bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted Musashi1 knockdown leads to reduce tau pathology and improves cognitive function in aged P301L mouse model
Authors: Montalbano Mauro , Fung Leiana , Bhatt Nemil , Gaikwad Sagar , Bittar Alice , Puangmalai Nicha , Sengupta Urmi , Kayed Rakez
Published: December 2022

Background

The buildup of toxic tau species in the brain is thought to lead to the development of Alzheimer’s disease. While our current understanding of the mechanisms underlying this aggregation is limited, growing evidence has pointed to RNA‐binding proteins (RBPs) playing a role. The dysregulation of RBPs is associated with various neurodegenerative diseases. For example, during amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD), dysregulated TDP‐43 accumulates in the brain. Similarly, our recent studies showed that the RBP, Musashi‐1 (MSI1), may co‐aggregate with toxic tau oligomers in Alzheimer’s disease. Clarifying the connection between these two proteins may provide novel insights into the mechanisms behind toxic tau buildup in Alzheimer’s, allowing for new therapeutic targets in treatment development.

Method

In this study, we investigated the role of MSI1 on the aggregation and deposition of tau in aged (18‐months old) P301L mouse models, which express the P301L mutant form of tau. MSI1 expression was knocked down (KD) by performing intracerebroventricular injections of MSI1 antisense oligonucleotides into the hippocampus. The effects of MSI1 KD on tau accumulation and pathology were studied in the hippocampus, cortex, and cerebellum.

Result

Western blot and immunofluorescence (IF) analysis revealed a significant reduction in MSI1 and tau proteins levels and aggregation in the P301L mouse brain, mainly in the hippocampus. Furthermore, brain Co‐IF microscopy and Dot Blot analysis of the PBS‐ and Sarkosyl‐soluble fractions showed that there was a significant reduction of MSI1 and tau oligomeric species in the hippocampus, cortex, and cerebellum in MSI1 KD mice. In addition, phosphorylated tau forms (pSer422, pSer202/Thr205, pThr212/Ser214 and pThr231/Ser235) were significantly decreased in the cortex, cerebellum, and most prominently, in the hippocampus. Increase in synaptic marker Synaptophysin suggesting an increase of synaptogenesis. Behavioral tests, Novel Object Recognition (NOR) and Y‐Maze spontaneous alternations tests, MSI1‐KD mice showed significant improvements.

Conclusion

These results suggest that MSI1 plays a major role in tau toxicity, revealing it as a possible target for treating Alzheimer’s disease.
Determining the amyloid PET and CSF inclusion criteria for the SKYLINE secondary prevention study with gantenerumab
Authors: Schiffman Courtney , Bittner Tobias , Giacobino Caroline , Hansson Oskar , Stomrud Erik , Rowe Christopher , Sperling Reisa A. , Delmar Paul , Fontoura Paulo , Ostrowitzki Susanne , Doody Rachelle S.
Published: December 2022

Background

SKYLINE is a secondary prevention study in Alzheimer's disease (AD) enrolling amyloid‐positive, cognitively normal (CN) individuals at risk for clinical AD between 60–80 years and treating them with gantenerumab or placebo for 4 years. There is no gold standard for determining amyloid positivity for this purpose. Thresholds for amyloid positivity used in trials in symptomatic AD may be suboptimal in a secondary prevention setting, where amyloid positivity prevalence is lower. We compared various amyloid‐positive definitions in a CN elderly population based on how well they enrich for clinical progression over 4 years and operational feasibility.

Method

Four cohorts (ADNI, BioFINDER‐1, AIBL, and HABS) were used to explore the relationship between amyloid PET visual read, centiloid values and CSF pTau/Abeta42 values in a CN population. For amyloid PET, we compared visual read with centiloid thresholds by evaluating the amyloid positivity prevalence, magnitude and variability of endpoint progression, and positive and negative predictive value (PPV and NPV). Operational advantages of CSF motivated a comparison of elevated CSF pTau/Abeta42 thresholds with amyloid PET. We interrogated which CSF thresholds were robust to preanalytical differences, had a high PPV and NPV compared with amyloid PET, and resulted in an acceptable degree of cognitive decline and variability.

Result

Higher centiloid thresholds (≥40 CL) showed good agreement with visual read, but visual read resulted in a lower coefficient of variation (CV) for change from baseline in PACC5, the primary endpoint in SKYLINE (CV=118–210 vs. CV=150–336). An elevated CSF pTau/Abeta42 threshold resulted in a similar amyloid positivity prevalence to amyloid PET (14–17% vs. 10–20%), had acceptable NPV (95–97%), PPV (69–87%), sensitivity (71–82%), and specificity (95–98%) for visual read, and resulted in a similar CV for change from baseline in PACC5.

Conclusion

There is no gold standard for determining the optimal amyloid positivity threshold in a secondary prevention trial. Determining patients to be amyloid‐positive if they are amyloid PET visual read‐positive or have elevated CSF pTau/Abeta42 offers not only operational advantages but also likely results in a trial population that has an acceptable level of endpoint progression and variability over the trial duration.
Association between markers of left atrial cardiopathy and cognitive decline in the absence of atrial fibrillation
Authors: Li Zhe , Marion Danielle , Blair Jessica , Soliman Elsayed Z. , Gladstone David J. , Kamel Hooman , Manuel Doug , Edwards Jodi D.
Published: December 2022

Background

Whether atrial cardiopathy is independently associated with cognitive impairment in the absence of atrial fibrillation (AF) remains unknown. This longitudinal cohort study aims to investigate associations between markers of left atrial cardiopathy and cognitive decline, and to identify longitudinal trajectories of cognitive decline in aging adults without AF over time.

