bluuebunny/crossref_metadata_2025 huggingface dataset:
When is a biomarker an AD biomarker? Face versus construct validity and practical implications for differential application
Authors: Schöll Michael
Published: December 2021

Background

Tremendous recent developments have expanded the portfolio of biomarkers that have been described as directly specific for Alzheimer’s disease (AD) pathophysiology or assessing its consequences. This presentation will aim to provide a snapshot of the current validation and readiness status of imaging‐ and bodily fluid‐based AD biomarkers for different potential application scenarios.

Method

An overview of AD biomarker characteristics will be provided, focusing on established and emerging positron emission tomography (PET) and blood‐based biomarkers for amyloid‐β (Aβ) and tau pathology as well as glial activation and synaptic and neurodegeneration. Summarizing and discussing the foregoing talks in this session as well as reviewing relevant literature, emphasis will be placed on unique validation and application aspects of the respective biomarkers and on practical considerations.

Result

AD‐related pathophysiology and its consequences can be assessed in vivo directly in the brain or in bodily fluids, most recently also in blood. The underlying modalities differ greatly in how their proposed face validity is confirmed, i.e. how specific the respective biomarker is to disease‐specific processes and how sensitive to longitudinal changes and different disease stages. Specifically, PET enables the direct mapping, quantification, and staging of regional pathology and related processes in the brain, while blood‐based measures generally provide information about peripheral, yet highly associated processes. Both yield continuous measures; however, this information is often discarded in favor of dichotomous, and global, biomarker classification. Novel blood‐based biomarkers have thus been claimed to have diagnostic and prognostic properties comparable with PET modalities. PET is limited to specialized centers, is resource‐hungry and involves radiation, while blood‐based biomarkers promise a scalable and accessible alternative or complement. However, the construct validity of blood biomarkers has hitherto mainly been established against relevant PET biomarkers. Finally, the various levels of harmonization and standardization of biomarker acquisition and analysis have major implications for their potential application.

Conclusion

The field of AD biomarkers is more dynamic than ever. Snapshot evaluations of their current state of validity, their potential use and their practical limitations are needed to establish their potential differential, joint, and complementary roles in AD diagnostics, population screening, clinical trial enrichment, and use as trial outcome measure.
Randomized trial of n‐3 PUFA for cerebral white matter hyperintensities, medial temporal lobe atrophy and white matter integrity in older non‐demented adults: Per‐protocol and ApoE stratified results
Authors: Bowman Gene L , Murchison Charles F , Silbert Lisa C , Dodge Hiroko H , Hagen Kirsten , Lahna David , Harris William S , Kaye Jeffrey A , Quinn Joseph F , Shinto Lynne
Published: December 2021

Background

Blood levels of marine n‐3 PUFA (20:5; 22:6) are inversely associated with cerebral white matter lesion volume (WML), suggesting that n‐3 may offer one approach to reduce this major vascular contributor to cognitive impairment and dementia. This trial determined whether n‐3 slows WML progression and sustains white matter integrity over 3‐years in older non‐demented adults with suboptimum n‐3 status and WML (NCT01953705).

Methods

Double‐blind, placebo‐controlled trial in non‐demented adults age 75 and older with plasma omega‐3 (20:5 + 22:6) < 110 ug/mL and total WML ≥ 5 cm3. Participants were randomized to 1.65 g of n‐3 (975 mg‐20:5, 675 mg‐22:6) or placebo. Primary outcome was the annual WML progression with biomarker‐based ITT, per‐protocol (PP) and APOE4 stratified analysis. Total brain, medial temporal lobe, and diffusion tensor imaging (DTI) of white matter integrity were secondary outcomes. Linear mixed‐effects models were used.

Result

102 participants randomized (51 per group; mean age 81; 60% female, 28% APOE4+), 78 completed 3‐year visit (39 per group). Under mITT, annual WML change was 1.34 cm3 (95%CI: 0.80‐1.88) vs. 1.19 (0.64‐1.74) (p = 0.303) and annual DTI fractional anisotropy (FA) change was ‐0.002718 vs ‐0.001352 (p = 0.069) in the placebo and active, respectively. PPA comparing participants with study exit plasma omega‐3 ≤ 110 ug/mL vs above this threshold exhibited WML change of 1.71 cm3 vs. 0.99 (p = 0.026) and DTI radial diffusivity change of 5.412e06 mm2/sec vs. 3.143e06 (p = 0.047). No effects on WML were observed by APOE genotype (e4 p = 0.196; non‐carriers p = 0.785), however, e4 carriers on placebo had annual DTI FA change of ‐0.005 vs. ‐0.002 in the active arm (p = 0.037).

Conclusion

Omega‐3 did not slow total WML progression in all randomized participants; however, those that superseded the plasma n‐3 threshold established in preliminary studies (110 ug/mL) had 50% and 43% reduction in annual WML and annual DTI RD progression, respectively. These results highlight responders and macro‐and microscopic structural features sensitive to omega‐3 that warrant more extensive studies powered to detect cognitive effects and dementia incidence.

