bluuebunny/crossref_metadata_2025 huggingface dataset:
Discordant low amyloid‐β PET and high neocortical tau PET retention
Authors: Krishnadas Natasha , Dore Vincent , Lamb Fiona , Tyrrell Regan , Bozinovski Svetlana , Villemagne Victor L.L. , Rowe Christopher C.
Published: December 2021

Background

Extracellular amyloid‐β (Aβ) plaques and intracellular tau neurofibrillary tangles characterize Alzheimer’s disease (AD). Combined use of Aβ and tau PET biomarkers demonstrates that high neocortical tau is rarely observed in the absence of high Aβ. We describe the prevalence of participants with high neocortical tau PET retention (visually and quantitatively) with a correspondingly low Aβ PET result and characterize these participants.

Method

AIBL participants who had both an Aβ and tau PET scan were included. Centiloid <25 defined a low (negative) Aβ result. Tau PET SUVR (standardized uptake value ratio) was estimated in three composite regions of interest (ROI): mesial temporal (Me), temporoparietal (Te) and rest of neocortex (R). The 99%ile of the Aβ‐ve cognitively unimpaired participants determined the threshold for each ROI.

Result

Four hundred and sixty‐six participants were included. Of all Aβ‐ participants (n=287), 12 were above the threshold in Te and R ROIs. Four participants (1.4% of all Aβ‐) had high neocortical tau tracer retention, quantitatively and visually, in a pattern consistent with AD (Braak stage V‐VI) (Figure 1). Despite the low Aβ PET, one participant had high plasma Aβ, while another had low CSF Aβ1‐42, high CSF pTau and tTau and an 18F‐FDG PET pattern consistent with AD. High plasma pTau‐217‐plus was observed for three of these four participants (result unavailable for one participant).

Conclusion

We have identified four participants with low Aβ PET and high neocortical tau PET retention. The alternative biomarker results in these cases are suggestive of a diagnosis of AD, despite the low Aβ PET result. We propose that in these instances, the Aβ PET ligand may not be detecting Aβ, maybe due to a different conformation of the aggregates. While infrequent, this finding has been reported using 11C‐PiB. Overall, the prevalence of this discordance was <2% in the sampled cohort, suggesting it is an uncommon occurrence. However, this study is limited by the lack of alternative Aβ biomarker results. Studies in larger cohorts are necessary to validate these findings, while genetic testing and postmortem correlation will enhance our understanding of the potential explanation for this finding.
Chronic habitual hypohydration that elevates serum sodium above 142 mmol/l is a risk factor for accelerated cognitive decline and dementia, suggesting lifelong optimal hydration as preventive measure
Authors: Dmitrieva Natalia I , Boehm Manfred
Published: December 2021

Background

With no known cure for dementia, finding preventive measures to delay onset of the disease represents an important goal for dementia research. Our previous studies demonstrated that chronic subclinical hypohydration accelerates degenerative changes and increases prevalence of many age‐dependent degenerative diseases including dementia (PMID:31484829). Worldwide surveys find wide differences in habitual water intake and substantial prevalence of hypohydration in general population (PMID:26066354). Hypohydration results in elevation of extracellular sodium triggering activation of water conservation mechanisms (PMID:18509340). Analysis presented here evaluates associations of serum sodium at middle age as a measure of hydration habits with cognitive decline and dementia diagnosis later in life.

Methods

Data from Atherosclerosis Risk in Communities (ARIC) study were obtained from the BioLINCC data repository. In ARIC study, 15,792 45‐65 year‐old participants were evaluated over 5 visits spanning 25 years (Fig. 1A). Here, association of serum sodium with dementia diagnosis by visit 5 (age:70‐90 years) was assessed by multiple logistic regression analysis. Multiple linear regression analysis was used to asses associations with cognition measures: Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT). The models were adjusted for age, sex, gender, education, BMI, eGFR, glucose, and cholesterol. For visit 5, the models were additionally adjusted for diagnosis of heart failure, stroke and high blood pressure.

Result

Midlife serum sodium is associated with dementia diagnosis at visit 5 both with adjustment for age only (OR=1.13 95%CI 1.05‐1.21, P<0.001) and in fully adjusted model (OR=1.09 95%CI 1.01‐1.19, P=0.03). This association is reflected in increased prevalence of dementia from 4% to 6‐7% in 70‐90 year‐old participants whose middle age serum sodium exceeded 142mmol/l: an approximate threshold for activation of water conservation mechanisms triggered by hypohydration (Fig. 1B). Consistently, higher serum sodium is associated with reduced performance on DSST and WFT cognition tests with substantial decline in upper half of the normal sodium range. The trend is already present at middle age (Fig. 1C‐D).

Conclusion

Habitual life‐long hypohydration accelerates cognitive decline and increases risk of dementia. Keeping serum sodium below 142 mmol/l by drinking appropriate amount of liquids may delay cognitive decline and decrease prevalence of dementia.
White matter hyperintensities and mild behavioural impairment: Findings from the MEMENTO Study
Authors: Miao Ruxin , Chen Hung‐Yu , Robert Philippe , Smith Eric E. , Ismail Zahinoor
Published: December 2021

Background

Mild behavioural impairment (MBI) is a neurobehavioural syndrome characterized by the onset and persistence of neuropsychiatric symptoms (NPS) in later life. While the ATN framework provides a robust overview of Alzheimer’s pathology, it does not fully capture the impact of small‐vessel cerebrovascular disease in the pathogenesis of dementia. White matter hyperintensities (WMH) may independently contribute to the development of Alzheimer’s dementia and predict risk of incident dementia in mild cognitive impairment (MCI). Few studies have established the link between NPS and WMH in MCI populations.