Method

A cohort of adults ≥45 years of age with no prior AF or cognitive impairment (N=21,869) was ascertained from the REGARDS (Reasons for Geographic and Racial Differences in stroke) prospective cohort study database. Markers of left atrial cardiopathy included atrial premature complexes (APCs) and N‐Terminal pro‐Brain Natriuretic Peptide (NTpro‐BNP). Cognitive status was measured using Six‐Item Screener (SIS) and an SIS score <5 was defined as cognitive impairment. Cox proportional hazards regression was used to estimate the cause‐specific hazard for primary (cognitive impairment) and secondary outcomes (stroke). Cognitive status trajectories were identified using latent class growth models. Baseline characteristics associated with each trajectory were identified using multinomial logistic regression.

Result

During a mean follow‐up of 9.9 years, 6,060 participants had incident cognitive impairment and 876 had a stroke. APCs increased the hazard of cognitive impairment by 10% (hazard ratio [HR], 1.10, 95%CI: 1.00‐1.20) and stroke by 9% (HR, 1.09, 95%CI: 1.01‐1.18). Elevated NTpro‐BNP increased the hazard of cognitive impairment by 55% (HR, 1.55, 95%CI: 1.17‐2.04) and stroke by 35% (HR, 1.35, 95%CI: 1.13‐1.60). Three unique cognitive trajectories were identified: while 85% showed a normal and stable trajectory of SIS scores, 13% showed a progressively decreasing trajectory, and 2% showed a dramatic decrease in SIS scores. Age, coronary artery disease, diabetes, and NTpro‐BNP were all associated with worse cognitive trajectories.

Conclusion

We showed that markers of left atrial cardiopathy including APCs and elevated NTpro‐BNP were associated with an increased risk of cognitive impairment and stroke in the absence of AF. Adults with these markers followed three unique longitudinal cognitive trajectories. These findings indicate that markers of left atrial cardiopathy (APCs and NTpro‐BNP) may have significant implications for early diagnosis and prevention of cognitive impairment.
Exercise‐Associated Signaling Reduces Tau Accumulation and Neuroinflammation in P301S MAPT Transgenic Mice
Authors: Cortes Constanza J , Birnbaum Allison , Nobles Amber C , Matthews Ian , McGraw Megan
Published: December 2022

Background

Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism‐modifying functions in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a potential new regulator of the neurocognitive benefits of exercise.

Method

We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E‐B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity and reduce neuroinflammation in the aging CNS. To directly test the potential neuroprotective effectsof enhancing skeletal muscle proteostasisin AD‐associated pathologies, we derived cTFEB;HSA‐Cre transgenic mice in the P301S MAPT background. This is a well‐characterized model of fronto‐temporal dementia and neurofibrillary tangle toxicity and has been previously shown to benefit from exercise interventions.

Result

We detected a significant reduction in the accumulation of hyperphosphorylated tau [AT8 phospho‐tau antibody] in whole hippocampal lysates and in the dentate gyrus of cTFEB;HSACre;P301S mice compared to their single transgenic P301S littermate controls. Nanostring nCounter®AD panel analysis reveals displayed reductions in microglia activation modules in P301S MAPT/cTFEB:HSACre hippocampi, suggesting reduced neuroinflammation. We also determined that these CNS benefits in P301S MAPT/cTFEB:HSACre mice were accompanied by activation of exercise‐associated neurotrophic signaling and reduced markers of advancing tau‐associated pathologies in the hippocampus.

Conclusion

These provocative results suggest that enhanced skeletal muscle proteostasis modifies the accumulation of pathogenic tau isoforms and reduces neuroinflammation in the CNS of P301S MAPT mice via activation of exercise‐associated signaling in the CNS.
Variability Independent of Mean Blood Pressure as an Electronic health record‐based Measure of Dementia Risk
Authors: Driver Matthew , Ebinger Joseph , Cheng Susan , Tan Zaldy S
Published: December 2022

Background

The risk of developing Alzheimer’s Disease and Related Dementias (ADRD) is associated with visit‐to‐visit blood pressure (BP) variability, including variability independent of the mean (VIM).1,2 The association between ADRD and VIM has primarily been evaluated using standardized BP measurements from clinical trials and cohorts, rather than utilizing measurements from clinical practice, potentially limiting generalizability to the real‐world context. As such, we sought to evaluate the relationship between ADRD and BP VIM utilizing real‐world data collected from the electronic health record (EHR).

Method

We studied all patients with repeated BP measurements and without a prior diagnosis of ADRD across ambulatory visits within a high‐volume academic healthcare system from 2013 to 2016. Using EHR data, we calculated BP VIM for all patients during the first 4 years of the study period and followed all patients through the end of 2019 or most recent office visit, whichever came first. The primary outcome of interest was incident ADRD, defined by presence of ICD‐10 codes for ADRD or prescription for dementia medication. We used multivariable adjusted Cox proportional hazards models to examine risk of incident ADRD associated with increasing BP VIM.

Result

We identified 46,703 patients with repeated BP measurements over 730,721 ambulatory visits between 2013 and 2016. In multivariable analyses, higher levels of both systolic (HR, 95% CI: 1.26, 1.15‐1.38) and diastolic (1.15, 1.04‐1.27) BP VIM were positively associated with risk of incident dementia (Figure A). In subgroup analyses, results were similar when stratified by age, diabetes, prior stroke, renal disease, and hypertension (Figures B‐D). For both systolic (p = 0.036) and diastolic (p = 0.043) BP VIM, risk of incident dementia was higher among patients below the age of 60 compared to those 60 and older.