NIH‐National Institute on Aging R01 AG043398 (GLB).
Cognition may improve with medium‐chain triglyceride oil supplementation: A pilot study
Authors: Hillebrandt Heidi L , Dias Cintia B , Barin Edward S , Chatterjee Pratishtha , Shah Tejal M , Basci Ann M , Kaplan Jason , Sohrabi Hamid R , Martins Ralph N
Published: December 2021

Background

Medium‐chain triglycerides (MCT), unlike other type of fats, are quickly digested into medium‐chain fatty acids (MCFA), which are metabolized by the liver into energy in the form of ketones. Ketones are then transported to the brain for energy supply. In Alzheimer’s disease (AD), the brain becomes less efficient in glucose uptake and metabolism, resulting in an energy deficiency. The only backup source of energy for the brain is ketones. In this study we examined the potential for MCT to serve as a fuel source during energy deprivation, such as what is observed in AD.

Method

Healthy males and females aged 50 to 77 years old (n=19) consumed MCT oil (40% caprylic acid, 28% capric acid, 32% lauric acid) for 7 weeks. The National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) neuropsychological battery was administered at baseline, midway and last appointment. Participants could discontinue at any time during the intervention period.

Result

Descriptive statistics determined the data were not normally distributed, therefor a non‐parametric Wilcoxon Rank Test was performed to compare cognitive performance at baseline to mid‐way, and baseline to last appointment. Baseline to mid‐way analyses showed significant (α=.05) improvement in performance for the Continual Performance Task (CPT) (p=0.012), N‐Back‐2 (p=0.049), and anti‐saccade (p=0.036). Baseline to last analyses showed significant improvement (α=.05) in performance for the CPT task (p=0.034), N‐Back‐1 (p=0.027), N‐Back‐2 (p=0.038), and saccades (p=0.036). Both the N‐back‐1 and Saccades measures for baseline to mid‐way analyses approached significance. No significant changes were observed in the remaining tasks of the NIH EXAMINER.

Conclusion

MCT oil may improve working memory, inhibitory processing, problem solving, and motor control in older adults with no currently diagnosed memory problems. However, a further longitudinal study with a larger sample size is required to validate these preliminary results.
Relationship between amyloid and tau levels and its impact on tau spreading
Authors: Dore Vincent , Krishnadas Natasha , Bourgeat Pierrick , Huang Kun , Li Shenpeng , Burnham Samantha C , Masters Colin L , Fripp Jurgen , Villemagne Victor L , Rowe Christopher C
Published: December 2021

Background

Previous studies have shown that Aß‐amyloid (Aß) likely promotes tau to spread beyond the medial temporal lobe. However, the Aß levels necessary for tau to spread in the neocortex is still unclear.

Method

466 participants underwent tau imaging with [18F]MK6420 and Aß imaging with [18F]NAV4694 (Fig. 1). Aß scans were quantified on the Centiloid (CL) scale with a cut‐off of 25CL for abnormal levels of Aß (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus and parahippocampus) using the cerebellar cortex as reference region. Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A‐ subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined.

Result

The plots of prevalence of T+ (Fig. 2) show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aß level between 10‐40 CL reaching 23% in Me, 15% in Te and 11% in R. Between 40‐70 CL, the prevalence of T+ subjects per CL increased four‐fold faster and at 70 CL was 64% in Me, 51% in Te and 37% in R. In cognitively unimpaired (Fig. 3), there were no T+ in R below 50 CL. The highest prevalence of T+ was found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL.

Conclusion

Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aß levels below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aß levels are required before neocortical tau becomes detectable.
Association between birth in the stroke belt and late‐life cognition with assessment of socioeconomic and cardiovascular risk factors: The Study of Healthy Aging in African Americans (STAR)
Authors: George Kristen M , Peterson Rachel L , Gilsanz Paola , Barnes Lisa L , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , DeCarli Charles S , Whitmer Rachel A
Published: December 2021

Background

The Southeastern U.S. (“Stroke Belt”) is known for high rates of cardiovascular diseases and cognitive impairment. Due to the high proportion of Black Americans born in the Stroke Belt and their elevated risk of cognitive impairment, we examined the relationship of birth in a Stroke Belt state with late‐life cognition in The Study of Healthy Aging in African Americans (STAR).

Method

STAR evaluated cognition in African Americans (N=764) ages 50+ who were long‐term Kaiser Permanente Northern California members. Participants completed Multiphasic Health Check‐ups (1964‐1985) at which early adulthood cardiovascular risk factors (CVRF) of body mass index, blood pressure, glucose, and total cholesterol were measured. At STAR wave 1 (2018), participants self‐reported birth state (all participants resided in northern California by the 1980s), childhood and young adulthood socioeconomic status (SES), and completed cognitive assessments using the Spanish and English Neuropsychological Assessment Scales (SENAS). We used linear regression to estimate the association between Stroke Belt birth state with cognition adjusting for birth year, gender, and parental education and evaluating SES and CVRF as potential mediators.

Result

After exclusions for missing data, 27% (n=197) of 728 participants were born in a Stroke Belt state and mean age at cognitive assessment was 69 years (SD=9). Birth in a Stroke Belt state was associated with worse late‐life executive function (β(95% CI): ‐0.18(‐0.33, ‐0.02)) and semantic memory (β(95% CI): ‐0.37(‐0.53, ‐0.21)), but not verbal episodic memory, compared to individuals born elsewhere. Having 2+ SES risk factors (β(95% CI): ‐0.77(‐0.97, ‐0.56)) or 2+ CVRF (β(95% CI): ‐0.20(‐0.37, ‐0.03)) was associated with significantly worse executive function compared to having no SES or cardiovascular risk factors, respectively. Additionally, having 2+ SES risk factors (β(95% CI): ‐0.64(‐0.85, ‐0.43)) was associated with worse semantic memory. Associations of birth in a Stroke Belt state with executive function (β(95% CI): ‐0.07(‐0.23, 0.08)) and semantic memory (β(95% CI): ‐0.30(‐0.47, ‐0.14)) were attenuated after adjusting for SES and cardiovascular risk factors simultaneously (as well as individually).

