bluuebunny/crossref_metadata_2025 huggingface dataset:
Supporting anti‐tau antibody trials using computer simulation of spatial tau propagation
Authors: Geerts Hugo , Rose Rachel , Walker Mike
Published: December 2021

Background

Although tau pathology is a major driver of AD pathology, the mere complexity of tau biology significantly hampers the identification and validation of the most impactful target. Recent clinical trials using antibodies against various forms of tau have come up short in improving cognitive readout.

Method

A Quantitative Systems Pharmacology computer platform of tau biology has been developed including tau species diversity, neuronal activity‐dependent tau secretion, tau binding to membrane surface receptors, subsequent internalization at the synaptic cleft and along the axonal membrane following a diffusion gradient, slow motor‐mediated axonal transport, intracellular degradation and templating of monomeric tau by seed‐competent tau to form higher‐order aggregates. Polysynaptic progression is implemented by modeling secretion from the first synapse and uptake in the second axon.

Result

The platform was calibrated to reproduce preclinical experiments from in‐vitro cellular assays and after injection of brain extract in Tg models. The model is humanized using published data on seed‐competent tau from postmortem AD brain at different Braak stages and spatio‐temporal progression over neuronal projections. By exploring the effect of target mediated drug disposal of antibodies, we show that depending upon the disease state only between 15 and 30% of misfolded tau protein can be captured by antibodies currently in clinical trials. Introducing PSP specific uptake parameters from preclinical experiments, the simulations suggest an even lower efficacy due to the higher affinity of PSP‐tau for membrane surface receptors. We further identify conditions under which specificity (i.e. monomeric vs misfolded tau) of antibodies outweigths sensitivity (affinity). Finally, the simulations suggest that reduced oligomerization and increased degradation have a greater impact on the accumulation of seed‐competent tau in distal regions, likely because they act during the long intracellular residence of misfolded tau protein.

Conclusion

Advanced Quantitative Systems Pharmacology computer modeling combining drug exposure with mechanistic modeling allows to ‘humanize’ preclinical experiments and aims to support tauopathy R&D projects.
Sleep and hippocampal function during an associative memory task are influenced by surgical menopause at midlife
Authors: Brown Alana , Gervais Nicole J. , Gravelsins Laura , Nicoll Gina , Rieck Jenny , Almey Anne , Sun Dorothy Leqi , Ge Jennifer Xiangning , Laird Kaz , Reuben Rebekah , Karkaby Laurice , Perovic Mateja , Grady Cheryl , Einstein Gillian
Published: December 2021

Background

17β‐estradiol loss is related to Alzheimer’s disease (AD) risk factors, including disordered sleep and associative memory decrements (Gervais et al., 2017; Rentz et al., 2017). Women have higher risk for AD than men, and those with mid‐life 17β‐estradiol loss due to surgical menopause, including bilateral salpingo‐oophorectomy (BSO) before age 48, have even higher risk (Rocca et al., 2007). Our learning objective was to investigate whether sleep and associative memory in women with BSO (mean age 44‐46) would be comparable to those with spontaneous/natural menopause (SM; mean age 57), and whether 17β‐estradiol‐based hormone therapy (ET) might mitigate these effects.

Method

We assessed sleep using the average of three nights of portable polysomnography (Temec) in women with BSO either taking ET (BSO+ET; n=16), or not (BSO; n=18), and in older spontaneously menopausal women (SM; n=14). Using EEG (Fp1‐Fp2), we obtained sleep staging automatically (Neurobit Technologies). Participants also completed a face‐name associative memory task during functional magnetic resonance imaging. Recognition accuracy and brain activation during encoding were measured.

Result

BSO exhibited reduced sleep efficiency compared to BSO+ET. For BSO, there was no relationship between percent of total sleep time in N3 and hippocampal activation during associative encoding, even though percent of total sleep time in N3 was negatively associated with hippocampal activation during associative encoding in BSO+ET. For all groups, including BSO, lower latency to consolidated N3 correlated with better associative memory accuracy. There were no group differences in associative memory accuracy. In contrast to BSO, SM showed significantly longer latency to consolidated N3 than BSO+ET.

Conclusion

Younger women with BSO have comparable sleep to older women in SM. In younger women with BSO, ET improves sleep efficiency. Further, while associative memory may be disrupted by increased latency to consolidated N3 in all women, BSO and BSO+ET showed similar associative memory accuracy and latency to consolidated N3. Only BSO+ET exhibited a significant correlation between hippocampal activity during associative encoding and time spent in N3, indicating that ET may support the negative relationship between N3 and hippocampal function. Overall, ET in younger women with BSO potentially ameliorates poor sleep and associative memory decrements.
Multimodal evaluation of the melanopsin retinal ganglion cells system in relation to circadian rhythms in Alzheimer’s disease and aging
Authors: La Morgia Chiara , Mitolo Micaela , Santoro Aurelia , Romagnoli Martina , Maserati Michelangelo Stanzani , Evangelisti Stefania , De Matteis Maddalena , Palombo Flavia , Bacalini Maria Giulia , Capellari Sabina , Carbonelli Michele , Park Jason C. , Liguori Rocco , Tonon Caterina , Lodi Raffaele , Carelli Valerio
Published: December 2021

Background

Melanopsin retinal ganglion cells (mRGCs) are deputed to circadian photoentrainment and pupillary light reflex (PLR) regulations. Circadian dysfunction is reported in Alzheimer’s disease (AD) and contributes to dementia. Single‐Nucleotide‐Polymorphisms (SNPs) in clock genes have been associated to AD.