Method

We included 760 participants from the French MEMENTO study with MCI and WMH data. WMH volumetry on T2‐weighted fluid attenuated inversion recovery images was identified using WHASA software, visually verified with the Fazekas and Schmidt scale, and expressed in cm3. Mean age was 72.7 (SD 8.0) and 57.9% of participants were female. Neuropsychiatric Inventory items were transformed to MBI domains using a published algorithm. MBI status was based on symptom persistence: NPS at both baseline and 6‐months was considered MBI+ (n = 227), whereas non‐persistent NPS (i.e., NPS at either time point but not both) or no NPS at either baseline or 6‐months was considered MBI‐ (n=549). We investigated the association between MBI status and the outcome variable, WMH, using a linear regression model adjusted for age, sex, education, Mini‐Mental Status Exam (MMSE) score, and total intracranial volume.

Result

MBI was present in 29.9% of participants (n = 227). MBI+ (i.e., persistent NPS) was significantly associated with lower MMSE score (p < 0.001) and male sex (p = 0.025). Compared to MBI‐, MBI+ was associated with 9.9% higher WMH volume [p = 0.006 (95% CI 2.8% to 18%), Table 1].

Conclusion

In a memory clinic sample of older adults with MCI, MBI+, operationalized as persistent NPS, is associated with higher WMH. These findings extend the evidence base linking MBI with known dementia biomarkers and raise the possibility that some forms of MBI can be caused by vascular brain injury.
Outreach Pro: The National Institute on Aging’s (NIA) online tool for AD/ADRD clinical studies recruitment and engagement of diverse and underserved populations
Authors: Massett Holly A , McGowan Melissa , Gallop‐Goodman Gerda
Published: December 2021

Background

NIA aims to increase awareness and interest in Alzheimer’s and related dementias (AD/ADRD) research among non‐White populations. Easily accessible, well‐tested, culturally appropriate outreach materials addressing AD/ADRD and clinical research is an identified need by researchers to better reach communities of color. To address this gap, NIA has both invested substantial resources to create materials for African Americans (AA), Hispanics/Latinos (H/L) and Asian Americans/Pacific Islanders (AAPI), and developed a new online platform, Outreach Pro, where researchers/stakeholders can tailor and brand communication campaigns locally.

Method

Outreach Pro and its content were created iteratively using a mixed‐method approach: literature reviews, environmental scans, stakeholder listening groups (N=9), focus groups (N=33), national surveys (N=3), and usability testing (N=20). Materials were developed working with creative designers and researchers representing each cultural group and languages. Final creatives were added into the Outreach Pro and tested with representatives from the AD/ADRD community.

Result

Outreach Pro is fully developed and will be formally launched as part of this presentation. The online tool, using a series of pre‐programmed questions, allows users to develop tailored and branded local campaigns selecting from the tool’s library of nationally tested messages, taglines, concepts, and images. User‐testing indicated overall high usability and user‐sentiment towards the site (SUSS=76; NPS=60). Outreach Pro contains materials developed for AA and H/L audiences, including: leave behind brochures/factsheets, online libraries of well‐tested photos/images, videos, social media posts, and motion graphics. H/L materials are available in both Spanish and English. A set of materials for AAPI is currently in development and being tested in three languages.

Conclusion

Our findings illustrate the importance of both designing well‐tested, culturally appropriate materials and making them easily accessible and customizable to stakeholders on a local level. NIA designed Outreach Pro to reduce redundancies; users of the platform can save and share their customized campaign in a centralized location. NIA plans to evaluate the tool and identify areas where its content can be scaled up to address other aging‐related research.
A 3‐month toxicity study of GB‐5001, a donepezil one‐month depot injection formulation, by intramuscular injection in dogs
Authors: Yoon Kwonhyeok , Choi Jaemook , Seol Eunyoung , Lee Juhan , Choe Heekyoung , Lee Soojung , Lee Heeyong
Published: December 2021

Background

Donepezil, an acetylcholinesterase inhibitor for treatment of Alzheimer’s disease (AD), is administered as daily tablets. The treatment compliance, however, is particularly challenging in AD patients for various reasons such as difficulty in swallowing medication, tolerating side effects, and/or complying with the appropriate dosage. GB‐5001 is a novel once monthly intramuscular (IM) depot injection of donepezil to improve treatment compliance developed using G2GBIO’s InnoLAMP® technology. The objective of this study was to evaluate the toxicity of GB‐5001 in beagle dogs for further development.

Method

GB‐5001 was administered once every 4 weeks via bolus IM injection to 16 male and 16 female beagle dogs (7.4∼13.3 kg) for 3 months, and 4 male dogs and 4 female dogs in the vehicle group and the highest dose level group were evaluated for the reversibility or long‐term effects following a 2‐month non‐dosing recovery period. The dose levels were 0 (vehicle), 280, 560, and 1120 mg/dose. The following parameters and endpoints were evaluated in this study: standard toxicology parameters, ophthalmoscopic, electrocardiographic examination, gross, histopathologic examinations, and toxicokinetic parameters.