Conclusion

Visit‐to‐visit variability in BP, a measure readily ascertainable from the EHR, is associated with increased risk for incident dementia independent of mean BP in the context of a high‐volume, real‐world patient care setting. These findings indicate the EHR derived VIM may serve as an additional tool in risk assessment for incident ADRD. Future research is needed to determine efficacy of targeted interventions aimed at lowering BP variability in clinical practice.
Biomarker modelling of Alzheimer's disease using in vivo Braak staging
Authors: Therriault Joseph , Pascoal Tharick A , Lussier Firoza Z , Tissot Cécile , Bezgin Gleb , Servaes Stijn , Benedet Andréa Lessa , Ashton Nicholas J. , Karikari Thomas K , Rodriguez Juan Lantero , Wang Yi‐Ting , Arias Jaime Fernandez , Massarweh Gassan , Soucy Jean‐Paul , Saha‐Chaudhuri Paramita , Blennow Kaj , Zetterberg Henrik , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2022

Background

Gold standard diagnostic methods for AD rely on staging systems to measure disease severity, which have not yet been incorporated into the in vivo biological research framework for AD. The topographical information conferred by tau‐PET offers the potential to translate the gold standard histopathological Braak staging system to living individuals.

Method

Using the topographical information from [18F]MK6240 tau‐PET, we applied the Braak tau staging system to 324 living individuals. We used PET‐based Braak stage to model the trajectories of amyloid‐b, phosphorylated tau in cerebrospinal fluid (pTau181, pTau217, pTau231, pTau235) and plasma (pTau181, pTau231), neurodegeneration and cognitive symptoms.

Result

PET‐based Braak stages were We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau‐PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III‐IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, while Braak stages V‐VI were incompatible with normal cognition. Follow up tau‐PET scans indicated sequential progression of in vivo Braak stages over time, with progression beyond Braak stage III requiring the presence of amyloid‐beta abnormality.

Conclusion

Our results support PET‐based Braak staging as a framework to model the natural history of AD, as well as monitor AD severity from presymptomatic to clinical dementia phases.
Tau‐Neurodegeneration mismatch reveals vulnerability and resilience in Alzheimer’s continuum and Non‐Alzheimer’s pathophysiology
Authors: Lyu Xueying , Duong Michael Tran , Xie Long , Richardson Hayley , de Flores Robin , DiCalogero Michael , McMillan Corey T , Robinson John , Trojanowski John Q , Grossman Murray , Lee Eddie B , Irwin David J. , Dickerson Brad C. , Xie Sharon X , Nasrallah Ilya M. , Yushkevich Paul A. , Wolk David A. , Das Sandhitsu R.
Published: December 2022

Background

In previous work (Das et al., 2021), we exploited the non‐specific nature of neurodegeneration by investigating the amount and spatial pattern of deviation from the level of neurodegeneration (N) expected for a given level of tau (T). Using a data‐driven clustering approach based on T‐N mismatch, we found phenotypes that had greater N than expected for T (“vulnerable”) and phenotypes with less N than expected for T (“resilient”) in specific patterns. Here we extend this work to include amyloid positive (A+) and negative (A‐) participants. The logic of inclusion of A‐ individuals is that areas of mismatch in A+ individuals is likely driven by factors outside of AD pathology, which can be present in the absence of AD pathology.

Method

We employed cortical thickness to represent N and 18F‐flortaucipir tracer uptake as T for 104 bilateral cortical regions of interest (ROI) in 343 symptomatic individuals including both A+ and A‐ from ADNI. We established T‐N robust regression and partitioned participants based on thresholded residuals. Longitudinal trajectories of cognitive scores were assessed with linear mixed‐effects model effect models using CDRSB as the dependent variable.

Result

We replicated prior work and obtained clusters with distinct T‐N mismatch patterns. We defined the largest group as “canonical”, as it displayed typical T‐N relationships (N∼T, low residuals). The limbic vulnerable cluster displayed N>T (negative residuals) in limbic regions, while diffuse vulnerable group displayed N>T throughout the cortex. Alternatively, the resilient (N<T, positive residuals) clusters were classified as limbic resilient or prefrontal resilient based on the pattern of this relationship. Note the highly similar regional patterns of the A+ and A‐ subgroups, supporting our hypothesis that this residual reflects non‐AD related phenomenology which could be present irrespective of amyloid status. Phenotypes differed in longitudinal cognitive trajectories. The vulnerable clusters declined significantly faster than the canonical cluster regardless of amyloid status likely attributable to the presence of non‐AD pathologies. The resilient groups tended to progress less than the canonical group.

Conclusion

Our findings suggest T‐N mismatch depicts vulnerability and resilience likely attributable to non‐AD factors. This may provide an approach for detecting co‐pathologies in AD continuum and benefiting therapeutic management.
Canada’s changing dementia landscape: Preliminary findings from The Landmark Study
Authors: Armstrong Joshua J. , Stiff David , Baraké Evelyn , Smetanin Paul , Guimond Josée , Sivananthan Saskia
Published: December 2022

Background

As with many nations, the prevalence of dementia in Canada is expected to rise dramatically in the upcoming decades as the population ages. The Landmark Study is aimed at updating these estimates and the broader population changes associated for the Canadian population made in the 2010 Rising Tide Report.