Method

We included 29 mild‐moderate AD and 26 matched controls performing neuroophthalmological evaluation including optical coherence tomography (OCT), actigraphic recordings of rest‐activity rhythms, chromatic pupillometry and brain functional MRI (fMRI) with light stimulation. 84 clock genes were analyzed by NGS and relevant SNPs validated in a larger cohort of AD (n=449) and controls (n=326).

Result

In AD disease duration was 3.9±2.8 years and MMSEc score 20.2±4.2. OCT showed a significant reduction of the infero‐temporal GCL thickness (p=0.036) in AD. Actigraphy did not disclose significant differences for circadian parameters (IS, IV, RA). However, a subgroup of “circadian‐impaired” AD was evident, and most of circadian parameters declined with aging. Pupillometry revealed a significant reduction of PLR peak amplitude in the rod protocol (p=0.006) significantly correlating with aging in AD. Brain fMRI documented the absence of significant responses in AD with sustained blue light stimulation at difference with controls. Genetic analysis in extended AD and control cohorts showed a significant association of the rs30127178 SNP in PER1 gene with AD.

Conclusion

These results demonstrate, by innovative multi‐modal approach, that mRGC system in AD is affected by neurodegeneration. This can be envisaged as a possible biomarker also for conversion from MCI to AD with potential implication for light therapy as a counteracting measure for dementia.
Global Alzheimer’s Platform Foundation® (GAP) development of a transatlantic Alzheimer’s disease clinical trial network
Authors: Dwyer John , Bork Jason , Zisko Leigh , Goldfeder Gabe , Trotter Jennifer , Ritchie Craig W. , Neild Julie , Syson Judi , Draper Kristy
Published: December 2021

Background

The Global Alzheimer’s Platform Foundation® (GAP) was launched in 2015 in response to the critical need to improve the delivery of Alzheimer’s disease (AD) clinical trials. Over 80 AD sites have joined GAP’s growing network (GAP‐Net). While initial efforts were focused on North America, a top priority of the platform was to develop an international trial network.

Method

Development of a transatlantic site network in Europe: (1) Site identification: European sites that participated in the European Prevention of Alzheimer’s Dementia (EPAD) network were approached as well as other leading sites. (2) Program identification: Sites were surveyed to understand what services were needed to improve AD trial delivery. Existing GAP programs that could be optimized in Europe with limited changes were identified along with new programs. (3) Infrastructure development: Europe‐specific agreements, regulatory strategies, and communication plans were developed to ensure alignment with the global mission. Evaluation and onboarding processes were also developed.

Result

Site identification: Over 50 sites in Europe are currently onboarding. Sites are located primarily in western Europe. Program identification: Existing GAP programs that can be optimized in Europe will include accelerated study start‐up services, rater certification, transportation support, and recruiting programs (media toolkits, trial videos, social / earned media support, and regional recruitment summits). Programs that will need to be modified or developed include trial design input, prescreening support, education of primary care physicians, and advocacy group collaboration. Infrastructure development: 44 sites have returned surveys and metrics, 20 sites have been approved to join the network, and will be approached to sign the European Network Agreement.

Conclusion

In partnership with leading clinical research sites in Europe, GAP has begun developing a European site network. The processes developed for GAP‐Net in North America will be leveraged to support a GAP European network that can reduce the duration and cost and improve the quality of AD clinical studies. GAP will intensify collaboration with site networks in other countries to share learning and, where possible, to implement GAP‐enabled trials. These efforts will further GAP’s aim of achieving a fully global network of sites to enhance speed, efficiency, and quality of AD clinical trials.
Poor sleep is associated with smaller hippocampal subfields in cognitively normal elderly individuals
Authors: Alperin Noam
Published: December 2021

Background

Sleep quality decreases in normal aging and is manifested in neurodegenerative diseases including Alzheimer’s disease (AD). Hippocampus is a critical structure for brain health and plays a major role in memory. Although recent studies have demonstrated that reduced hippocampal volume is associated with poor sleep quality, the relationship between sleep quality and volumes of hippocampal subfields (HSs) remains unknown. The objective of this study is to investigate associations between self‐reported sleep quality measures and HS volumes in cognitively normal elderly individuals.

Method

Sixty‐seven cognitively normal elderly individuals aged 60 to 83 years with self‐reported Pittsburgh Sleep Quality Index (PSQI) were classified into two groups: 30 normal sleepers with PSQI < 5 and 37 poor sleepers with PSQI ≥5. The two groups were equivalent in terms of age, gender, ethnicity, education, handedness and cognitive performance. HSs were segmented in very high resolution T2‐weighted MRI sequence (with an in‐plane resolution of 0.4×0.4 mm2 and 2 mm slice thickness) using the automatic segmentation of hippocampal subfields (ASHS) tool. The HS Volumes were normalized with respect to intracranial volumes. We compared HS volumes between subjects with normal and poor sleep quality. Furthermore, we evaluated associations between the HS volumes and different sleep quality measures, and between the HS volumes and performance of different cognitive tests.