Result

No fatality occurred during this study and there were no toxicologically significant clinical changes or pathological findings related to GB‐5001 in all groups. Systemic exposure to Donepezil was independent of sex. Following IM injection once every 4‐weeks of GB‐5001, mean Cmax and AUC0‐last values of Donepezil increased dose dependently on Days 1 and 57. And systemic exposure (AUC0‐last) to Donepezil increased slightly (<2 fold) on Day 57 compared to Day 1.

Conclusion

GB‐5001 was tolerated at all dose levels when administered once every 4 weeks via IM injection to male and female beagle dogs for 3 months at doses of 0, 280, 560 and 1120 mg/dose. The clinical observations of swelling and nodules at the dose sites are considered to be vehicle‐related as evidenced by the similar incidence in control. Consequently, the no‐observed‐adverse‐effect‐level (NOAEL) is considered to be 1120 mg/dose.
Investigating predictors of incident cognitive impairment in women
Authors: Casanova Ramon , Gaussoin Sarah A , Hayden Kathleen M , Shadyab Aladdin H , Canell Brad , Chen Jiu‐Chiuan , Liu Simin , Chan Kei Hang Katie , Henderson Victor , Craft Suzanne , Rapp Stephen R
Published: December 2021

Background

More women than men are affected by Alzheimer’s disease (AD). However, risk factors for cognitive impairment (CI) among older women by race/ethnicity are not completely understood. The well‐characterized Women’s Health Initiative Memory Study (WHIMS) has followed for more than 25 years postmenopausal women to assess cognitive and brain outcomes. WHIMS provides a unique opportunity to determine the extent to which risk factors for CI vary between White and Black women. Due to the high‐dimensional nature of this problem we based our analyses on machine learning methods.

Method

To investigate signatures of predictors of incident CI (either mild cognitive impairment or probable dementia) in women, we included 6778 women (503 Black and 6275 White) with up to 25 years of follow‐up including annual cognitive assessments. Mild cognitive impairment and probable dementia were adjudicated annually across all phases of the trial and subsequent observational study by a central, multidisciplinary adjudication panel of experts. We selected 52 potential predictors collected at baseline representing different domains–demographic, health, social, psycho‐social, biological, and medical. Survival Random Forests (SRF) were used to identify the most reliable predictors of incident CI. Here we use the SRF implementation available in the RandomForestSRC R library. SRF models were fitted independently using White and Black participants based on the default parameters of the software. The permutation index was used to determine predictors’ relevance. The concordance index was used as a measure of model performance.

Result

The most important predictors of incident CI in Black women were lower education, higher systolic blood pressure, lower income and higher high‐density lipoprotein cholesterol. The concordance index was 0.64. A different profile of predictors was observed among White women. Baseline age was the most relevant predictor of ICI followed by self‐reported forgetfulness, self‐reported difficulty concentrating, physical function and higher depression. The concordance index for this model was 0.71.

Conclusion

Phenotypic signatures predicting incident CI differed between older Black and White women. Education, markers of vascular disease and income were major predictors in Black women and age, self‐reported cognitive difficulties, physical function and mood were major predictors in White women.
The crosstalk between beta‐amyloid, retina, and sleep for the early diagnosis of Alzheimer’s disease: A mini review
Authors: De Guia Isaiah‐Lorenzo , Gupta Sunil M. , Naismith Sharon L. , Chatterjee Pratishtha , Dias Cintia B. , Fuller Stephanie , Shah Tejal M. , Martins Ralph N.
Published: December 2021

Background

Retinal imaging has the potential to be used as an early diagnostic tool in Alzheimer’s disease (AD). However, direct visualisation of AD related hallmark proteins in the live human retina is challenging and may require the inclusion of additional factors to be effective. This mini review gathers evidence to understand the associations and underlying mechanisms between beta‐amyloid (Aβ, a hallmark feature found in the AD brain), the retina and sleep as collectively they would enhance the diagnostic accuracy of the retinal markers in AD.

Method

Retinal imaging has the potential to be used as an early diagnostic tool in Alzheimer’s disease (AD). However, direct visualisation of AD related hallmark proteins in the live human retina is challenging and may require the inclusion of additional factors to be effective. This mini review gathers evidence to understand the associations and underlying mechanisms between beta‐amyloid (Aβ, a hallmark feature found in the AD brain), the retina and sleep as collectively they would enhance the diagnostic accuracy of the retinal markers in AD.

Result

Retinal imaging has the potential to be used as an early diagnostic tool in Alzheimer’s disease (AD). However, direct visualisation of AD related hallmark proteins in the live human retina is challenging and may require the inclusion of additional factors to be effective. This mini review gathers evidence to understand the associations and underlying mechanisms between beta‐amyloid (Aβ, a hallmark feature found in the AD brain), the retina and sleep as collectively they would enhance the diagnostic accuracy of the retinal markers in AD.