Conclusion

Birth in a Stroke Belt state has lasting influence on cognitive function that is only partially mediated by childhood and early adulthood SES and cardiovascular risk factors.
Semi‐quantitative [11C]PiB and [15O]H2O PET measures of cerebrospinal fluid dynamics discriminate amyloid load but not cognitive status
Authors: Minhas Davneet S , Laymon Charles M , Lopresti Brian J , Cohen Ann D , Tudorascu Dana L , Mason Neale S , Lopez Oscar L. , Villemagne Victor L , Aizenstein Howard J , Mathis Chester A , Klunk William E
Published: December 2021

Background

Altered interstitial and cerebrospinal fluid (CSF) dynamics have been linked to impaired amyloid clearance in animal models of Alzheimer’s disease (AD). Recent dynamic PET studies using tau and amyloid PET tracers [18F]THK5117 and [11C]PiB have sought to quantify CSF dynamics in humans [de Leon 2017, Schubert 2019]. The aim of this work was to examine the relationships between [11C]PiB and [15O]H2O semi‐quantitative measures of CSF dynamics, efflux and influx, respectively; amyloid load; and cognitive status.

Method

Nineteen participants consisting of n=5 cognitively normal (CN; 71.6±8.9 years, 3 female), 9 mild cognitive impairment (MCI; 68.6±9.9 years, 2 female), and 5 Alzheimer’s disease (AD; 67.0±9.0 years, 0 female) subjects underwent [11C]PiB PET (0‐90min post‐injection, 34 frames), [15O]H2O PET (0‐3min post‐injection, 20 frames), and 1.5T T1 MR imaging. MR images were processed using FreeSurfer 7.1 (FS). Amyloid load status (PiB‐/+) was assessed using a FS Global [11C]PiB 50‐70min SUVR (cerebellar gray matter [GM] reference) and a cutoff of 1.35 SUVR. FS lateral ventricle ROIs were eroded using a 5mm kernel to minimize partial volume contamination from neighboring tissue and used to calculate three semi‐quantitative ventricular CSF outcomes: [11C]PiB ventricular SUVR50‐70 (cerebellar GM reference), [11C]PiB ventricular AUC35‐90 (cerebellar GM reference), and [15O]H2O ventricular influx ratio (IR; 1.0‐3.0min, whole brain reference). Relationships between PET outcomes were assessed using Spearman’s correlations, and group differences across cognitive and amyloid statuses were assessed using the Mann‐Whitney U test.

Result

Eleven subjects were classified as PiB+ (1/5 CN, 5/9 MCI, 5/5 AD). Both [11C]PiB ventricular outcomes were significantly correlated with [15O]H2O IR ([11C]PiB SUVR50‐70 p<0.001; [11C]PiB AUC35‐90 p<0.001). In this population, no significant differences were observed across any pair of diagnostic groups for any of the three ventricular outcome measures (Figure 1). However, significant differences were observed between PiB‐ and PiB+ groups across all three ventricular CSF outcomes (Figure 2; [11C]PiB SUVR50‐70 p=0.033; [11C]PiB AUC35‐90 p=0.041; [15O]H2O IR p=0.001).

Conclusion

The results observed in this population suggest CSF dynamics are altered early in the AD pathophysiological spectrum and are associated with amyloid load. In addition, ventricular CSF dynamics measured using [15O]H2O IR provided greater discriminatory power than [11C]PiB CSF outcomes.
Differentiating memory clinic patients and healthy volunteers using machine‐learning analysis of speech and eye movements during a reading task
Authors: Soroski Thomas , Barral Oswald , Jang Hyeju , Newton‐Mason Sally May , Shajan Sheetal , Tutt Pavan , Granby Saffrin , Rizzo Matteo , Chui Diego , Teng Minnie Y , Chatterjee Atri , Hsiung Ging‐Yuek Robin , Nygaard Haakon B. , Conati Cristina , Carenini Giuseppe , Field Thalia S.
Published: December 2021

Background

Clinical trials investigating novel disease‐modifying therapies for Alzheimer’s disease (AD) are increasingly targeting participants with preclinical or early‐stage neurodegeneration. Artificial intelligence may improve ascertainment of these individuals and thus enrich clinical trial cohorts. We examined classification accuracy of machine learning analysis of speech and gaze data to distinguish memory clinic patients from controls.

Method

We recruited individuals with a clinical diagnosis of AD, mild cognitive impairment (MCI), and subjective memory complaints (SMC) from a subspecialty memory clinic, and controls from the community. Clinical diagnosis was ascertained by trained Behavioural Neurologists aided by cognitive tests and neuroimaging. Participants read a paragraph from the International Reading Speed Texts (IReST). Speech was recorded, automatically transcribed, and manually verified. Eye movements were recorded with an infrared eye‐tracker. Features extracted included lexical and acoustic parameters for speech, fixation and saccade‐related features from gaze, and novel multimodal features leveraging speech and gaze signals in combination. We explored predictive models combining using logistic regression, Gaussian Naïve Bayes classifiers, and Random Forests.