Result

Compared to normal sleepers, poor sleepers exhibited lower normalized volumes in the left cornu ammonis field 1 (CA1) (p=0.020), dentate gyrus (DG) (p=0.008) and subiculum (p=0.018). Global PSQI was significantly and negatively associated with the normalized volumes of the left CA1 (r=‐0.266), left DG (r=‐0.295) and left subiculum (r=‐0.276). Sleep duration was significantly associated with normalized volumes of the bilateral CA1 (left: r=0.428, right: r=0.438), DG (left: r=0.381, right: r=0.367), left CA2 (r=0.231) and subiculum (r=0.219). Verbal memory scores were associated with the normalized volumes of left CA1 (r=0.382).

Conclusion

We found association between poor sleep quality and volume decreases in multiple HSs. Improving overall sleep quality, especially sleep duration, could prevent or slow volume loss of the HSs, which are associated with cognitive decline and onset of mild cognitive impairment (MCI) and AD.
Identifying predictive factors of patient dropout in Alzheimer’s disease clinical trials
Authors: Crimin Kimberly , Allen Patricia J , Abba Iman , Ahlberg Corinne , Benz Luke , Lau Hiuyan , Liu Jingshu , Melhem Fareed , Fisseha Nahome , Florian Hana
Published: December 2021

Background

Improving retention of clinical trial participants plays a vital role in developing treatment and prevention strategies for Alzheimer’s disease (AD). Participant retention is critical to maintaining statistical power, preventing scientific error, and minimizing bias in research (Grill JD, et al., 2020). The purpose of this analysis was to identify factors that are predictive of participant dropout in AD trials using pooled data from randomized clinical trials run on the Medidata platform. These factors can be used to improve operational aspects of future trial design as well as to support patients with prevention strategies during future trials.

Method

8,103 AD patients from 7 completed Phase 3 clinical trials were included in the analysis. The follow‐up time across studies was 1.4 ± 1.6 years (m ± sd) and the dropout rate was 21.2 ± 10.8%. A limited set of clinical and operational data were standardized across trials using proprietary machine learning algorithms combined with human review. Factors were assessed by survival analysis using Cox proportional hazards modeling. A 70/30 train‐test split was used to evaluate model performance in the prediction at baseline of dropouts within 3, 6, and 12 months of the trial. Additional models specific to dropouts due to reasons other than adverse events (AE) or death were also explored.

Result

The models were observed to predict dropouts at an acceptable level above random guessing with an ROC‐AUC ≥ 0.60 within 3, 6 and 12 months. However, the models typically overestimated the probability of dropout, leading to more false positives and reduced precision overall (PR‐AUC < 0.24). Several patient and site factors were associated with increased risk of dropout, including age, race, certain medical histories and AEs (e.g. anxiety), friend as caregiver, low surrounding population density & the size of the clinical staff at the site. Significant interactions between factors were also identified.

Conclusion

This study offers additional evidence that a combination of patient‐ and site‐specific factors influence risk of patient dropout in AD trials. These results both confirmed hypotheses of subject matter experts and suggest additional factors for consideration in planning future AD clinical trials, including supportive care for patients.
Effect of Alzheimer’s pathology on the functional architecture of memory networks during rest and task states in aging
Authors: Cassady Kaitlin , Adams Jenna N. , Chen Xi , Maass Anne , Harrison Theresa M. , Ziontz Jacob , Baker Suzanne L. , Jagust William J.
Published: December 2021

Background

Intrinsic brain networks are relatively consistently organized between rest and task states in young individuals. We performed this study in order to determine whether the same is true in aging, and whether measures of AD pathology affect this relationship.

Method

We used task‐based (mnemonic discrimination task with object and scene stimuli) and rest fMRI to measure functional connectivity (FC) in an anterior temporal (AT) and posteromedial (PM) network in older (OA; N=49, 74±5 years, 31F) and younger adults (YA; N=24, 27±4 years, 9F). We calculated the correlation between rest and task FC states by conducting a Pearson’s correlation between the rest and task FC matrices for each participant. We used PiB‐PET to measure global Aβ (using threshold of 1.065 to classify OA as PiB+/‐) and FTP‐PET to measure tau within an AT and PM composite ROI in OA. We also measured recognition memory performance during the mnemonic discrimination task requiring discrimination of repeated stimuli from lures.

Result

Resting state and task FC in the ATPM network were less correlated in older compared to younger adults. In addition, less correlated rest vs. task FC was associated with higher levels of FTP in ATPM networks in PiB+ older adults. Finally, less correlated rest vs. task FC was associated with worse recognition performance (among all participants and OA alone) during the object trials.

Conclusion

These findings link AD pathology to disruption of the functional architecture of intrinsic brain networks during rest and memory task states in OA. They also suggest that memory decline in some older adults may be influenced by the extent of change in functional architecture between rest and task demands. Overall, dynamic FC changes from rest to task may provide a novel mechanism in which aging impacts cognition.
How many Black men in cognitive intervention trials? A persistent barrier to equity
Authors: Forrester Sarah N , Thorpe Roland J , Hill Carl V , Whitfield Keith E
Published: December 2021

Background

There has been sparse attention paid to the cognition of older men and potential race differences in cognitive ability among older men. Men’s health disparities are likely to continue to increase in the next few decades, likely due to an aging baby boom cohort; increases in racial diversity in the US; and increases in life expectancy among both Black and White men. Our objective was to examine the completed cognitive intervention trials to ascertain the proportion of Black men and racial differences in such trials.