Conclusion

There is mounting evidence that the coupling of chronobiological information such as circadian rhythm dysfunction and sleep deficiency to retinal biomarker changes will increase the potential utility of retinal imaging in early AD diagnosis.
Amyloid‐tau‐neurodegeneration (ATN) profiles and influence of age‐of‐onset on cognitive trajectories in a Southeast Asian cohort: SYNC project
Authors: Vipin Ashwati , Koh Chen Ling , Wong Benjamin , Zailan Fatin Zahra , Tan Yi Jayne , Soo See Ann , Satish Vaynii , Kumar Dilip , Wang Brian Zhiyang , Ng Adeline Su Lyn , Chiew Hui Jin , Ng Kok Pin , Kandiah Nagaendran
Published: December 2021

Background

The amyloid‐tau‐neurodegeneration (ATN) scheme enables unbiased biomarker‐based diagnoses, independent of cognitive status and temporal ordering of AD pathogenic mechanisms [Jack et al.,2016]. ATN profiles in the diverse Southeast‐Asian region will provide important insights into the ATN framework and its association with cognition [Hilal et al.,2017; Knopman et al., 2018]. We examined the effect of amyloid‐beta status on longitudinal cognitive trajectory in young and late‐onset patients as well as impact of ATN categories on longitudinal cognition in a Southeast‐Asian cohort. We hypothesized that age of onset would differentially influence the association between amyloid status and longitudinal cognition.

Method

We studied 92 patients with cognitive impairment from the Singapore YouNg Dementia Cohort. Patients underwent structural‐MRI and lumbar puncture for cerebrospinal fluid amyloid‐beta (1–42), phosphorylated‐tau (p‐tau) and total‐tau (t‐tau) to assess biomarker positivity [Blennow et al., 2020]. A cut‐off age of 60 years was used to define young‐onset cognitive impairment. Separately, ATN profiles were assigned based on cerebrospinal fluid biomarker levels: normal biomarker profile (A‐T‐N‐), suspected non‐Alzheimer’s pathology (SNAP: A‐T±N±) and Alzheimer’s continuum (A+T±N±). Linear mixed effects models assessed longitudinal group differences in mini‐mental state examination (MMSE) trajectory.

Result

Young (<60yrs) sporadic amyloid‐positive, patients demonstrated significantly greater decline in longitudinal MMSE scores (AmyloidStatus*AgeOfOnset*Time: β=2.82, p=0.0193; Fig. 1) compared to older (≥60yrs) amyloid‐positive counterparts. Across the three ATN categories, there were no differences in baseline age, sex, white matter hyperintensities, medial temporal atrophy or APOE4 status (Table 1). Patients along the Alzheimer’s continuum showed a greater decline in MMSE scores over time compared to both normal biomarker A‐T‐N‐ (β=−2.23, p=0.001; Fig. 2‐3) and SNAP patients (β=−2.05, p=0.004; Fig. 2‐3). MMSE decline did not differ between SNAP and A‐T‐N‐ groups.

Conclusion

We show steeper MMSE decline in young amyloid‐positive patients than their amyloid‐positive older counterparts. Additionally, Alzheimer’s continuum patients showed steeper MMSE decline than A‐T‐N‐ and SNAP patients. These findings provide insights into mechanisms for the more aggressive cognitive decline frequently observed in younger patients.
The amnestic syndrome of hippocampal type is frequent in patients without hippocampal atrophy in a memory clinic population
Authors: Beaulieu Emilie , Perrier‐Ferland Louis‐Charles , Langlois Francis , Bocti Christian
Published: December 2021

Background

Since 2011, diagnostic criteria for Alzheimer’s Disease have led to the introduction of biomarkers. Hippocampal atrophy, either volumetric or visually‐rated is arguably the most widely available biomarker of neurodegeneration. An association with a specific type of amnestic disorder has been claimed, but the clinical validity of this concept remains to be established in unselected patient populations. This problem is important as the amnestic syndrome of the hippocampal type is theoretically a key element in the diagnosis of the most common clinical syndrome of Alzheimer’s disease. Our objective was to determine the correlation between the amnestic syndrome of hippocampal type and hippocampal atrophy.

Method

This is a retrospective study of 274 consecutive patients who were assessed in the Memory Clinic between 01/2014 and 11/2018. Verbal memory was assessed with the Free and Cued Selective Reminding Test (FCSRT) and the Montreal Cognitive Assessment Memory Index Score. Brain imaging was performed within six months of the neuropsycholgical assessment and hippocampal atrophy was estimated using the Scheltens Scale, adjusted for age.

Result

The Scheltens scale had a moderate correlation with FCSRT free recall (Pearson correlation = ‐0,425, p<0,001) and weak correlation with FCSRT Cueing index (Pearson correlation = ‐ 0,293, p< 0,001). However, 34% of our cohort (n=93) had an abnormal FCSRT Cueing index (< = 71%), but a normal Scheltens score. As for the MoCA‐MIS, 26% of our cohort (n=57) had an abnormal score (< = 7), but a normal Scheltens score.