Method

Using the Canadian Centre for Economic Analysis’s socio‐economic statistical analysis platform, a simulation model was developed using demographic characteristics (age, sex, ethnicity) and risk factors for dementia to forecast the burden of dementia in Canada over the next 30 years. This approach allows for comparisons across sex, ethnicity, provinces, while accounting for population dynamics including immigration. The model was also used to examine how a delay in incidence (1‐year, 5‐years, 10‐years) would impact prevalence and incident cases.

Result

As expected, the model forecasts the number of Canadians with dementia to more than double in the next 30 years: 493,718 (2020; 59.6% female) to 1,296,707(2050; 61.2% female; Figure 1). With changing immigration patterns, the ethnic background of people with dementia will be quite different than today. People with Asian origin could increase from 8% of people with dementia today to 24% by 2050 (Figure 2). The changes are driven both by future immigration, and people who have already immigrated to Canada in the past. Delays in onset of 1 year would avoid over 300K cases, whereas a deferred incidence of 10 years would bring Canadian dementia rates to lower than where it is today (Figure 3). With the increase in prevalence of dementia, comes an increase in the number of informal caregivers and the number of hours providing care to persons living with dementia. The number of informal caregivers in 2020 (349,551; 472.6 million hours/year) is projected to increase in 2050 to 1,005,815 (1,386 million hours/year; Figure 4).

Conclusion

This study forecasts rising dementia prevalence in Canada, illustrates the changing landscape of ethnicity in Canadians living with dementia, and estimates the population‐level impacts of interventions that delay onset of dementia would have on prevalence, incidence, and informal care.
Diagnosing Alzheimer Disease: Which Dementia Screening Tool to Use in Elderly Puerto Ricans with Mild Cognitive Impairment and Early Alzheimer Disease?
Authors: Rodriguez‐Santiago María A. , Sepulveda Vanessa , Valentin Eric Miranda , Arnold Steven E. , Jiménez‐Velázquez Ivonne Z. , Wojna Valerie
Published: December 2022

Background

Most of the time, Alzheimer Disease (AD)’s diagnosis is not made at its earliest periods and prodromal stages, for instance at Mild Cognitive Impairment (MCI) and Early Alzheimer Disease (E‐AD) stage. Commonly, AD’s diagnosis is made when significant impairment interferes with the habitual daily activities (1). Our pilot study, serves to demonstrate a correlation between the screening tools, including the Mini‐mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating Scale (CDR), and the biological biomarkers in the cerebral spinal fluid (CSF) (Amyloid Beta 1‐42 (Aβ42 pg/mL), Tau proteins (tTau (pg/mL) and tTau/Aβ42 ratio in Puerto Ricans > 55 years old with MCI and E‐AD. To our knowledge, this is the first study trying to create a correlation between memory tests scores and underlying AD pathology to improve early detection in elderly Puerto Ricans.

Method

Thirty participants were evaluated including, demographics, clinical characteristics, memory scales and CSF biomarkers. CSF biomarkers (Aβ42, tTau protein, and tTau/Aβ42 ratio) were determined using the Meso Scale Discovery Platform (MSD). Associations between memory scales (MOCA, MMSE, CDR) and CSF markers were performed using Spearman’s rho correlation.

Result

Our study revealed statistical association in favor of a direct relationship between MMSE and tTau/Aβ42 ratio in CSF (p= .022, 95.00% CI = [‐.69, ‐.07] (Figure 1). We found a trend towards significance with an inverse relationship with MMSE and Aβ42 (p=.069) (Figure 2) and a direct relationship with MMSE and tTau (p= .098) (Figure 3). Besides, MoCA and tTau/Aβ42 ratio had a statistically significant direct relationship (p = 0.035) (Figure 4). There was no significant statistical association between CDR test with CSF biomarkers in elderly Puerto Ricans.

Conclusion

MMSE was the dementia screening test consistently identifying a statistically significant or a‐trend‐towards a significant association with the CSF Alzheimer Disease’ s biomarkers (Aβ42, tTau protein, and tTau/Aβ42 ratio) in elderly Puerto Ricans with MCI and E‐AD. Clinically, > 55 y/o Puerto Rican patients with MCI and E‐AD should be screened with MMSE for a higher likelihood of earlier detection and, thus, initiation of disease‐modifying treatment.
Comparing neuroimaging and cerebrospinal fluid markers of amyloid, tau, and neurodegenerative biomarkers: implications for understanding the biology of the disease
Authors: Gordon Brian A. , Wisch Julie K. , Hobbs Diana A. , McKay Nicole S. , Schultz Stephanie A. , Flores Shaney , Keefe Sarah J. , Dincer Aylin , Ances Beau M , Morris John C. , Schindler Suzanne E. , Fagan Anne M. , Benzinger Tammie L.S.
Published: December 2022

Background

Alzheimer disease (AD) is a complex disorder characterized by changes in amyloid, tau, as well as neurodegeneration. Neuroimaging and cerebrospinal fluid (CSF) assays provide complimentary measures of these pathologies although the Correspondence between such biomarkers is not well elucidated.

Methods

Data from 313 cognitively unimpaired and 59 impaired individuals aged 45 to 91 was drawn from the Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants had neuroimaging, CSF, and clinical data acquired within one year. Neuroimaging variables included summary measures of amyloid (Centiloids from either PiB or Florebetapir), tau (Flortaucipir), and atrophy (MRI cortical signature). CSF variables were the Aβ42/40 ratio, ptau181, and neurofilament light chain (NfL). Biomarker cutoffs were determined using Gaussian‐Mixture modeling as well as a Youden Index to maximally separate cognitively unimpaired individuals from those with a clinical AD diagnosis. Rank order congruence between biomarkers was determined using Kendall correlations (t).