Result

Here we report baseline IReST task data from 60 clinic patients (12% SMC, 30% MCI, 58% AD, mean age 73 ± 9, 52% female) and 66 controls (mean age 65 ± 9, 68% female). Best speech‐based models distinguished patients from controls with an Area Under the ROC Curve (AUC) of 0.75 (95% CI 0.72‐0.78). Best gaze models yielded an AUC of 0.73 (0.71‐0.75). Models integrating speech and gaze data yielded best results with AUC 0.78 (0.76‐0.80). We have previously reported data from a separate task where participants describe the Cookie Theft photo from the Boston Aphasia Battery while undergoing infrared eye‐tracking; the best AUC model combining speech and gaze was 0.80 (0.78 ‐ 0.92).

Conclusion

Machine‐learning based analysis of speech and gaze data demonstrates promising classification accuracy in distinguishing memory clinic patients from healthy controls, particularly when leveraging speech and gaze data in combination. We will explore the additional classification accuracy of combining data from multiple tasks.
Does clinical data capture modifiable midlife risk factors for Alzheimer’s disease?
Authors: Shaaban C Elizabeth , Taneja Sanya B , Witonsky Kailyn F , Malec Scott A , Karim Helmet T , Pratt Sheila , Levine Arthur S , Munro Paul , Boyce Richard D , Albert Steven M
Published: December 2021

Background

The 2020 Lancet Dementia Commission Report highlighted 5 modifiable midlife risk factors for dementia across multiple datasets: hearing loss, traumatic brain injury (TBI), hypertension, alcohol use, and obesity. We tested associations of these risk factors with Alzheimer’s disease (AD) 10 or more years later within clinical care data from a large health system.

Method

We used University of Pittsburgh Medical Center electronic health record data including diagnoses, demographics, social history, and medications from inpatient, outpatient, and emergency visits. Cases were aged 50‐75 at the time of a first ICD‐9 or 10‐based diagnosis of AD between 2016‐2020. Controls were age‐matched to cases 4:1, selected with replacement; they were free from neurodevelopmental, neurodegenerative, or demyelinating disorders, and had a visit from 2016‐2020. Cases and controls had at least one visit 10+ years prior (“early visit”). Risk factors from the early visit were defined as follows: hearing loss and TBI were based on diagnoses; obesity and hypertension were based on diagnoses or 2 measures of body mass index ≥ 30 or systolic blood pressure (BP) ≥ 140 and diastolic BP ≥ 90, respectively; alcohol use was based on diagnoses or self‐reported use ≥ 21 drinks/week. We tested associations of risk factors with AD using logistic regression models; results are presented as unadjusted odds ratios [95% confidence intervals].

Result

Participants had a mean age of 67 in 2016‐2020; N=2382 cases (56% female, 80% white, 19% Black) and N=9528 controls (58% female, 88% white, 10% Black). All midlife risk factors were associated with significantly increased odds of AD. In order of largest to smallest effect size: TBI, 4.5 [4.1, 5.0]; alcohol use, 3.5 [3.0, 4.0]; hypertension 2.6 [2.4, 2.9]. hearing loss, 1.9 [1.7, 2.1]; and obesity, 1.2 [1.1, 1.4]. Narrower definitions of alcohol use and TBI only slightly altered their respective effect sizes.

Conclusion

In agreement with the Lancet Report, we find that these modifiable factors in late‐early to midlife are associated with AD. Information about these risk factors is already captured in clinical electronic health records and should be used to guide dementia risk reduction beginning early in midlife.
INCREASE‐DEPTH: MTM and DEPrescribing THerapy recommendations for medication‐related problems among elderly adults in the INCREASE trial
Authors: Smith Noah I , Huffmyer Mark , Eckmann Lynne , Martinez Ashley I , Beech Brooke F , George Rosmy , Abner Erin L , Jicha Gregory A , Moga Daniela C
Published: December 2021

Background

A growing body of literature supports the hypothesis that cognitive reserve (CR) may offset the characteristic progression of dementia symptomatology. The cognitive function of polypharmacy‐prone populations, such as older adults, can be negatively impacted by various factors, including medication‐related exposures. The INCREASE trial prospectively measures the effect of targeted medication management therapy (MTM) services for medication‐related problem (MRP) reduction, maintaining CR, and delaying AD manifestations.

Method

Community‐dwelling individuals aged ≥65 years, routinely exposed to ≥1 potentially inappropriate medication (PIM), and without baseline dementia were recruited for the INCREASE trial. Pharmacists board certified in geriatrics provided blinded comprehensive medication review (CMR) to identify MRPs (e.g., per 2015 Beers Criteria, drug‐drug/drug‐disease interaction, etc.) for all patient‐reported prescriptions, over‐the‐counter (OTC) drugs, vitamins, and supplements. Individualized risk‐benefit assessments and plans were discussed collaboratively between pharmacists, clinicians, and participants. Recommendations were categorized by medication type and recommendation type (e.g., adjusting medication exposure, non‐pharmacologic intervention, etc.) and identifying potential drug‐drug or drug‐disease interactions.

Result

Of 104 participants recruited for the study, 90 were randomized; mean (SD) age at enrollment was 75.3 (8.5), with 64% female, and 89% Caucasian. Baseline CMRs identified 6.8 (SD 3.6) MRPs per participant, 2.4 (SD 1.3) of which were PIMs per 2015 Beers Criteria (Table 1). Almost half of MRPs involved medications available without a prescription (e.g., acid suppressants, diphenhydramine, vitamins, etc.). CMRs also identified 0.94 (SD 1.35) drug‐drug and 0.98 (SD 1.07) drug‐disease interactions of concern per patient. Recommendations to optimize treatment included switching therapy (27%) or stopping/reducing medication exposure (22%) (Table 2).