Conclusion

A large subgroup of our patients demonstrate an amnestic syndrome of the hippocampal type, without showing hippocampal atrophy on routine brain imaging. Our results show the limits of equating hippocampal atrophy with the particular profile of amnesia that does not improve with cueing. The claimed specificity of this type of cognitive deficit in the differential diagnosis of dementia needs to be re‐assessed.
Conversational artificial intelligence and affective social robot for monitoring health and well‐being of people with dementia
Authors: Wairagkar Maitreyee , De Lima Maria Raposo , Harrison Matthew , Batey Philippa , Daniels Sarah , Barnaghi Payam , Sharp David J , Vaidyanathan Ravi
Published: December 2021

Background

Social robots are anthropomorphised platforms developed to interact with humans, using natural language, offering an accessible and intuitive interface suited to diverse cognitive abilities. Social robots can be used to support people with dementia (PwD) and carers in their homes managing medication, hydration, appointments, and evaluating mood, wellbeing, and potentially cognitive decline. Such robots have potential to reduce care burden and prolong independent living, yet translation into PwD use remains insignificant.

Method

We have developed two social robots ‐ a conversational robot and a digital social robot for mobile devices capable of communicating through natural language (powered by Amazon Alexa) and facial expressions that ask PwD daily questions about their health and wellbeing and also provide digital assistant functionality. We record data comprising of PwD’s responses to daily questions, audio speech and text of conversations with Alexa to automatically monitor their health and wellbeing using machine learning. We followed user‐centric development processes by conducting focus groups with 13 carers, 2 PwD and 5 clinicians to iterate the design. We are testing social robot with 3 PwD in their homes for ten weeks.

Result

We received positive feedback on social robot from focus group participants. Ease of use, low maintenance, accessibility, assistance with medication, supporting with health and wellbeing were identified as the key opportunities for social robots. Based on responses to a daily questionnaire, our robots generate a report detailing PwD wellbeing that is automatically sent via email to family members or carers. This information is also stored systematically in a database that can help clinicians monitor their patients remotely. We use natural language processing to analyse conversations and identify topics of interest to PwD such that robot behaviour could be adapted. We process speech using signal processing and machine learning classifiers to identify emotions and mood.

Conclusion

Affective social robots with voice and facial expressions have a great potential for enhancing dementia care at home. Combining responses to daily questions, topics of conversations and emotions from speech analysis can help assess daily status of PwD automatically and monitor their health and well‐being over time remotely.
A Month in Neurodegenerative Disease Research (AMiNDR): The evolution of an open‐access podcast series for Alzheimer's researchers
Authors: Rowe Elyn M , Louadi Sarah , Koch Ellen , Kuhlmann Naila , Kamesh Anusha
Published: December 2021

Background

With the increasing strain on researchers’ time and the constant flow of new publications, staying up to date with the latest findings in the field of Alzheimer’s disease research is more challenging than ever. To address this problem, we launched a podcast series in June 2020 which covers primary peer‐reviewed articles. Each episode comes with a bibliography citing the abstracts covered, and a description by theme. Since then, we have focused on program evaluation and quality improvement with the following aims: 1) Implement a systematic and consistent approach within the team and across episodes, 2) Increase our global reach, and 3) Provide a valuable service to researchers.

Methods

Areas for improvement were identified by the core founders of the podcast, 25 new team members, and listener feedback. 1) A systematic approach to sorting papers into defined themes was developed based on thematic coding of abstracts to identify major themes and sub‐themes. We also implemented quality control measures and standardized hosting procedures. 2) To evaluate our reach, we used analytics from the Simplecast podcast platform to track the number of downloads over time and the geographical location of our listeners. 3) Formal and informal feedback was collected through a survey and social media platforms, respectively. We also plan to assess additional analytics to track the use of our bibliographies to evaluate their value and whether our podcast prompted listeners to consult the original article.

Results

From our original four broad‐strokes themes in early 2020, we have expanded to 25 themes to curate focused episodes on topics relevant to researchers. We also developed a semi‐automated quality control regimen to ensure that we cover all papers that appear on PubMed each month, without duplicates. To standardize summarizing and hosting procedures, we created guidelines to train new members of our team. We have received significantly more positive feedback for our recent series that implemented the improvements, and observed a gradual increase in our weekly downloads from a global listener base.

Conclusion

With the feedback received and data collected on listener trends, it seems that researchers worldwide are benefiting from our podcast platform and its improvements.
Individualized subtypes prognosis of MCI using deep‐learning based jointly optimized clustering‐classification method
Authors: Kang Sohyun , Seong Joon‐Kyung , Kim Sung‐Woo
Published: December 2021

Background

The heterogeneity of Alzheimer’s disease is important theme for studying the epidemiology of the disease. Practically, understanding disease phenotypes helps deciding treatment before proceeding to dementia. Generally, it is known that AD’s subtype can be divided into three.

Method

We used 660 mild cognitive impairment (MCI) patients’ T1‐weighted magnetic resonance images (MRI) from Alzheimer’s Disease Neuroimaging Initiative (ADNI). Inputs are atrophy vectors which mean excluding the positive part and resigned W‐scores calculated from 81,924 vertex‐level cortical‐thicknesses extracted from T1. Unlike existing clustering‐only or separated clustering‐classification models, we used a model which is jointly optimized with respect to both clustering and classification. The model is comprised of three parts: 1) feature extractor, 2) clustering module, and 3) classifier. In first part, we extract important features using simple neural network. Then, we do clustering using the deep‐features and obtain pseudo‐labels in latent space. Finally, we implement classification at last layer with the answers which are assigned from clustering module. It is end‐to‐end training being able to find the solution of combined objective function.