Results

Gaussian Mixture Modeling (dashed lines) and Youden Index (solid lines) approaches produced disparate cutoffs, particularly for neurodegenerative markers (NfL/atrophy) indicating the challenges inherent to binarizing continuous variables (Figure 1). Kendall’s t provide an estimate of pairwise congruence between biomarkers in cognitively unimpaired (CN, CDR=0, upper left diagonal) and impaired individuals (CI, CDR >0, lower right diagonal) (Figure 2). Measures of amyloid had generally high concordance (t ‐0.45 and ‐0.43 for CN and CI respectively ) than those of non‐specific neurodegeneration, which were quite low (t ‐0.16 and ‐0.23). Although ptau181 and tau were moderately related (t 0.21 and 0.23), ptau181 had higher Correspondence with both PET and CSF measures of amyloid. A sequential timing of biomarkers could be clearly seen when plotting z‐scored biomarkers as a function of amyloid PET (Figure 3).

Conclusions

Neuroimaging and CSF markers provide complimentary information and help to deeply phenotype the AD biological cascade. While measures of amyloid are highly congruent, non‐specific markers of neurodegeneration have poor agreement., CSF measures of phosphorylated tau likely index a response to amyloidosis rather than being a marker of tau aggregation.
A More Efficient Outcome for Alzheimer Disease Research: the Item Response Theory Based Score for the Clinical Dementia Rating (CDR®)
Authors: Li Yan , Wang Guoqiao , Xiong Chengjie , Moulder Krista L. , McDade Eric , Hassenstab Jason J. , Aschenbrenner Andrew J. , Benzinger Tammie L.S. , Gordon Brian A. , Fagan Anne M. , Chatterjee Saptarshi , Cheng Yun‐Ju , Bateman Randall J. , Morris John C.
Published: December 2022

Background

CDR sum of boxes (CDR‐SB) is widely used as a primary outcome in Alzheimer disease (AD) research due to its reliability and accuracy. However, it is an ordinal rank measure instead of a continuous measure and therefore may not be able to capture subtle changes in cognition. Additionally, it weights each domain equally, without accounting for the patterns of the responses scores across CDR items. To generate a more optimal score, we developed a bi‐factor model based on the item response theory (IRT) which can account for different response pattern, item difficulty and discrimination level to provide an improved estimate of the dementia severity. We demonstrated the superiority of the IRT score in two independent cohorts.

Method

Baseline item level CDR data from 2949 participants enrolled in the WashU Knight ADRC study were used to develop the IRT model. The best fitting IRT model was then applied to the longitudinal item level CDR data in both the Knight ADRC and DIAN‐TU‐001 (142 participants) studies to generate the IRT scores (a continuous measure) for each participant at each visit.

Result

Correlations between the CDR IRT score and SB were consistent at different visits (0.89 ∼ 0.92 for DIAN‐TU cohort, 0.92 ∼ 0.94 for Knight ADRC cohort). The IRT score had a much larger effect size (> 60% for the DIAN‐TU cohort and > 40% for the Knight ADRC cohort) than that of CDR‐SB when comparing converter to stable cognitively normal participants. For CDR‐SB of 0 group, the IRT score was significantly associated with some of the clinical/cognitive outcomes and biomarkers. For CDR‐SB > 0 group, the IRT score had slightly higher correlations with other outcomes than CDR‐SB. The IRT score correlated better with the estimated age from dementia onset in the DIAN cohort. Using IRT score as the primary outcome in clinical trials could save 10% ∼ 30% of the sample size compared to that of using CDR‐SB.

Conclusion

The CDR IRT score could potentially be used as a more efficient outcome in AD research to gain precision in detecting cognitive decline and improve power (or reduce sample size).
White Matter Degeneration Pathways Associated with Tau Deposition in Alzheimer’s Disease
Authors: Tian Jianqiao , Reid Robert I. , Przybelski Scott A. , Raghavan Sheelakumari , Gebre Robel K , Graff‐Radford Jonathan , Lowe Val J. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi
Published: December 2022

Background

The dynamics of white matter (WM) changes are understudied in Alzheimer’s disease (AD). Leveraging tau deposition measured from Tau‐PET, our goal was to study the association between tau and white matter health using NODDI from multi‐shell diffusion MRI (dMRI). Specifically, we focused on the Neurite Density Index (NDI) from NODDI, which in WM captures the signal from axons.

Method

We identified 251 participants (126 cognitively normal, 58 MCI, 67 dementia) from the Mayo ADRC and Mayo Clinic Study of Aging with Aβ‐PET, Tau‐PET, and multi‐shell dMRI who were Aβ‐positive (mean age of 77 years and 55% male). We limited to Aβ‐positive participants because Aβ deposition accelerates tau deposition. For Tau‐PET, we estimated SUVRs from three regions corresponding to Braak I/II, III/IV, and V/VI (Figure 1.a). To understand the associations between Tau‐PET SUVRs at three Braak regions and NDIs at 30 candidate WM tracts, we implemented three analyses methods ‐ Pearson correlation, linear regression, and multilayer perceptron machine learning regression.

