses indicated the intermediate group had a faster rate of decline than the negative (β‐estimate: 2.04, t=4.88, p= 3.5x10‐6) but slower than the positive group (β‐estimate: 4.68, t=10.4, p=1x10‐14).

Conclusion

Our findings demonstrate that the proposed three‐range system for interpreting CSF biomarkers in AD prognostically outperforms binary cutpoints for all evaluated biomarkers, supporting the existence of an intermediate zone beyond the current normal/abnormal paradigm. This approach has clear potential applications to clinical trial recruitment and to clinical practice.
Cortical arousal is differently related with resting‐state electroencephalographic delta rhythms in healthy seniors and in patients with dementia due to Alzheimer’s disease
Authors: Lopez Susanna , Babiloni Claudio , Ferri Raffaele , Noce Giuseppe , Lizio Roberta , Soricelli Andrea , Nobili Flavio Mariano , Giubilei Franco , Marizzoni Moira , Güntekin Bahar , Yener Gorsev , Frisoni Giovanni B , Del Percio Claudio
Published: December 2021

Background

Keeping in mind Başar’s theory of event‐related EEG oscillations, here we hypothesize that transient increases in delta rhythms in quiet wakefulness may enhance global cortical arousal as revealed by the desynchronization of alpha rhythms in normal (Nold) seniors with some derangement in Alzheimer’s disease dementia (ADD).

Method

Clinical and EEG datasets in 100 ADD and 100 Nold individuals matched as demography, education, and gender were taken from an international archive. Standard delta (< 4 Hz) and alpha1 (8‐10.5 Hz) bands were used for the main analysis, while alpha2 (10.5‐13 Hz), theta (4‐8 Hz), beta1 (13‐20 Hz), beta2 (20‐35 Hz), and gamma (35‐40 Hz) served as controls. In the interpretation, the higher the alpha1 power (density), the lower that arousal.

Result

As expected, when compared to the Nold group, the ADD group showed higher global (scalp) power density at the delta‐theta band and lower global power density at the alpha‐beta bands. As novel findings, we observed that: (1) in the Nold group, the global delta and alpha1‐2 power were negatively and linearly correlated; (2) in the ADD group, this correlation was just marginal; and (3) in both Nold and AD groups, the EEG epochs with the highest delta power (median value for stratification) were associated with the lowest voxel‐based eLORETA solutions at the alpha1 band (i.e., eLORETA alpha1 current density at 8‐10.5 Hz). In the Nold group, the maximum t values of the differences between DELTA+ and DELTA‐ were localized in the occipital Brodmann area (BA) 18 at the Talairach coordinates X = 0, Y = −100, and Z = 5 (p < 0.05 corrected; Figure 1). In the ADD group, those maximum t values were instead localized more anteriorly, namely in the central BA 6 at the Talairach coordinates X = 40, Y = −10, and Z = 45 (p < 0.05 corrected; Figure 2).

Conclusion

These results suggest that even in quiet wakefulness, delta and alpha rhythms are related to each other, and ADD partially affects this cross‐band neurophysiological mechanism.