bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered central and peripheral glutathione in Alzheimer disease and mild cognitive impairment: A meta‐analysis
Authors: Chen Jinghan Jenny , Thiyagarajah Mathura , Song Jianmeng , Chen Qi Zhen , Herrmann Nathan , Lanctôt Krista L.
Published: December 2021

Background

Increasing evidence implicates oxidative stress (OS) in Alzheimer Disease (AD) and Mild Cognitive Impairment (MCI). Depletion of the brain antioxidant glutathione (GSH) may be important in OS‐mediated neurodegeneration, though post‐mortem brain GSH changes in AD have been inconclusive. Recent in vivo measurements of brain and peripheral GSH may shed light on GSH changes, with implications for its role as a biomarker and therapeutic target. Aim: To quantitatively review in vivo GSH in AD and MCI compared to healthy controls (HC) using meta‐analysis.

Method

Studies published before June 2020 containing measurements of in vivo brain or peripheral GSH in MCI or AD with a HC group were identified using Medline, PsychInfo, and Embase. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcomes using random effects models. Outcome measures included brain GSH (Meshcher‐Garwood Point Resolved Spectroscopy (MEGA‐PRESS versus non) in AD and MCI, and peripheral GSH (intracellular versus extracellular) in AD and MCI. The Q statistic and Egger’s test were used to assess heterogeneity and risk of publication bias respectively.

Results

For brain GSH, 4 AD (AD=175, HC=272) and 4 MCI (MCI=254, HC=260) studies were included. For peripheral GSH, 26 AD (ADD=981, HCl=993) and 7 MCI (MCI=434, HC=408) studies were included. Brain GSH did not differ in AD or MC compared to HC; however, the subgroup of studies using MEGA‐PRESS reported lower brain GSH in AD (SMD [95%CI] = ‐1.47 [‐1.91, ‐1.02], p=0.02) and MCI (‐1.08 [‐1.53,‐0.64], p=0.01). Peripheral GSH was lower in AD (‐0.94 [‐1.37, ‐0.51], p<0.001). In a subgroup analysis, intracellular GSH was lower in MCI (‐0.66 [‐1.11, ‐0.21], p=0.02). Significant heterogeneity was observed in all analyses and supported the use of random effect models. Egger’s test indicated risk of publication bias in MCI brain GSH literature.

Conclusion

In vivo measures of GSH in AD and MCI had significant heterogeneity. Peripheral analyses suggested intracellular GSH decreases may be prominent in early disease stages with both intra‐ and extracellular decreases in later stages. Brain GSH may be decreased in AD and MCI but heterogeneity and potential bias indicate the need for measurement standardization and replication.
Oxidative stress biomarkers in individuals with Down syndrome: Implications to the pathogeny of Alzheimer's disease
Authors: de Mendonça Gabriella Ayub , Forlenza Orestes Vicente
Published: December 2021

Background

The concentration and activity of a set of oxidative stress markers in peripheral blood of individuals with Down syndrome (DS), individuals with mild cognitive impairment (MCI) and with Alzheimer’s disease (AD) were determined to study the possibility of AD biomarkers based on oxidative stress.

Method

Plasma was obtained from control individuals (n=30) and individuals with DS (n=30), MCI (n=30) and AD (n=30) and six markers of oxidative stress were analyzed: the plasma concentrations of three markers of lipid peroxidation (malondialdehyde, 4‐hydroxynonenal and protein carbonyls), quantified by enzyme‐linked immunosorbent assays, as well as the activity of three enzymes involved in the regulation of oxidative stress (SOD1, catalase and glutathione peroxidase), assessed by colorimetric assays.

Result

Levels of catalase and malondialdehyde were significantly higher in Down syndrome group than for controls. The SOD activity was also higher in Down syndrome group than for controls. None of the markers presented different levels relating the control group and the MCI and AD groups.

Conclusion

Despite being expressed differently in Down syndrome, stress oxidative biomarkers do not seem to be strong and differential markers for dementia in individuals with DS, MCI and AD.
The women’s Alzheimer’s prevention center at Cleveland Clinic: Centering women in Alzheimer’s prevention care and research
Authors: Caldwell Jessica ZK , Crocker‐Sabbagh Ida , Kaplan Nikki , Sabbagh Marwan N
Published: December 2021

Background

Women represent two‐thirds of individuals currently diagnosed with Alzheimer’s disease (AD), and up to 40% of current AD cases may be attributed to modifiable lifestyle‐based risks. Our Women’s Alzheimer’s Prevention Center (WAPC) is designed to offer women personalized assessment and recommendations regarding known lifestyle risks for AD and support best practices for lifetime brain health.