Method

We conducted a scoping review of reported cognitive intervention trials between the years 2000 and 2020. We searched PubMed, Google Scholar, CINHAL, Cochrane, and Clinicaltrials.gov for cognitive intervention trials using the following MeSH terms – “cognitive intervention”, “mild cognitive impairment”, “dementia”, “Alzheimer’s disease”, and “cognitive disorder”. Inclusion criteria included U.S, based interventions intended to improve cognition.

Result

We found 293 unique trials that met our search terms of which 66 were included for final analysis. The rest were excluded due to not being in the US, only including healthy participants, and use of non‐cognitive interventions. We were able to assess the number of Black men in 9 out of the 66 trials, because the trials were either all White (n=8) or all Black (n=1). Of the 9 trials we could assess, 8 had no Black participants (thus no Black men) and the one with all Black participants had 21% men. Of the remaining 57 trials, 32 did not report race and 25 included race and sex data but did not include race‐sex categories and thus we were unable to determine the number of black men included.

Conclusion

We were unable to determine if cognitive intervention trials included sufficient proportions of Black men due to non‐reporting of race, race‐sex categories, and lack of inclusion of Black persons in trials. Our results beg the question of how we can understand cognitive health disparities and improve representation in trials if we don’t include the information that would allow us to make that determination.
Male sex is associated with an increased risk of developing cognitive impairments
Authors: Wang Ge , Li Wei
Published: December 2021

Background

It is inconclusive on how sex works as a risk factor for developing mild cognitive impairment (MCI) or dementia.

Method

A secondary data analysis was performed on data collected from participants enrolled at Alzheimer’s Disease Research Centers funded by National Institute on Aging. There were two inclusion criteria: 1) participants were free of dementia at the baseline visit; 2) every participant must have at least one follow‐up visit. A Cox proportional hazards model was used to investigate how sex affects the risk of developing cognitive impairments.

Result

During a follow‐up period of more than 10 years, male participants had a slightly higher incidence than female participants for either MCI or dementia. Not surprisingly, a higher prevalence was also observed in male than female participants for either MCI or dementia. Although both sexes had comparable lifespan in years, male participants had a higher mortality rate than their female counterparts.

Conclusion

The male sex is associated with a higher risk for developing cognitive impairments along the aging process.
Feasibility of short imaging protocols for [18F]PI‐2620 tau‐PET in progressive supranuclear palsy
Authors: Song Mengmeng , Scheifele Maximilian , Barthel Henryk , van Eimeren Thilo , Beyer Leonie , Marek Ken , Eckenweber Florian , Palleis Carla , Finze Anika , Kaiser Lena , Kern Maike , Nitschmann Alexander , Biechele Gloria , Katzdobler Sabrina , Bischof Gerard N , Hammes Jochen , Jessen Frank , Saur Dorothee , Schroeter Matthias L. , Rumpf Jost‐Julian , Rullmann Michael , Schildan Andreas , Patt Marianne , Neumaier Bernd , Stephens Andrew W , Rauchmann Boris‐Stephan , Perneczky Robert , Levin Johannes , Classen Joseph , Höglinger Günter , Bartenstein Peter , Boening Guido , Ziegler Sibylle , Villemagne Victor L L , Drzezga Alexander , Seibyl John P , Sabri Osama , Brendel Matthias
Published: December 2021

Background

Dynamic 60‐minute positron‐emission‐tomography (PET) imaging with the novel tau radiotracer [18F]PI‐2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). We now aimed to investigate if shorter acquisition and static time windows of [18F]PI‐2620 tau‐PET can be used for imaging of patients with PSP.

Method

We evaluated 37 patients at five different centers with probable or possible PSP Richardson syndrome (PSP‐RS) together with ten HCs. [18F]PI‐2620 PET was performed by a dynamic 60 minute scan. Distribution volume ratios (DVRs, multilinear reference tissue model 2, cerebellar reference) were calculated using full and truncated scan durations (0‐60, 0‐50, 0‐40, 0‐30, and 0‐20 minutes p.i.). Standardized uptake value ratios (SUVrs, cerebellar reference) were obtained from static imaging windows with 20 minutes duration (20‐40, 30‐50, and 40‐60 minutes p.i.). All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP‐RS from HCs in predefined subcortical and cortical target regions (effect size, receiver operating area under the curve (AUC), multi‐region classifier). Finally, we tested if shorter [18F]PI‐2620 PET imaging can also be applied to patients with Alzheimer’s disease (n=11).

Result

The effect size of 0‐50 and 0‐40 DVR was equivalent to 0‐60 DVR (averaged Cohen’s d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0‐30 or 0‐20 DVR. The 20‐40 SUVr indicated the best performance of all short static acquisition windows (averaged Cohen’s d: 0.99). The globus pallidus internus discriminated patients with PSP and healthy controls at a similarly high level for 0‐60 DVR (AUC: 0.96), 0‐40 DVR (AUC: 0.96), and 20‐40 SUVr (AUC: 0.94). The multi‐region classifier sensitivity of these time windows was consistently 86%. 0‐40 DVR showed similar performance in Alzheimer’s disease when compared to 0‐60 DVR.