Result

Higher tau burden in all three Braak regions was associated with lower neurite density in 10 significant WM tracts (Table 1). Interestingly, uncinate fasciculus (UNC) was found significantly associated with all three Braak regions. All three analysis methods consistently showed differential involvement of WM pathways for Braak staging such as ‐ Cingulum adjoining Hippocampus (CGH) for Braak I/II regions, Medial Temporal WM (MTWM) for Braak III/IV regions, and Inferior Occipital WM (IOWM) for Braak V/VI regions (Figure 1.b). The linear regression and machine learning regression models also suggested that WM measurements reflected 18‐35% of variance due to tau deposition

Conclusion

We found that CGH and UNC WM were the most impacted ROIs associated with Braak I/II regions as expected. UNC, directly connecting anterior temporal lobes to the orbitofrontal cortex, was a key WM tract identified as important for all Braak I‐VI regions and warrants further investigation in the study of AD progression. This study highlights the significant impact tau deposition may have on WM. This work also demonstrates the feasibility of using NODDI as an informative supplementary imaging modality for monitoring AD progression.
One‐year Longitudinal Stability of Plasma Biomarkers Associated with Dementia in Normal Controls
Authors: Liu H.C. , Chen Hsin‐Hsien , Wang Pei‐Ning , Yang Shieh‐Yueh
Published: December 2022

Background

Regular examinations to assess dementia play a role in its prevention and early diagnosis. Plasma biomarker assays are possibly the most appropriate for routine assessments or monitoring severity of dementia in the clinic. To accomplish this task, the natural changes in biomarker levels over time should be determined first. With this information, the abnormal changes in plasma biomarker levels in longitudinal clinical visits could be determined. However, such studies are very rare.

Method

In this study, 27 subjects with normal cognition were enrolled for a 1‐year longitudinal study. Two of the 27 subjects returned for a follow‐up visit 71 days and 195 days after the first visit. Fourteen subjects returned 112–139 days after the first visit. Four subjects returned 132 and 405 days after the first visit. Five subjects returned 190 days after the first visit. Four participants returned 299 and 344‐405 days after the first visit. Plasma biomarkers of total tau protein (T‐Tau), amyloid β 1‐42 (Aβ1‐42), α‐synuclein and TAR DNA‐binding protein (TDP‐43) were assayed using immunomagnetic reduction (IMR).

Result

The occurrence percentages in the set of recovery rates were 0.8–1.2 and nearly higher than 85% for T‐Tau, Aβ1‐42 and Aβ1‐42xT‐Tau but were 74.1% for α‐synuclein and 77.8% for TDP‐43. Plasma T‐Tau and Aβ1‐42 showed a high degree of longitudinal stability, whereas plasma α‐synuclein showed poor stability over time.

Conclusion

Although there was a certain variation range for the plasma biomarker concentrations compared to baseline in the return visits, the concentration measurements of each biomarker for every normal subject at each visit were below the cutoff values to discriminate Alzheimer’s disease, Parkinson’s disease or frontotemporal dementia from normal controls. These results imply that the risk of misdiagnosis of dementia due to longitudinal instability using plasma biomarkers is low.
Comparing neuroimaging and cerebrospinal fluid markers of amyloid, tau, and neurodegenerative biomarkers: implications for understanding the biology of the disease
Authors: Gordon Brian A. , Wisch Julie K. , Hobbs Diana A. , McKay Nicole S. , Schultz Stephanie A. , Flores Shaney , Dincer Aylin , Keefe Sarah J. , Ances Beau M , Morris John C. , Schindler Suzanne E. , Fagan Anne M. , Benzinger Tammie L.S.
Published: December 2022

Background

Alzheimer disease (AD) is a complex disorder characterized by changes in amyloid, tau, as well as neurodegeneration. Neuroimaging and cerebrospinal fluid (CSF) assays provide complimentary measures of these pathologies although the Correspondence between such biomarkers is not well elucidated.

Methods

Data from 313 cognitively unimpaired and 59 impaired individuals aged 45 to 91 was drawn from the Charles F. and Joanne Knight Alzheimer Disease Research Center. Participants had neuroimaging, CSF, and clinical data acquired within one year. Neuroimaging variables included summary measures of amyloid (Centiloids from either PiB or Florebetapir), tau (Flortaucipir), and atrophy (MRI cortical signature). CSF variables were the Aβ42/40 ratio, ptau181, and neurofilament light chain (NfL). Biomarker cutoffs were determined using Gaussian‐Mixture modeling as well as a Youden Index to maximally separate cognitively unimpaired individuals from those with a clinical AD diagnosis. Rank order congruence between biomarkers was determined using Kendall correlations (t).

Results

Gaussian Mixture Modeling (dashed lines) and Youden Index (solid lines) approaches produced disparate cutoffs, particularly for neurodegenerative markers (NfL/atrophy) indicating the challenges inherent to binarizing continuous variables (Figure 1). Kendall’s t provide an estimate of pairwise congruence between biomarkers in cognitively unimpaired (CN, CDR=0, upper left diagonal) and impaired individuals (CI, CDR >0, lower right diagonal) (Figure 2). Measures of amyloid had generally high concordance (t ‐0.45 and ‐0.43 for CN and CI respectively ) than those of non‐specific neurodegeneration, which were quite low (t ‐0.16 and ‐0.23). Although ptau181 and tau were moderately related (t 0.21 and 0.23), ptau181 had higher Correspondence with both PET and CSF measures of amyloid. A sequential timing of biomarkers could be clearly seen when plotting z‐scored biomarkers as a function of amyloid PET (Figure 3).