Conclusion

CMR and MTM prompts nuanced discussion between healthcare providers and patients, highlighting many drug‐related safety concerns. Certain implicated medications may be potentially associated with CR and/or dementia (e.g., anticholinergics). This analysis describes the baseline MTM recommendations provided by blinded pharmacy specialists in the INCREASE trial before randomization and participant intervention. Final recommendations for those randomized to the intervention were made after the pharmacists‐clinician team met with the participant. Evaluation of CR preservation and delay of AD onset post‐randomization are pending completion of the data collection (anticipated data collection completion by March 31, 2021).
Sex differences in levels of plasma neurofilament light and total tau in adults with Down syndrome
Authors: Dang Lam‐Ha T , Krinsky‐McHale Sharon J , O'Bryant Sid , Pang Deborah , Zigman Warren B. , Silverman Wayne , Schupf Nicole , Lee Joseph H.
Published: December 2021

Background

Plasma neurofilament light (NfL) and total tau (t‐tau) are emerging as promising biomarkers of Alzheimer’s disease (AD) in adults with Down Syndrome (DS). Sex may influence the levels of these biomarkers however, research on sex differences in these biomarkers is limited. In this study, we examined whether sex influences plasma levels and clinical classification accuracy of NfL and t‐tau.

Method

We performed a cross‐sectional analysis of 275 adults with DS (106 males; 169 females) from a community‐based cohort. Levels of plasma NfL and t‐tau were measured using the Simoa platform. Based on consensus diagnosis using a battery of direct neuropsychological testing and informant interviews, participants were classified into three clinical dementia groups: cognitively stable (CS), mild‐cognitive impairment (MCI‐DS) and Alzheimer’s dementia (AD‐DS). Two‐way analysis of covariance was used to assess group differences in males and females, adjusting for age. Post‐hoc pairwise comparisons were adjusted for multiple comparisons using the Bonferroni correction. Receiver operating characteristic analyses were conducted to evaluate the performance of the biomarkers to classify dementia status in males and females, separately.

Result

In this study, 27 (16%) and 10 (6%) females while 12 (11%) and 13 (12%) males exhibited MCI‐DS and AD‐DS, respectively. Females were, on average, 4.5 years younger than males. Age‐adjusted levels of plasma t‐tau (pinteraction = 0.047), but not NfL (pinteraction = 0.138), significantly differed by sex. NfL levels were higher in MCI‐DS and AD‐DS groups than in the CS group in both sexes (all padjusted < 0.05). T‐tau levels were significantly higher in the MCI‐DS and AD‐DS (both padjusted < 0.01) groups than in the CS group in females but did not differ across clinical groups in males. NfL showed excellent accuracy in females (range AUCNfL: 0.74‐0.97) and males (AUCNfL: 0.71‐0.88), while t‐tau showed classification utility in females (AUCt‐tau:0.69‐0.90), but not in males (AUCt‐tau: 0.48‐0.66).

Conclusion

Our findings suggest that levels and accuracy of plasma NfL and t‐tau to classify dementia differed by sex in adults with DS. These differences underscore the need to further elucidate sex specific patterns of fluid biomarkers, critical in the development of personalized medicine approaches in AD.
Visual memory test equal to commonly used verbal memory test in predicting tau in the medial temporal lobe
Authors: Poltronetti Nina Margherita , Arias Jaime Fernandez , Pallen Vanessa , Lussier Firoza Z , Therriault Joseph , Mathotaarachchi Sulantha , Tissot Cécile , Benedet Andréa Lessa , Wang Yi‐Ting , Pascoal Tharick A. , Stevenson Jenna , Rahmouni Nesrine , Bezgin Gleb , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2021

Background

The Aggie Figures Learning Test (AFLT) is a visual memory assessment tool, constructed as an analog to the Rey Auditory Verbal Learning Test (RAVLT). The AFLT includes three sequences of abstract drawings as stimuli –a primary set which is repeated across five trials, an interference set, and a recognition set. After about twenty minutes, the test assesses free delayed recall (DR) and delayed recognition of the learned material. This test is very similar to the RAVLT in terms of administration; therefore, the present study will evaluate whether the predictive value of DR scores from both tests is comparable in relation to Tau PET.

Method

Tau PET ([18F]‐MK6240) was acquired for 130 individuals for analysis involving only AFLT, 139 for analysis involving only RAVLT, and 127 individuals for analysis including both AFLT and RAVLT. Demographic data is shown on Tables 1, 2, and 3. MRI were segmented into probabilistic grey (GM) and white (WM) maps, non‐linearly registered to the ADNI template using Dartel and smoothed with an 8mm FWHM gaussian kernel. Voxel‐wise linear regression models were applied, using VoxelStats, with Tau PET as the dependent variable and either DR AFLT or DR RAVLT as predictors. We ran three analyses where one included both DR scores. Additionally, we corrected for age, sex, diagnosis, APOE, and amyloid load. All other variables that were tested did not significantly contribute to predict Tau PET.

Result

We found negative associations between tau binding in the medial temporal lobe and both DR scores when looking at each of them separately. More importantly, we found that DR AFLT scores lose their predictive value when including DR RAVLT in the same model.