Conclusion

Short dynamic acquisition and static imaging windows can be used for [18F]PI‐2620 PET imaging of PSP. 0‐40 minute dynamic scanning offers the best balance between accuracy and economic scanning and is may also be suitable for [18F]PI‐2620 PET imaging of Alzheimer’s disease.
Association of dual impairment in physical performance and cognition with cognitive change over two years in older adults
Authors: Peng Tao‐Chun , Chen Yen‐Ching , Chen Ta‐Fu , Chiou Jeng‐Min , Chen Jen‐Hau
Published: December 2021

Background

Dementia has a great impact in the ageing world. Much of the growing will happen in low and middle income regions, especially in Asia and Africa. Identifying the target population before clinical symptoms is most important for early intervention of preventing dementia. Recently, the concept of motoric cognitive risk syndrome has been introduced. However, the analogue of this syndrome is poorly evaluated. Therefore, we aim to explore the association of dual impairment in physical performance and cognition with cognitive impairment.

Method

This cohort study is part of the ongoing Taiwan Initiative of Geriatric Epidemiological Research. A total of 315 participants aged 65 and older were identified between 2015 and 2017 at the University Taiwan University hospital with a two‐ year follow‐up (2017‐2019). Dual impairment were defined as the concurrence of slow gait speed (< 1 m/s) and poor cognitive domain or low grip strength (< 28kg for men and < 18kg for women) and poor cognitive domain. Cognitive impairment was defined as the lowest tertile of the change of Taiwanese version of Montreal Cognitive Assessment (MoCA‐T) over 2 years. Logistic regression models were used to evaluate the association between dual impairment and the change of cognitive function adjusted for age, sex, education, and apolipoprotein e4 status.

Result

The mean age of this population was 75.17 years old. Forty‐eight participants (15.24%) with dual impairment of low handgrip strength and low verbal fluency were identified. Multivariable analyses showed that dual impairment of low grip strength and low verbal fluency increased the risk of cognitive decline [adjusted odds ratios (aOR)=2.42, 95% confidence interval (CI)=1.20−4.88]. However, dual impairment of slow gait speed and low verbal fluency were not associated with cognitive decline (aOR=1.62, 95% CI=0.94–2.78).

Conclusion

Our findings indicate that older adults with dual impairment of low grip strength and low verbal fluency were at a higher risk of cognitive impairment, which emphasizes the importance of complexity in pre‐dementia syndrome. Further research is warranted to clarity the underlying mechanisms of cognitive impairment and opportunities for early intervention.
Classified biomarker panel with tau microtubule binding regions identifies pathophysiological changes in Alzheimer’s disease continuum
Authors: Horie Kanta , Barthelemy Nicolas R. , Sato Chihiro , Li Yan , McDade Eric , Bateman Randall J.
Published: December 2021

Background

Accumulations of tau aggregates and amyloid plaques in brain are hallmarks of Alzheimer’s disease (AD). Recent studies in characterizing tau species, especially phosphorylated tau‐181 (p‐tau181) and p‐tau217 in AD brain and biofluids suggested that these species start increasing at preclinical stage, correlate with amyloid plaques, and improve the diagnosis. However, it is still unclear if these changes in p‐tau reflect tau pathology in AD. Recently, we identified truncated tau species containing microtubule binding regions, e.g., residues 243‐254 (MTBR‐tau243) and 299‐317 (MTBR‐tau299), associate with tau pathology in AD brain. In this study, we show how these MTBR‐tau change and correlate with p‐tau species in AD cerebrospinal fluid (CSF). We discuss the potential use of these composite biomarker panel to understand whole AD continuum.

Method

We established methods to quantify more than dozen of CSF tau species including MTBR‐tau and p‐tau, using immunoprecipitation or chemical extraction followed by mass spectrometry analysis. These methods were applied to CSF analyses of several sporadic AD cohorts. Subsets of the participants were assessed for brain tau aggregation measured by positron emission tomography (PET) to investigate the correlations with various CSF tau biomarkers.

Result

CSF MTBR‐tau were specifically increased in amyloid positive group. Especially, MTBR‐tau299 showed the most significant increase even in preclinical stage and discriminated amyloid status (AUC=0.923), whereas the correlation with tau‐PET measure was moderate (Spearman r=0.458) and the increase was saturated at high tau‐PET measure. MTBR‐tau243 showed the best correlation with tau‐PET measure (Spearman r=0.759) in all tau species quantified in this study and no saturation was observed. MTBR‐tau299 was the most highly correlated with p‐tau217 (Spearman r=0.849), suggesting MTBR‐tau299 is highly corresponding to amyloid pathology. Notably, the phosphorylation occupancy at p‐tau217 was also saturated at high tau‐PET measure as seen in MTBR‐tau299.

Conclusion

MTBR‐tau complement p‐tau to classify biomarker panel to stage AD, reflecting tau as well as amyloid pathology in whole AD continuum. Of note, it remains to be addressed if p‐tau217 increases in response to amyloid plaques rather than tau tangles.
Executive dysfunction is the earliest sign of preclinical Alzheimer’s disease detected by regional Ab‐PET SUVr in the precuneus and posterior cingulate cortex
Authors: Ali Doaa , Barber Justin M. , El Khouli Riham H. , Gold Brian T. , Harp Jordan , Van Eldik Linda J. , Wilcock Donna M. , Jicha Gregory A.
Published: December 2021

Background

Amyloid (Aβ) deposition occurs many years or even decades before the appearance of cognitive decline (preclinical Alzheimer’s disease (pAD)). The diagnosis of pAD is based on biomarker positivity using diagnostic tests such as amyloid‐PET that can provide regional quantification of Aβ deposition in the brain. The precuneus and posterior cingulate gyri are thought to represent the earliest brain regions affected by AD pathology. The present study sought to explore the associations of amyloid‐PET standardized uptake value ratio (SUVr) positivity with global, executive, and memory‐specific domain involvement in pAD.