Conclusions

Neuroimaging and CSF markers provide complimentary information and help to deeply phenotype the AD biological cascade. While measures of amyloid are highly congruent, non‐specific markers of neurodegeneration have poor agreement., CSF measures of phosphorylated tau likely index a response to amyloidosis rather than being a marker of tau aggregation.
Asian American and Pacific Islanders’ Attitudes on Alzheimer’s Disease and Related Dementias
Authors: Tan Zaldy S , Kremen Sarah , Garg Nimish , Joo Jin Hui , Sicotte Nancy
Published: December 2022

Background

Asian American and Pacific Islanders (AAPI) are the fastest growing minority population in the United States. While 14% of older AAPIs have been reported to experience memory loss and confusion, the prevalence and incidence of Alzheimer’s disease and related dementias (ADRD) in the AAPI population are not well understood. Moreover, little is known about AAPI attitudes on memory loss and confidence in managing ADRD.

Method

We administered an 8‐item survey on attitudes and beliefs regarding memory loss and ADRD to attendees of a virtual conference on brain health. Responses were on a 5‐point Likert scale with range of 1 = strongly disagree to 5 = strongly agree. We analyzed responses (agree/strongly agree vs. disagree/strongly disagree) of AAPI participants and non‐AAPI attendees using chi‐square test.

Result

Fifty‐four participants completed the survey, with majority of respondents aged 65 years or older (56%) and women (72%). AAPI participants (N = 37) self‐identified to be Chinese, Filipino, Indian, Japanese, Korean, Vietnamese, Native Hawaiian or other Pacific Islander. Non‐AAPI respondents (N = 14) self‐identified to be White, Black or African American, American Indian or Alaska Native. We found that compared to non‐AAPI, AAPI individuals were less confident in navigating the healthcare system for persons with ADRD (p = 0.049). AAPI respondents were also less confident in finding community resources for ADRD, though this did not reach statistical significance (p = 0.073). We found no significant differences between AAPI and non‐AAPI participants’ attitudes and beliefs on the normality of memory loss with age, understanding of ADRD as a medical condition, or interest in participating in and understanding of clinical trials for ADRD.

Conclusion

Asian Americans and Pacific Islanders (AAPI) have less confidence in navigating the complex healthcare system for patients with Alzheimer’s disease and related dementias (ADRD). More research is needed to better characterize the differences in prevalence, presentation, challenges, and outcomes of ADRD in the AAPI population.
Evidence of Plasma Biomarkers Indicating High Risk of Dementia in Cognitively Normal Subjects with a History of Stroke, a Family History of Alzheimer’s Disease, Diabetes Mellitus, End‐stage Renal Disease and Obstructive Sleep Apnea
Authors: Pai Ming‐Chyi , Yang Shieh‐Yueh
Published: December 2022

Background

Subjects with comorbidities are at risk for neurodegeneration. There is a lack of a direct relationship between comorbidities and neurodegeneration.

Method

In this study, immunomagnetic reduction (IMR) assays were utilized to assay plasma Aβ1‐42 and total tau protein (T‐Tau) levels in poststroke (PS, n = 27), family history of Alzheimer’s disease (ADFH, n = 35), diabetes (n = 21), end‐stage renal disease (ESRD, n = 41), obstructive sleep apnea (OSA, n = 20), Alzheimer’s disease (AD, n = 65). Thirty‐seven healthy controls (HCs) were enrolled.

Result

The measured concentrations of plasma Aβ1‐42 were 14.26±1.42, 15.43±1.76, 15.52±1.60, 19.74±2.92, 16.52±0.59, 15.97±0.54 and 20.06±3.09 pg/ml in HC, PS, ADFH, diabetes, ESRD, OSA and AD groups, respectively. The corresponding concentrations of plasma T‐Tau were 15.13±3.62, 19.29±8.01, 17.93±6.26, 19.74±2.92, 21.54±2.72, 20.17±2.77 and 41.24±14.64 pg/ml. The plasma levels of Aβ1‐42 and T‐Tau in the PS, ADFH, diabetes, ESRD and OSA groups were relatively high compared to HC group but were lower than AD group.

Conclusion

This evidence indicates the high risk for dementia in these groups from the perspective of plasma biomarkers.
Effect of Concurrent Use of Memantine on The Efficacy of Masupirdine (SUVN‐502): A Post‐hoc Analysis of a Phase‐2 Randomized Placebo‐Controlled Study
Authors: Goyal Vinod Kumar , Pandey Santosh Kumar , Benade Vijay , Shinde Anil K , Rasheed Mohammed Abdul , Badange Rajesh Kumar , Palacharla Veera Raghava Chowdary , Ravulu Jyothsna , Jetta Satish , Subramanian Ramkumar , Nirogi Ramakrishna
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder manifested by progressive deterioration in cognition, memory and activities of daily living. The commonly used treatments in the management of cognitive and memory deficits associated with AD are either minimally effective, provide temporary relief or limited to use in a highly selected population. Selective blockade of serotonin‐6 (5‐HT6) receptors, which are exclusively localized in the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5‐HT6 receptor antagonist with pro‐cognitive properties in animal models of cognition.

Method

The efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio, using permuted blocked randomization. The study consisted of a 2 to 4‐week screening period, a 26‐week double blind treatment period, and a 4‐week washout period. The primary efficacy outcome was the 11‐item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐Cog 11). In post‐hoc analyses, patients were subdivided based on the use of memantine dosage form and memantine plasma concentrations to assess the impact of memantine on the efficacy of masupirdine.