Conclusion

Our results support the use of both tests interchangeably when testing memory in elderly populations, even though they tap into two different modalities. This piece of evidence confirms what was reported by the authors who published the original AFLT article. Nonetheless, that article dealt with a sample whose demographics and clinical presentation strongly differed from those of our sample.
Effects of GERAS DANCE on cognitive function in older adults with and without cognitive impairment
Authors: Hewston Patricia , Kennedy Courtney , Ioannidis George , Merom Dafna , Marr Sharon , Hladysh Genevieve , Papaioannou Alexandra
Published: December 2021

Background

Mild cognitive impairment (MCI) is highly prevalent in older adults aged 60+ with prevalence rates of 16‐20% and one of the first cognitive expressions of Alzheimer's Disease and other dementias. Dance activates many brain regions to integrate complex movement patterns with musical and emotional expression and may lower the risk of dementia over time. We investigated the effect of 12‐weeks of GERAS DANcing for Cognition and Exercise (DANCE) on cognitive function in older adults (aged 60+) with and without cognitive impairment.

Methods

GERAS DANCE is a specialised program tailored for older adults with early memory or mobility problems. It was offered across 12 YMCAs in Southern Ontario, Canada with in‐person classes 2x weekly (1‐hour each) and homework (10‐minutes daily) for a period of 12 weeks. Cognitive function was assessed with the Montreal Cognitive Assessment [MOCA]. Changes in cognitive function from baseline to 12 weeks were evaluated using ANOVA [2 (Time: pre‐ post‐intervention) x 2 (Group: cognitive impairment, no cognitive impairment)].

Result

A total of 106 older adults participated in the analysis (mean age = 76.12 ± 7.03, range 61 to 93 years, 81% female). Overall GERAS DANCE improved cognitive function [F(1,105) = 4.928, p = 0.029]. In older adults with cognitive impairment, the mean difference of MOCA total scores improved by 1.04 points (pre = 21.71 ± 3.34, post = 22.74 ± 4,12).

Conclusion

GERAS DANCE has the potential to improve or maintain cognitive function in older adults with and without dementia. Next steps include testing for efficacy of GERAS DANCE as a part of an overall approach for cognitive health and to inform clinical practice guidelines.
Emotion regulation in mild cognitive impairment and subjective cognitive decline
Authors: Mah Linda , Vandermorris Susan , Verhoeff Nicolaas Paul L.G. , Herrmann Nathan
Published: December 2021

Background

Our previous research in emotional verbal memory in mild cognitive impairment (MCI) and work from others suggest the hypothesis that emotion dysregulation is a signature of Alzheimer’s disease (AD) risk. Whether subjective cognitive decline (SCD), conceptualized as a possible preclinical stage of AD, is associated with emotion dysregulation is unknown. In the current study, we compared responses on the Cognitive Emotion Regulation Questionnaire (CERQ) and behavioural responses on a threat task amongst SCD, MCI, and cognitively unimpaired (CU) older adults.

Methods

The sample included 146 older adults free of lifetime history of psychiatric illness/neurological conditions: 33 MCI [17F, age 72.3(SD7.6)] defined as subjective memory/other cognitive complaints, impaired neuropsychological (NP) test performance, and functional independence, 71 SCD [49F, age 71.1(SD6.3)] based on subjective memory decline with worry with normal NP performance, and 42 CU [27F, age 70.6(SD6.8)] based on absence of subjective memory decline and normal NP test scores. Participants completed the CERQ which assesses cognitive coping strategies in negative emotional situations. A subset (19 MCI, 43 SCD, 19 CU) completed a computerized task in which they rated a physical feature or threat level of faces with varying degrees of threat. Multivariate ANOVA was used to examine group differences, followed by Sidak‐adjusted post hoc comparisons.

Results

On the CERQ, groups differed in use of catastrophizing [F(2, 142)=3.51, P=.032], with a trend for use of rumination (P=.07), attributable to greater use of both strategies in MCI compared to CU (P=.04). On the threat task, groups differed in response latencies to judging physical features of threatening faces relative to neutral [F(2, 78)=3.17, P=.048)]. Relative to CU, SCD participants were slower to make physical judgements of threatening faces compared to neutral (P=.026).

Conclusions

Older adults with SCD do not report greater use of maladaptive emotion regulation strategies compared to CU. However, alterations in behavioural responses to threat versus neutral in SCD may represent deficits in regulating attention towards negative emotional information, similar to mood‐congruent cognitive biases observed in depression. These preliminary data highlight the need to increase our understanding of explicit and implicit emotional processing in older adults at risk for AD.
Telehealth‐based assessment of cognition in older adults during COVID‐19 and beyond
Authors: Cullum Munro
Published: December 2021

Background

Evidence supporting the use of telehealth techniques in the assessment and diagnosis of dementia has been growing steadily. This began with the use of telephone‐based cognitive screening in the 1980s and televideoconference‐based assessments in the 2000s. The COVID19 pandemic brought telehealth suddenly to the forefront of healthcare, particularly for aging and at‐risk populations, as well as for clinical providers and researchers. While clinicians have been challenged to continue to provide patient care in a safe manner, researchers have been faced with the challenge of maintaining study protocols and continuing to advance the science of dementia. Fortunately, a growing body of research has demonstrated the feasibility, reliability, validity, and consumer acceptability of telehealth‐based assessment procedures, including teleneuropsychological (teleNP) techniques.