Results

Results were represented from 10 fold cross‐validation. Average log‐likelihood of Gaussian mixture and normalized mutual information of labels between adjacent iterations are used as clustering performance metric, cross‐entropy loss and accuracy as classification. It is difficult for such models to converge according to referenced studies. But, in this study, all the metrics were well‐converged. Atrophy maps show group comparison results of cortical thicknesses between each subtype and cognitive normal (CN) patient with FDR correction and W‐score averaged in each subtype. The demographic table about Aβ positivity and dementia conversion percentages without missing information and neuropsychological test scores table of each subtypes showed that subtype‐I has highest degree of disease severity, then subtype‐II and finally III. External validation with 662 aMCI patients’ data from Samsung Medical Center (SMC) used in similar study represented bigger gap of dementia conversion percentages between subtype‐I and II.

Conclusions

In this study, we made clustering‐classification model for individualized subtype prediction. It is end‐to‐end training method optimizing clustering and classification loss simultaneously. The results showed our model exceeds existing subtype clustering model.
High education, but not occupation or work experience, is related to a lower risk of dementia in the oldest‐old: The 90+ Study
Authors: Melikyan Zarui A , Phelan Michael J , Kawas Claudia H , Corrada Maria M
Published: December 2021

Background

Most studies find that high education, work experience, and cognitively demanding occupations are independently associated with a lower dementia risk, and that the association may be strongest for occupation. It is hypothesized that these three factors provide cognitive reserve. Here we examine the risk of dementia in relation to education, work experience, and occupation in the oldest‐old (age 90+), an age group with the highest dementia risk.

Method

We analyzed data on 598 participants of The 90+ Study, a longitudinal study of aging and dementia, who were previously part of the population‐based Leisure World Cohort study, had no dementia at entry into The 90+ Study, had additional follow‐up, and reported their education and occupation. Education was categorized as college. Occupation categories were assigned based on 1970 US Census and grouped according to cognitive demand: more (managers/administrators and professionals) and less (all other occupations). Participants who never worked/ housewives were a separate group. We estimated risk of dementia in relation to education, occupation, and having worked vs. never worked using Cox regression.

Result

At baseline, the average age was 93 years, 42% had ≥college education, and 52% had more cognitively demanding occupations (Tables 1, 2). Over an average of 3 years of follow‐up, 48% of participants developed dementia. Compared to participants with college education had a 32% lower risk of dementia (HR=0.68) in the unadjusted model and 35% lower risk when adjusted for occupation (HR=0.65). Adjustment for sex or for sex and occupation did not change the results (Table 3). Occupation (men and women) (Table 4), or having worked (women only) (Table 5), were not related to dementia risk.

Conclusion

In this oldest‐old group, education, an early life experience, remains strongly associated with dementia risk. This is in contrast to other life‐long dementia risk factors, such as APOEe4, which are no longer associated with dementia risk at very advanced ages. These results suggest that education determines cognitive reserve and life‐long lifestyle factors that protect against dementia, whereas occupation or work experience do not contribute to cognitive reserve.
Systemic inflammation is associated with dementia status in the health and retirement study
Authors: Higgins Cesar , Ware Erin B , Hicken Margaret , Zawistowski Matthew , Bakulski Kelly M
Published: December 2021

Background

The prevalence of dementia is expected to increase in the coming decades. The highest burden of this chronic condition will likely be borne by racial/ethnic minorities. Systemic inflammation is associated with dementia. This effect may be modified by race/ethnicity, since racial minorities are more likely to have elevated levels of systemic inflammation due to the accumulation of compounded negative experiences (e.g., discrimination, racism, and marginalization). Our goal was to test baseline systemic inflammation in relation to cognitive function in a racially/ethnically representative cohort of US adults.

Methods

In a cross‐sectional analysis of the Health and Retirement Study (2006 and 2008 waves, n=9,983), highly sensitive C‐reactive protein (hsCRP) was measured in dried blood spots. Cognitive status (dementia, cognitive impairment non‐dementia (CIND), and normal cognition) was measured and categorized using the Langa‐Weir classification of a modified telephone interview for cognition scale. We estimated the adjusted associations between hsCRP and cognitive status, using multivariable logistic regression. We stratified models by race/ethnicity to explore race‐dependent associations.

Results

Our study prevalence of dementia and CIND is 3.5% and 15.8%, respectively. Similarly, 26.7% of dementia and 30.1% of CIND cases occurred among participants with circulating hsCRP levels above the 75th quartile. We observed a racial and gender gradient in the levels of hsCRP in our cohort. For example, Black females had the highest average concentration of hsCRP (7.53 mg/L, SD =15.1) and Whites males the lowest (3.95 mg/L, SD = 7.42). Among participants with hsCRP >75th we observed higher odds of CIND (OR = 1.45; 95%CI: 1.22, 1.72) with respect to those in the . Similarly, elevated hsCRP >75th was associated with dementia (OR= 1.21; 95%CI: 0.86, 1.69), in comparison to the reference lower quartile. We did not observe a race‐dependent relationship between hsCRP and cognitive status.