Method

Ninety‐nine clinically‐normal, aged participants with Montreal Cognitive Assessment (MoCA) scores ≥ 23 that had undergone amyloid‐PET scanning were analyzed. The participants were divided into two groups based on SUVr in the posterior cingulate and precuneus gyri (SUVR≥1.17). Between group differences in MoCA, Trail Making Test (TMT), and California Verbal Learning Test‐II (CVLT‐II) scores were analyzed using two‐sided independent t test.

Result

The sample included 45 participants in the pAD group and 54 participants in the healthy control group that did not differ in age or education. Statistically significant between group differences were seen for TMT B, TMT B‐A and MoCA (p = 0.006, 0.001 and 0.034, respectively). No significant differences were seen between groups in delayed recall measures on the CVLT‐II.

Conclusion

While the prevailing view in the field suggests that early memory change is the hallmark of AD, the present data demonstrate that changes in executive function may be the earliest signs of pAD. Ongoing and future efforts at developing more sensitive tests for preclinical executive function deficits may serve as the most sensitive, low cost, non‐invasive clinical biomarkers of pAD.
Risk factors and association of cognitive impairment among older adults with concurrent vision and hearing impairment: A scoping study
Authors: Jaiswal Atul , Gupta Shikha , Santhakumaran Sangeetha , Holzhey Peter , Aubin Gabrielle , Dumassais Shirley , Wittich Walter
Published: December 2021

Background

The concurrent loss of vision and hearing, termed dual sensory impairment (DSI), can have a significant impact on one’s functioning. Evidence is emerging on the prevalence of DSI in the older population, including those with cognitive impairment (CI). In the context of an ageing population with increasing prevalence of DSI, we aimed to synthesize existing evidence on the association of CI with DSI and identify risk factors for the development of CI in older adults with DSI, establishing its relevance to primary prevention.

Method

The scoping review was performed using Arskey and O’Malley’s framework (2005). In June 2020, eleven scientific databases (CINAHL, Embase, Global Health, Mednar, OAIster, OpenGrey, PsycEXTRA, PsycINFO, PubMed, Web of Science, and WorldWideScience) were searched using index terms and keywords relating to CI and DSI. To be included, studies had to be empirical, peer‐reviewed, had older adults with DSI as the focal population, and have explored the concept of CI as an impairment of one or more cognitive domains, such as memory, attention, or executive functions. The screening of the retrieved studies was completed using Covidence, and relevant data were extracted using an a priori data extraction tool.

Result

Out of 11,595 identified sources, 56 articles were included. Twelve studies reported the prevalence of CI in older adults with DSI, while 20 reported risk factors for CI in older adults that could be applied to older adults with DSI as well, such as depression, hearing impairment, and social isolation. Thirteen studies presented DSI alone as a risk factor for CI in older people. Seven studies reported other risk factors for CI in older adults with DSI, such as non‐sensory comorbidities, illiteracy, physical inactivity, and gender.

Conclusion

Our review indicates that further population‐based longitudinal research is needed to explore the association between CI and DSI and identify whether there are risk factors that are unique for CI among older adults with DSI. With the prevalence of DSI increasing in the older population, robust evidence is needed to inform the recommendations regarding screening, assessment and management of CI in older adults with DSI.
Identifying amine fragments as potential inhibitors of acetylcholinesterase and butyrylcholinesterase through in silico analysis and validation through in vitro enzyme inhibition analysis
Authors: Kandasamy Saravanan , Loganathan Chitra , Sakayanathan Penislusshiyan , Subramani Karthikeyan , Marimuthu Dinesh Kumar , Ravichandran Saravanan , Sivalingam Vignesh , Thayumanavan Palvannan
Published: December 2021

Background

The cholinesterases [ChEs; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] which are involved in cholinergic neurotransmission are target for drug development against cognitive dysfunction in Alzheimer’s disease. The search for novel ChEs inhibitors with improved biological profiles continues to be of great interest. Currently know inhibitors of ChEs such as galatamine, tacrine, donepezil and rivastigmine are amine‐based compound. Keeping this view, in the present study virtual screening was carried out to identify the potential amine fragment that interacted with the ChEs in in silico. The selected molecules were analyzed by molecular docking and molecular dynamics simulation. The best interacted molecule in in silico was further characterized for its inhibition against AChE and BChE in in vitro.

Method

High Throughput Virtual Screening (HTVS) of various amine fragments was carried out in Schrödinger suite. Identified top ten molecules were subjected to molecular docking analysis using Induced Fit Docking (IFD) module. Molecular dynamics (MD) simulation of top three scored compounds were carried out to understand the stability of the interaction with ChEs. In silico quantum crystallography studies was done to understand the involvement of functional group in the interaction with ChEs. In vitro inhibition and kinetic analysis of these compounds against ChEs was performed to determine the inhibitory constant and type of inhibition.