Method

We first reported results from a study of 202 adults age 50‐85 using a brief battery of common neuropsychological tests administered via teleNP vs in‐person in counterbalanced fashion which showed generally strong intraclass correlations (Cullum et al., 2014). Additional studies have since examined the validity and consumer acceptability of teleNP assessment in older adults, including recent reviews and findings from surveys and observations using teleNP during the COVID19 pandemic.

Result

Our initial investigation revealed essentially equivalent results across teleNP vs traditional in‐person test conditions, with intraclass correlations around .80 and high levels of satisfaction with the procedures. Additional findings revealed validity by the discrimination of impaired and non‐impaired older adults with and without cognitive impairment similar to traditional in‐person assessment. Subsequent studies and reviews have added to this growing body of literature supporting the use of teleNP in older adults.

Conclusion

In this presentation, the literature supporting the evidence for telehealth applications in the assessment and diagnosis of dementia will be reviewed, along with commonly used assessment instruments. A critical review of the strengths and limitations of remote clinical/cognitive evaluations as applied to aging individuals with and without cognitive impairment will be provided, along with practical recommendations for application of these procedures, including in‐home and computerized evaluations. Last, needs, opportunities, and future directions for remote cognitive assessment in clinical and research settings, including large‐scale surveillance and treatment studies, will be discussed.
Utility and usability of brief, remote, and self‐administered cognitive assessment for older adults with intact cognition and mild cognitive impairment: A novel approach to increase access during the COVID‐19 pandemic
Authors: Dorociak Katherine E , Mattek Nora , Lee Jonathan , Leese Mira I , Bouranis Nicole , Imtiaz Danish , Gothard Sarah , Kaye Jeffrey A , Hughes Adriana M
Published: December 2021

Background

Given the COVID‐19 pandemic and necessary restrictions on older adults’ in‐person clinical and research exposure, there is an urgent need for validated cognitive measures that can be self‐administered remotely in the home to expand the reach of cognitive assessment. The current presentation describes the implementation, validity, and usability of the Survey for Memory, Attention, and Reaction Time (SMART) assessment protocol that has been deployed in longitudinal cohort studies of older adults for over two years.

Method

Participants were 69 older adults classified as cognitively intact (n=44) or mild cognitive impairment (MCI; n=25). The SMART was sent to participants via email once per month. Participants completed SMART using their computer (n=55), tablet (n=10), or smart phone (n=4). The SMART consists of four face‐valid cognitive tasks available in the public domain assessing visual memory, attention, processing speed, and executive functioning. Participants also completed a neuropsychological battery and self‐ and informant‐rated measures of everyday cognition. Primary SMART outcomes consisted of subtest completion time; secondary meta‐metrics included outcomes indirectly calculated within the SMART (e.g., click count, total completion time). Analyses were based on initial SMART administration.

Result

Stepwise logistic regression analyses indicated that the SMART executive functioning subtasks (Trails B Completion Time (p=.05) and Stroop Click Count (p=.02)) were the strongest predictors of cognitive status (MCI vs. cognitively intact). Longer Total Completion Time (i.e., worse performance) on the SMART was correlated with reduced global cognition and lower self‐ and informant‐rated perceptions of everyday cognition (p<.05). The SMART was rated as highly usable (M=21.8 out of 25), with no difference in MCI and cognitively intact group scores. Over a three‐month period, 87% of participants completed the SMART within the first three days of receiving it, with 100% completion following a reminder call.

Conclusion

This study provides preliminary support for remote, self‐administered cognitive assessment of cognitively intact and MCI older adults using the SMART. Given the prevalence of executive functioning deficits among non‐amnestic MCI presentations, the SMART may prove particularly valuable for increasing access to cognitive assessment for diverse, heterogenous older adults with increased vascular risk factors, medical comorbidities, and health disparities.
Activity‐dependent dysfunctional gene expression patterns are normalized by in vivo treatment of late‐stage Aβ pathology mice with a TrkB/C small molecule ligand
Authors: Latif‐Hernandez Amira , Moran‐Losada Patricia , Yang Tao , Tran Kevin C , Liu Harry , Butler Robert R. , Massa Stephen M. , Longo Frank M.
Published: December 2021

Background

Neurotrophin signaling via TrkB and TrkC receptors participates in long‐term potentiation (LTP), a biological substrate of memory formation that is disrupted by amyloid‐β (Aβ) in APP mice. In this study, we ask whether there are alterations in activity‐dependent gene expression signatures in APP mice, and if so, could elements of these alterations be restored by prior treatment with a small molecule TrkB/C partial agonist, PTX‐BD10‐2.

Method

We administered PTX‐BD10‐2 (50 mg/kg) or vehicle (VEH) orally once daily to male wild type (WT) and APP mice expressing London and Swedish mutations (APP‐L/S) for 3 months starting at 13 months of age. Paired‐pulse ratios (PPR) and Theta Burst Stimulation (TBS) were applied to acute hippocampal slices, in absence of drug, to induce short and long‐term synaptic plasticity. Upon completion of recordings, we examined whole tissue transcriptomic profiles for differential gene expression and enrichment of ontological terms and pathways.