Result

In this exploratory post‐hoc analysis, less worsening of cognition (ADAS‐Cog 11 scores) was observed with masupirdine treatment as compared to placebo in subjects whose trough memantine plasma concentrations were ≤100 ng/mL.

Conclusion

These exploratory and thought provoking observations merit better understanding and further possible investigations of masupirdine effects and its role as a potential future drug in the AD pharmaceutical armamentarium.
Relationship between alcohol consumption and dementia with Mendelian randomization approaches among older adults in the United States
Authors: Campbell Kyle A , Fu Mingzhou , MacDonald Elizabeth , Zawistowski Matthew , Ware Erin B , Bakulski Kelly M
Published: December 2022

Background

Prior research is mixed concerning the association between alcohol consumption, a modifiable factor, and dementia. Genetic causal inference approaches may help elucidate the relationship between alcohol consumption and dementia.

Method

We performed a two‐sample Mendelian randomization study using harmonized, genome‐wide significant (p‐value<10−8), and independent (r2<.001) single nucleotide polymorphisms’ (SNPs) summary statistics from the largest publicly available meta‐analyses of genome‐wide association studies of weekly alcohol consumption (Liu et al., 2019, n = 941,280) and late onset Alzheimer’s disease (Kunkle et al., 2019, n = 21,982 cases, 41,944 controls). Next, in the 2012 wave of the United States Health and Retirement Study (HRS), we employed individual polygenic scores of alcohol consumption via one‐sample Mendelian randomization. Polygenic scores were calculated and standardized within genetic ancestry across 1,399,824 SNPs overlapping Liu et al. without HRS and 23andMe samples (n = 522,159). G‐estimation provided odds ratios (ORs) of the relationship between a standard deviation increase in genetic risk of alcohol consumption and dementia and cognitive impairment without dementia compared to normal cognition in models stratified by genetic ancestry.

Result

Of 99 SNPs associated with weekly alcoholic drink consumption and 71 SNPs associated with late onset Alzheimer’s disease, 59 overlapping and harmonized SNPs met instrument selection criteria. We did not observe evidence of a relationship between alcohol consumption and late‐onset Alzheimer’s disease using the inverse variance weighted two‐sample Mendelian randomization estimator (OR = 1.15, 95% confidence interval (CI):[0.78, 1.72]), nor with complementary estimators. In HRS, Mendelian randomization revealed no relationship between cumulative genetic alcohol consumption risk and cognitive impairment without dementia (African ancestry sample (n = 2,402, OR = 0.86, 95% CI:[0.47, 1.58]); European ancestry sample (n = 9,576, OR = 0.96, 95% CI:[0.86, 1.07])) and dementia in the African ancestry sample (n = 1,908, OR = 0.50, 95% CI:[0.13, 2.00]). Alcohol consumption genetic risk was inversely associated with dementia in the European ancestry sample (n = 8,518, OR = 0.77, 95% CI:[0.62, 0.95]).

Conclusion

Our results largely suggest there is no causal relationship between alcohol consumption and dementia. The protective association observed between alcohol consumption and dementia among those of European ancestry in an aging American cohort may be due to genetic pleiotropy and/or selection bias in our empirical sample within the Health and Retirement Study.
The relationship between everyday functioning and cerebral tau burden in cognitively normal older adults
Authors: Dubbelman Mark A. , Sanchez Justin S , Schultz Aaron P. , Rentz Dorene M. , Amariglio Rebecca E. , Sikkes Sietske A.M. , Sperling Reisa A. , Johnson Keith A. , Marshall Gad A ,   A4 Study team
Published: December 2022

Background

Alzheimer’s disease is characterized by accumulation of amyloid and tau in the brain. While amyloid is hypothesized to accumulate earlier, tau has been shown to be more strongly related to clinical outcomes. Higher‐order cognitive functioning in daily life is a clinically meaningful outcome that has been shown to decline, even in early disease stages. We aimed to understand the cross‐sectional relationship between regional cerebral tau accumulation and everyday functioning in cognitively normal older adults.

Method

We used data from the A4 and LEARN Studies and included participants who underwent tau positron emission tomography (PET) scans using 18F‐flortaucipir (n = 447, age 71.9±4.9 years, 57.5% female). Everyday functioning was reported by both participant and study partner using the Alzheimer’s Disease Cooperative Study Activities of Daily Living‐Prevention Instrument (ADCS ADL‐PI). We dichotomized ADCS ADL‐PI total scores as ≤44 vs 45 (the maximum score). Additionally, based on previous analyses, we focused on four items and dichotomized scores as no difficulty vs. some/a lot of difficulty. We performed logistic regressions adjusting for age, sex and education.

Result

Participants (median 45, range 33–45) and study partners (median 45, range 23–45) reported high levels of everyday functioning. Neither entorhinal nor inferior temporal tau was associated with overall self‐ or study partner‐reported everyday functioning (Table; Figure1). Greater entorhinal tau was associated with study partner‐reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008). Greater inferior temporal tau was associated with self‐reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018). Greater entorhinal and inferior temporal tau were associated with study partner‐reported difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007 and OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005, respectively). Tau was not associated with difficulties remembering current events (Table; Figure2).

Conclusion

Our results suggest a weak cross‐sectional relationship between everyday functioning and tau in cognitively normal older adults. These findings are likely driven by the restricted variability in scores on the ADCS ADL‐PI, which could improve with longitudinal data. Moreover, future work should incorporate a measurement of everyday functioning that has a wider range of performance in this population even at baseline.