Result

Among the amine compounds screened, three compounds 2‐aminoquinoline (2AQ), 2‐aminobenzimidazole (2AB) and 2‐amino‐1‐methylbenzimidazole (2AMB) was identified to interact with ChEs with lowest docking score. Further MD simulation confirmed the stable binding of these compounds in the active site of the ChEs. Topological and electrostatic properties of intermolecular interactions between these compounds with ChEs showed that amine group played important role in interacting with protein structure. These amine compounds inhibited the BChE and different molecular forms of AChE at micromolar concentration. Kinetic analysis revealed the mixed‐type of inhibition.

Conclusion

Amine fragments screened for interaction with ChEs in in silico. Three compounds (2AQ, 2AB and 2AMB) showed better interaction in molecular docking and molecular dynamics analysis. These compounds showed inhibition against ChEs in in vitro.
Association of pulmonary function with cognitive trajectories and structural brain differences: A population‐based cohort study
Authors: Wang Jiao , Song Ruixue , Qi Xiuying , Ma Jun , Bennett David A. , Xu Weili
Published: December 2021

Background

The relation of poor pulmonary function (PF) to cognitive trajectories and the mechanisms behind the relation remains unclear. We aimed to investigate the association of poor PF with cognitive decline in different domains and structural brain volumes.

Method

Within Rush Memory and Aging Project, 1377 dementia‐free subjects were followed up to 21 years. PF was assessed with a composite score (tertiled as the lowest, middle, and highest) based on peak expiratory flow, forced expiratory volume in 1 second, and forced vital capacity measured at baseline. Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually constructed from 19 cognitive tests. A sub‐sample of the participants (n=373) underwent brain magnetic resonance imaging (MRI), and total, regional brain (white matter, gray matter) and white matter hyperintensities volumes were assessed. Data were analyzed using linear mixed‐effect models and linear regression models.

Result

At baseline, the PF score was ranged from ‐2.36 to 3.47. In multi‐adjusted mixed‐effect model, compared with the highest PF, the lowest PF was related to decline in global cognition (β=‐0.039, 95% CI: ‐0.054 to ‐0.024), episodic memory (β= ‐0.053, 95% CI: ‐0.072 to ‐0.033), semantic memory (β= ‐0.032, 95% CI: ‐0.048 to ‐0.015), working memory (β= ‐0.028, 95%CI: ‐0.041 to ‐0.014), visuospatial ability (β= ‐0.027, 95% CI: ‐0.042 to ‐0.013), and perceptual speed (β= ‐0.038, 95% CI: ‐0.053 to ‐0.022). In MRI data analysis, the lowest PF was associated with smaller volumes of total brain (β= ‐29.61, 95% CI: ‐45.25 to ‐13.98), white matter (β= ‐12.62, 95% CI: ‐23.56 to ‐1.68), and gray matter (β= ‐16.95, 95% CI: ‐28.93 to ‐4.96), but greater white matter hyperintensities (β= 0.214, 95% CI: 0.094 to 0.334), compared to the highest PF.

Conclusion

Low PF accelerates cognitive decline in global cognition, episodic memory, working memory, semantic memory, visuospatial ability and perceptual speed. Neurodegeneration and vascular lesions in the brain may underlie the association of PF with cognitive decline.
The relationship of regional abdominal adiposity and adiposity‐related factors with cognitive functioning among middle‐aged individuals at high Alzheimer’s dementia risk
Authors: Boccara Ethel , Golan Sapir , Ravona‐Springer Ramit , Inbar Yael , Yore Iscka , Heymann Anthony , Beeri Michal Schnaider
Published: December 2021

Background

Obesity in midlife has been consistently associated with late‐life cognitive decline and Alzheimer’s dementia (AD). Obesity is typically assessed by body mass index (BMI) rather than specific anatomical location of stored excess fat. These fat depots can affect the secretion of adipose‐related factors that in turn may affect AD risk. In this study we examined whether regional abdominal adiposity and adiposity‐related secreted factors are related to cognition in middle‐aged adults at high AD risk due to a parental history of AD.

Method

Participants were from The Israel Registry for Alzheimer’s Prevention (IRAP) study following middle‐aged offspring of Late‐Onset AD patients (N=390). To date, 46 participants who have complete cognitive assessment (summarized as global cognition and four cognitive domains—episodic memory, executive functions, language and working memory) have also been scanned for hepatic and pancreatic adiposity, and abdominal adipose tissue (AAT) via magnetic resonance imaging (MRI). Adiposity‐related factors primarily secreted by the liver (PAI‐1), visceral fat (TNF‐α), and the pancreas (PYY) were quantified by MILLIPLEX® MAP for 26 participants. Linear regressions examined the association of regional fat and adiposity‐related factors with cognition adjusting for age, sex, education, and BMI.

Result

Participants (52% women) averaged 51.5 (SD=5.5) years of age, 17.3 (SD=2.1) years of education. Higher AAT was associated with lower global cognition (r=‐0.347, p=0.024), executive function (r=‐0.471, p=0.024) and approached significance for language (r=‐0.301, p=0.053). Higher hepatic fat was associated with lower executive functions (r=‐0.334, p=0.031) and the association of higher pancreatic fat with poorer executive function approached significance (r=‐0.273, p=0.081). All three adipose‐related secreted factors were associated with lower executive functions (PAI1 (r=‐0.635, p=0.003), TNF‐α (r=‐0.478, p=0.033) and PYY (r=‐0.420, p=0.065)) but not with global cognition or other cognitive domains.