Method

The WAPC is a clinic first and foremost, for women of any age who self‐report risk for AD. Target age is 40‐60, with opportunity for approximately 400 women to participate over three years. Research participation is optional. Women undergo comprehensive online and in‐person assessment including measures of mood, sleep, diet, exercise, stress, cognition, current medical health, and medical and family history. Women have an in‐person, two‐hour results and recommendations visit with a neuropsychologist and family medicine physician, in which they received specific and personalized recommendations for reducing their modifiable AD risks. A lab panel including AD‐specific risk factors is ordered at this visit and reviewed at a 2‐month follow‐up visit with the family medicine physician. Women receive quarterly assessment of memory, treatment satisfaction, and adherence, as well as one‐year follow‐up reassessment. Scientific goals of the WAPC include assessing patient satisfaction and treatment adherence for practice improvement, and assessing women’s collective one‐year success in reducing lifestyle risks for AD based on self‐report and objective measures of physical health.

Result

To date, 61 women patients have been seen for initial assessment and recommendation visits.

Conclusion

The WAPC is the only women‐specific Alzheimer’s prevention center in the country, and offers unique opportunities to study women’s use of and satisfaction with comprehensive prevention services and recommendations, as well as a long‐term opportunity to assess impact of prevention lifestyle on women’s specific indicators of AD risk.
Increased functional connectivity of the precuneus in individuals with a family history of Alzheimer’s disease
Authors: Green Zachary D. , Vidoni Eric D , Swerdlow Russell H , Burns Jeffrey M. , Morris Jill K , Honea Robyn A
Published: December 2021

Background

First‐degree relatives of individuals with late‐onset Alzheimer’s Disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. We sought to test how structural or functional abnormalities in the default mode network (DMN) during the brain’s “resting state” characterized individuals at risk for AD.

Method

We used MRI and fMRI to study cognitively healthy individuals (n=28) with and without AD family history (FH+ and FH‐, respecitvely), those with amnestic mild cognitive impairment (aMCI; n=31) and early‐stage AD (n=25). We tested connectivity within the DMN, as well as measures of volume and thickness within both the medial temporal cortex and in selected seed regions. Our primary hypothesis was that there would be a linear decline within the risk groups on all measures of AD risk (FH‐>FH+>aMCI>AD).

Result

As expected, we identified significantly decreased medial temporal cortex volumes in the aMCI and AD groups compared to both nondemented groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH‐ and AD groups. This pattern emerged primarily in connectivity between the precuneus and frontal regions.

Conclusion

We present distinct structural and functional brain imaging profiles for two AD‐risk groups; cognitively healthy, FH+ individuals, and individuals with aMCI. These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.
Transfer learning with related tau PET radioligands improves 3D neural network performance
Authors: Zou James , Park David , Johnson Aubrey S , Tomljanovic Zeljko , Devanand Davangere P. , Luchsinger Jose , Brickman Adam M. , Kreisl William Charles , Provenzano Frank
Published: December 2021

Background

Neural networks are increasingly being applied towards neuroimaging problems in AD, but performance is often limited by lack of adequate numbers of samples. This is commonly alleviated by pre‐training the model on a related task beforehand (i.e. ‘transfer learning’). To our knowledge, there exists no set/standard of widely available pretrained model weights for 3D medical images. Tau PET radiotracers such as AV‐1451 and MK‐6240 have highly similar binding patterns, and so may be well suited to transfer learning tasks.

Method

Subjects with AV‐1451 scans (n=446) were downloaded from ADNI, while subjects with MK‐6240 scans (n= 320) were pooled from multiple studies recruiting at CUIMC. We trained multiple 3D neural networks (all with the same modified InceptionV3 architecture) to differentiate patients (i.e. MCI/AD) from controls based on their tau PET scan, both with and without pretraining information from prior training iterations of our models. We compare performance on holdout sets for each validation fold (n= 64 for MK‐6240 and n=89 for AV‐1451) using DeLong’s test for ROC curves and analyze features learned by models with t‐SNE plots.

Result

The AV‐1451 Model pretrained on MK‐6240 scans had superior performance to the AV‐1451 model not using pretraining (AUC = 0.74 vs. 0.91, Z = ‐5.5, p < 0.0001), whereas there was no significant difference with pretraining for MK‐6240 models (AUC = 0.84 vs. 0.83, Z = 0.47 ,p = 0.6). Visually, there appears to be greater separation in model learned features following pretraining in the AV‐1451 model.