Result

Pronounced deficits in PPR (at 10 and 20 ms) and LTP were found in APP‐L/S relative to WT slices, and entirely restored in slices from APP‐L/S mice treated with PTX‐BD10‐2 (Fig. 1). To identify candidate mechanisms of this pre/post synaptic plasticity rescue, we examined activity (TBS)‐dependent transcriptomic signatures. Analysis of TBS‐only slices demonstrated alterations in gene expression between WT_VEH_TBS and APP‐L/S_VEH_TBS mice. In particular, significant downregulation of genes in pathways known to be important for synapse function: axoneme, glutamatergic/GABAergic synaptic signaling, neurotransmitter release/transmission and neuronal action potential; and upregulation of gene pathways that are candidates contributing to degeneration in AD and in APP‐L/S_VEH_TBS mice: immune system processes, inflammatory responses, aging and neuron death; when compared to WT_VEH_TBS. Remarkably, the altered expression levels of most of the genes from these pathways were reverted to WT pattern in APP‐L/S_BD10‐2_TBS mice (Fig. 2), thus revealing candidate mechanisms to restore PPR and LTP deficits in APP‐L/S mice.

Conclusion

PTX‐BD10‐2 treatment mitigates Aβ‐related synapse dysfunction and alterations in synapse‐relevant gene expression profiles in APP‐L/S mice in the context of stimulation. These findings point to therapeutic potential of targeting TrkB/C, and moreover, provide a cellular model to identify candidate signaling modules for understanding synaptic impairment and revealing novel therapeutic targets.
Comparison of modifiable risk factors for dementia among rural and urban elderly adults: Data from two cohorts in India
Authors: Lingegodwa Abhishek Mensegere , Sundarakumar Jonas S , Hameed Shafeeq K Shahul , Ravindranath Vijayalakshmi
Published: December 2021

Background

Modifiable risk factors for dementia such as, diabetes, hypertension, dyslipidemia, hyperhomocysteinemia and lack of physical exercise contribute significantly to the etiology of dementia. SANSCOG and TLSA are prospective, community‐based cohort studies of aging population to identify risk and protective factors for cognitive decline and Alzheimer’s disease among individuals more than 45 years of age from rural Srinivaspura and urban Bengaluru respectively, in the state of Karnataka, India.

Method

We have recruited 1860 and 464 participants in SANSCOG (rural cohort) and TLSA (urban cohort) respectively. We calculated prevalence of modifiable risk factors and chi square test was used to determine group difference between both cohorts.

Result

The mean age and year of education in SANSCOG was 58.2years and 4.34years respectively, while in TLSA it was 66.6years and 16.3years.

There was a statistically significant (p<0.001) difference in prevalence of chronic medical conditions between the groups with SANSCOG having low prevalence in hypertension, diabetes mellitus and hyperhomocysteinemia when compared to TLSA. However SANSCOG had high prevalence of dyslipidemia. The average metabolic equivalents (MET) as calculated from GPAQ for SANSCOG cohort was 5200, while it was 2500 for TLSA cohort.

Conclusion

The rural cohort (SANSCOG) has less prevalence of hypertension, diabetes mellitus, and hyperhomocysteinemia, more physically active and higher prevalence of dyslipidemia when compared to urban cohort (TLSA).
Intra‐hemispheric event‐related brain functional connectivity is resilient in patients with amnestic mild cognitive impairment, but not Alzheimer’s disease dementia: A study of event‐related EEG oscillations
Authors: Fide Ezgi , Yener Gorsev
Published: December 2021

Background

Alzheimer’s disease (AD) causes abnormalities in structural and functional brain connectivity in relation to cognitive deficits and disabilities in daily living activities.Electroencephalographic (EEG) techniques revealed the part of those abnormalities based on neurophysiological oscillatory mechanisms underpinning the maintenance of quiet vigilance in AD patients (Babiloni et al.,2020).However, it is poorly known the extent to which the brain functional connectivity based on oscillatory mechanisms may be affected in mild cognitive impairment due to AD (ADMCI) and dementia (ADD) involved in the performance of cognitive tasks.In our previous studies, event‐related (ER) EEG oscillations at delta (<4Hz), theta (4‐7Hz), and alpha (8‐12Hz) frequencies were markedly altered in ADMCI and ADD patients engaged in a classical visual oddball‐paradigm requiring focused attention, short‐term memory, and mental counting (Yener et al.,2009,2014).In the present study, we tested the hypothesis that the brain functional connectivity revealed by the ER‐EEG oscillations may be affected in ADD and ADMCI patients as a function of their clinical status.

Method

We enrolled 67 ADMCI, 44 ADD, and 73 demographically‐matched healthy cognitively‐unimpaired persons.The EEG activity was recorded during a visual oddball paradigm with mental counting. The functional brain connectivity was estimated by computing the imaginary part of coherency (ICoh) from the target‐related EEG activity recorded at electrode pairs. Delta, theta, and alpha frequency bands were considered.ICoh values within the hemispheres were compared among ADD, ADMCI, and control groups by an ANOVA design (p<0.05).

Result

All participants tolerated well the experimental setting after instructions, an adequate support, and a preliminary familiarization with the experimental apparatus.They all performed the cognitive task.Notably, the intra‐hemispheric ER‐ICoh at delta, theta, and alpha bands were reduced in the ADD group as compared to ADMCI and control groups (p<0.05).No statistical differences were observed between ADMCI and control groups (p>0.05).

Conclusion

The results of the present study suggest that the neurophysiological oscillatory mechanisms underpinning the intra‐hemispheric functional connectivity are resilient during a cognitive task engaging visual focused attention and short‐term memory as they are still normal in ADMCI patients.These mechanisms become abnormal in ADD patients possibly in relation to the worsening of cognitive functions and the occurrence of disabilities in daily living.