Conclusion

Higher regional abdominal adiposity and related secreted factors were associated with poorer cognitive functions, especially executive functions, already in midlife, in asymptomatic individuals enriched for AD risk, and regardless of global body fat measured by BMI. By AAIC 2021, we anticipate 100 IRAP participants will be assessed for regional abdominal adiposity and adipose‐related factors. Targeting regional adiposity is expected to prevent or delay cognitive decline, and ultimately AD.
Disparities in dementia and AD biomarkers in the ARIC study: The important contribution of social determinants of health
Authors: Gottesman Rebecca F. , Schneider Andrea L.C. , Rawlings Andreea , Power Melinda C. , Walker Keenan A. , Wruck Lisa , Wong Dean F. , Jack Clifford R. , Knopman David S. , Mosley Thomas H.
Published: December 2021

Background

Dementia disproportionately impacts people of color in the U.S.. Whether these disparities are due to differences in vascular risk factors, cognitive reserve, or AD pathophysiology remains unclear.

Method

Black and White participants from four U.S. communities were recruited into the Atherosclerosis Risk in Communities (ARIC) study at ages 45‐64. Vascular risk factors were evaluated in midlife and at multiple visits over 30+ years, as were markers of cognitive reserve, with expert classification of dementia. In participants with brain MRI, brain volumes were evaluated in association with dementia. In nondemented participants in the ARIC‐PET ancillary study, florbetapir PET scans were used to quantify brain cortical amyloid; differences in levels by race, vascular risk factors, and white matter hyperintensities (WMH) were evaluated.

Result

In 15744 ARIC participants, dementia was more common in Black vs White participants. Although midlife vascular risk factors were related to dementia, the impact of these risk factors on dementia risk and cortical volumes didn’t differ by race. Lower education was nonsignificantly more strongly associated with dementia in Blacks vs Whites, and an APOE e4 allele was more strongly associated with dementia in Whites. In ARIC‐PET (N=322), vascular risk factors from midlife were associated with PET amyloid, without similar associations for late‐life risk factors; these associations did not significantly differ by race. WMH volume was more strongly associated (cross‐sectionally) with PET amyloid in Blacks vs Whites, but differences were not statistically significantly different. Finally, Blacks had an over two‐fold increased odds of elevated florbetapir PET vs Whites, independent of vascular risk factors, demographics, WMH volume, cognitive status, and APOE genotype.

Conclusion

Consideration of racial disparities in dementia should consider vascular risk, cognitive reserve, and social determinants of health, across the life course. Vascular risk factors do not appear to differentially impact dementia risk or brain amyloid in Blacks vs Whites, but the greater prevalence of these risk factors in Blacks must be considered. Although the A/T/N framework may clarify underlying biology contributing to Alzheimer’s disease, inclusion of these additional factors is needed to understand and reduce racial disparities in dementia rates.
Cognitive decline related to substance consumption in a Colombian kindred with familial Alzheimer's disease: A retrospective cohort study
Authors: Ramos‐Perez Claudia Patricia , Villalba Arvey Camilo , Garcia Jenny , Lanata Serggio , Lopez Hugo Elias , Aguirre‐Acevedo Daniel C , Lopera Francisco
Published: December 2021

Background

Substance use is a presumed risk factor for Alzheimer's Disease (AD). So, it would be essential to evaluate it in people who already have a high risk of dementia. Neuroscience Group of Antioquia, GNA, is a research group from Medellin, Colombia, which studies Presenilin 1 (PS1) E280A mutation carriers. These carriers will course four stages of AD: 1) asymptomatic Pre‐Mild Cognitive Impairment (Pre‐MCI), 2) symptomatic pre‐MCI, 3) MCI; and 4) Dementia. Substance consumption could modify age‐at‐onset of those stages, but this association has not been deeply explored.

Method

We performed a retrospective cohort study with 163 subjects enrolled between January 25, 2019, and April 29, 2020. Of those participants, 69 (42.3%) were non‐carriers, and 94 (57.7%) were carriers. A psychiatrist interviewed the subjects through the "CACoS" questionnaire, an instrument specifically designed for this research. The subjects' cognitive information included CERAD test battery, MMSE, CDR, and a subjective memory complaints checklist. We analyzed the relationship between the onset of AD stages and substance consumption through a time‐to‐event analysis (survival analysis and Cox proportional hazards regression).

Result

For dementia onset, there was an association with less than one time per month of alcohol consumption in the last year (HR 0.42, CI 0.18‐0.96). For MCI onset, there was a relationship with less than one time per month of alcohol consumption in the last year (HR 0.39, CI 0.17‐0.91), and also with consumption of 5 to 11 drinks per day of consumption in the previous twelve months (HR 0.12, CI 0.01‐0.99). For pre‐MCI onset, there was a relationship with daily coffee consumption throughout life (HR 2.37, CI 1.07‐5.25).

Conclusion

A low frequency of alcohol consumption could be protective against MCI and dementia, but coffee was associated with Pre‐MCI acceleration. It would be critical to continue exploring these substances' role as modifiable risk factors soon.