Conclusions

Systemic inflammation, as represented by high levels of hsCRP, was associated with concurrent cognitive status. Despite racial minorities exhibiting higher levels of hsCRP; in our study, the association between inflammation on cognition did not differ by race. Further studies should explore whether the established relationship is causal, seek larger sample sizes in diverse populations, and examine longitudinal relationships
Cortical thinning and white matter abnormalities relate to longitudinal neuropsychiatric symptoms differentially in predementia and dementia stages
Authors: Ji Fang , Xu Xin , Ong Marcus Qin Wen , Kan Cheuk Ni , Tan Boon Yeow , Venketasubramanian Narayanaswamy , Pasternak Ofer , Chen Christopher , Zhou Juan Helen
Published: December 2021

Background

Subjects with cognitive impairment and dementia often suffer from neuropsychiatric symptoms (NPS). Recent studies reported the association between brain structural damages and NPS. However, little is known about how domains of NPS map to region‐specific multimodal macro‐ and micro‐structural brain changes and whether the patterns vary across different cognitive stages. Importantly, most existing evidence is cross‐sectional. Here, we sought to investigate how baseline cortical thickness (CTh) and white matter (WM) microstructure influenced longitudinal progression of NPS in predementia and dementia.

Method

Longitudinal neuropsychiatric inventory (NPI) total severity and subsyndrome scores (Hyperactivity, Psychosis, Affective, Apathy) over 5 years were reported in 334 memory‐clinic patients (187 cognitive impairment no dementia (CIND) and 147 dementia). All participants underwent T1‐weighted structural and diffusion MRI at baseline. A free‐water (FW) imaging method was applied to derive individual‐level WM‐FW and tissue‐compartment maps from diffusion‐MRI. The grey matter (GM) CTh was derived using Freesurfer. We examined the association of baseline WM‐FW, WM‐tissue or GM‐CTh with baseline/longitudinal NPI (total severity and sub‐syndrome) using general linear models.

Result

In CIND, higher total NPI severity was associated with widespread WM‐FW increases (fronto‐parietal projection, temporal and callosal fibres) and more focal tissue fractional‐anisotropy (FAt) reductions (fronto‐parietal/callosal fibres) cross‐sectionally (Fig‐1). Specifically, such WM‐measures were associated with affective and hyperactive sub‐syndromes, but not with psychosis and apathy. No NPI‐cortical thickness association was detected in CIND. By contrast, in dementia, GM‐CTh in frontal executive and default mode and central sensory networks, but not WM‐alteration, was related to higher total NPI severity (Fig‐2). Also, GM‐CTh was associated with apathy and psychosis, but not with affective and hyperactive sub‐syndromes.

Furthermore, baseline WM‐measures were associated with longitudinal changes in total NPI severity (Fig‐3) and affective and hyperactive in CIND. By contrast, no association was found between GM‐CTh and longitudinal NPI (total and subsyndromes) in dementia.

Conclusion

This study demonstrated that WM‐abnormalities, which were early marker of disease, were related to NPS in CIND, while GM‐CTh was associated with NPS in dementia. Early identification and interventions should be developed for timely management of affective and hyperactive disorders, followed up by close monitoring of the progression of cerebral structural disruptions.
Quantitative systems pharmacology model of amyloid and tau to explore efficacy of therapy targeting modified forms of amyloid
Authors: Karelina Tatiana , Lerner Stepan
Published: December 2021

Background

Amyloid targeting therapy in different variations is still under development. One of the potential targets is modified forms of amyloid, Ab3p. They are very specific marker found in plaques of AD subjects, and demonstrate higher toxicity to neurons. Its correlation with tau load and AD severity is stronger than for non‐modified forms. Specific therapy targeting modified Ab may be more effective and less toxic due to lower required concentration of antibodies. Glutaminyl cyclase (QC) inhibitors have considerable BBB penetration and concomitant anti‐inflammatory activities. Monoclonal antibodies to specific to pGlu3‐Ab successfully reduce cognitive impairment in preclinical settings. Quantitative systems pharmacology QSP model is a good tool to study contribution of protein modification to disease progression and investigating sensitivity of overall system to specific targeting.

Method

QSP model was developed to describing amyloid production and distribution, hetero‐oligomerization of Ab1‐40, Ab1‐42 and pGlu3‐Ab. It has been combined with description of tau pathology and neuron homeostasis (NH) model. NH model describes processes regulating protein degradation and transport. Modified amyloid polymerizes with higher rate and resistant to degradation. Rate of amyloid modification was assumed to be one of the drivers, depending on age (we assumed it can be related to the calcium EPR stress in neurons and microglia activation due to inflammatory stimuli). Amyloid and tau during accumulation disrupt transport, proteasomal and autolysosome system. The model was calibrated on multiple in vitro and in vivo data, as well as preclinical and clinical data for treatments by immunotherapies.

Result

Integrated model describes accumulation of amyloid and tau according to Braak stages. It captures the role of intraneuronal processes on tau and amyloid metabolism. Model describes influence of amyloid modification on total accumulation of amyloid. Both QC inhibition and targeting by antibodies attenuate accumulation of amyloid in brain. Tau pathology progression is reduced, assuming that binding of antibody prevents toxicity of pGlu3‐Ab on tau kinase activation and calcium influx.

Conclusion

Model can be used to analyze contribution of different amyloid forms to pathology and efficacy of specific therapies on multiple biomarkers. It can be used for explorations of different combinations and regimens.
Efficacy of a vectorized anti‐tau antibody using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies
Authors: Liu Wencheng , Holth Jerrah , Paranjpe Maneesha , Ren Xiao‐Qin , Shu Yanqun , Murlidharan Giridhar , Chung Charlotte , Powers Alex , Peterson Emalee , Ecker Abigail , Hameedi Usman , Grant Kyle , Kurella Vinodh , Kavanagh Dillon , Khwaja Omar , Hou Jay , Paul Steven M. , Bales Kelly R. , Carter Todd
Published: December 2021

Background

Anti‐tau immunotherapy is a promising therapy for tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). While passive immunization with anti‐tau monoclonal antibodies has been shown by several laboratories to reduce age‐dependent tau pathology and neurodegeneration in mouse tauopathy models, these studies have typically used repeated high weekly doses of antibody and reported only moderate reduction of tau pathology. To circumvent these limitations, using an adeno‐associated virus (AAV) vector to deliver a tau monoclonal antibody into hippocampus by direct injection to the location have been described. High levels of antibody and marked reduction of tau pathology is achieved by this approach. To further optimize this approach with a lesser invasive administration route, we have previously demonstrated broad distribution and expression of a vectorized anti‐tau antibody in the mouse brain using a blood‐brain barrier (BBB) penetrant AAV capsid administered intravenously (IV). This gene therapy‐based approach has potential advantages, including continuous expression of antibody in the central nervous system (CNS) after a single administration of vector, increased CNS levels of tau antibody relative to passive immunotherapy, and the potential to target intracellular tau aggregates. Here we describe studies characterizing the onset of transduction following dosing with a vectorized tau antibody and its efficacy in mouse models of tauopathy.

Method

AAV vectors comprising the BBB‐penetrant AAV capsid and a transgene encoding an anti‐tau monoclonal antibody were administered by IV bolus to mouse models of tauopathy. Biodistribution and cellular tropism in the CNS were evaluated by ELISA and (or) immunostaining. Tau pathology was measured by AT100 immunohistochemistry and AT8 ELISA.

Result

We then investigated efficacy in reduction of tau pathology in mouse tauopathy models. Treatment with our vectorized antibody resulted in durable antibody expression in the CNS and a corresponding reduction in CNS insoluble pathological tau and neurofibrillary tangles.

Conclusion

Our results indicate that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies.
High precision plasma Aβ42/Aβ40 ratio detects early amyloid deposition in non‐demented elderly adults
Authors: Shi Dai , Zhang Lei , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2021

Background

Plasma Aβ42/Aβ40 ratio measured by an immunoprecipitation and liquid chromatography–mass spectrometry assay showed high accordance with amyloid PET. However, it is still unclear about the risk factors related to plasma Aβ42/Aβ40, whether it can detect Aβ pathology earlier than Aβ PET, and how it relates to tau deposition, neurodegeneration and cognitive decline. In this study, we aim to investigate: 1) the risk factors related to plasma Aβ42/Aβ40; 2) the concordance and discordance of plasma Aβ42/Aβ40 and Aβ PET, and their associations with tau deposition at follow‐up and perspective changes of Aβ PET, neurodegeneration and cognition in cognitively unimpaired (CU) and mild cognitive impairment (MCI) elderly adults.

Method

We analyzed 181 (97 CU, 85 MCI) ADNI participants with plasma Aβ42/Aβ40, Aβ PET, white matter hyperintensities (WMH), vascular factors, adjusted hippocampal volume (aHCV) measured by structural MRI, 18F‐fluorodeoxyglucose (FDG) PET and memory score obtained within one year. The associations of plasma Aβ42/Aβ40 with age, sex, APOE‐ε4 status, vascular risk factors were tested using Pearson’s correlation or Mann‐Whitney U test. Participants were classified into Plasma±/PET± groups according to the thresholds of plasma Aβ42/Aβ40 and Aβ PET (Fig.2A). Longitudinal changes of Aβ accumulation, aHCV, FDG PET and cognition, and tau PET measured at a mean of 5.32±1.24 years later were compared among different Plasma±/PET± groups.

Result

We found older age, APOE‐ε4 carrier and greater WMH burden (Fig.1) were significantly related to reduced plasma Aβ42/Aβ40. Plasma Aβ42/Aβ40 may become abnormal earlier than Aβ PET. Plasma+/PET‐ individuals were accumulating Aβ burden in early‐affected brain regions (Fig. 2), had no evidence of tau deposition, neurodegeneration and cognitive decline at follow‐up (Fig. 3), suggesting Plasma+/PET‐ individuals are very likely in the very early stage of Alzheimer’s disease (AD).

Conclusion

In summary, our results suggest that age, APOE4 carrier and white matter lesion may be related to lower plasma Aβ42/Aβ40. Individuals with abnormal plasma Aβ42/Aβ40 but normal Aβ PET may be at early stage of Aβ pathology, are significantly accumulating Aβ in AD typical cortical regions. These findings may provide useful reference for screening Aβ+ participants by using plasma Aβ42/Aβ40.