Conclusion

3D pretraining for neural networks involving PET imaging could be accomplished with related but structurally different radioligands, though more work is needed into determining why certain pretraining experiments are successful. This procedure can enable better training of complex models with fewer constraints due to sample size.
Error relationship to an everyday monitoring in mild cognitive impairment: Cognitive correlates and task
Authors: Pagán Carolyn R. , Arrota Kayela , Cunningham Reanne , Schmitter‐Edgecombe Maureen
Published: December 2021

Background

Accurate error monitoring is important for successful completion of everyday tasks and use of compensatory strategies. This work examined error monitoring in individuals with amnestic MCI (aMCI) as compared to healthy older adults (HOA) using a computerized task. We also examined cognitive domains associated with error monitoring and the contribution of error monitoring to objective and self‐reported measurement of everyday functioning.

Methods

Twenty‐four individuals with aMCI and 24 HOAs were administered a battery of neuropsychological tests (domains assessed: attention, working memory, executive functioning, memory, language, visuospatial abilities); a sustained attention task that included an error‐monitoring score (Sustained Attention to Response Task; SART); a naturalistic, performance‐based measure of everyday functioning (Day Out Task; DOT); and self‐ and informant‐report measures that captured everyday dysexecutive difficulties (DEX).

Results

T‐test comparisons revealed the aMCI group (M = 0.48; SD = 0.22) exhibited poorer error monitoring (measured by the number of accurately self‐corrected errors on the SART divided by total errors) compared to the HOA group (M = 0.71; SD = 0.23), d = 1.02. Partial correlation analyses with age as a covariate revealed significant correlations between the error monitoring score and the cognitive domains of working memory and executive functioning for both the aMCI group and the HOA group. Hierarchical regression analyses revealed that after accounting for age and global cognitive status, the SART error monitoring score significantly predicted DOT total time, but not accuracy, as well as both self‐ and informant DEX scores.

Conclusion

This study revealed that the ability to recognize errors was significantly poorer in individuals with aMCI compared to HOAs and most associated with the cognitive domains of executive functioning and working memory. After controlling for age and general cognitive status, error monitoring predicted performance in everyday functioning as assessed by a naturalistic, performance‐based test and questionnaires assessing everyday dysexecutive difficulties. This suggests that if individuals with aMCI do not recognize performance inaccuracies, they will not be able to correct errors, leading to mistakes in everyday task completion and reduction in implementation of appropriate compensatory strategies. These results implicate error monitoring as a potential target for early interventions with individuals with aMCI.
Factors associated with subjective cognitive decline in older adults in pre‐clinical dementia phases
Authors: Rivera‐Fernandez Claudia , Soto Marcio
Published: December 2021

Background

The phase of subjective cognitive decline (SCD) has shown inconsistency as a preclinical phase of dementia. Recent data show a greater association with emotional disturbances than cognitive aspects. Our objective was to analyze the factors associated with SCD in preclinical phases of dementia. Recent data show a greater association with emotional disturbances than cognitive aspects. Our objective was to analyze the factors associated with SCD in preclinical phases of dementia.

Method

We evaluated 94 older adults (Mean Age = , SD = ) with the MMSE, the Pfeiffer functional scale and the Yesavage geriatric depression scale. We also used a neuropsychological protocol that included memory, executive function, visuospatial, fluency and processing speed tasks. We applied a principal component analysis (PCA) to reduce dimensionality. Finally, we use logistic regression considering SCD as a dichotomous variable and sociodemographic and components extracted as a predictor.

Result

We observed that 48.35% of the older adults manifest subjective cognitive decline. Regression analysis shows that emotion (OR=1.839, IC95%: 1.268‐2.667) and older age (OR=1.282, IC95%: 1.068‐1.538) are associated with higher risk for SCD. Surprisingly, higher scores in memory factor are associated with an increased risk for SCD (OR=3.243, IC95%: 1.163‐9.038). On the other hand, lexical access factor Is associated with reduced risk of SCD (OR=0.389; IC95%: 0.159‐0.953).

Conclusion

The SCD phase seems to be more associated with emotional states than cognitive performance, even older adults with better memory scores shows more complains about their cognitive performance. We suggest to follow‐up the sample and use validated instruments of SCD, neuroimaging data or fluid markers, to deep in the construct and validate its relevance as clinical marker.
Falls predict cognitive status
Authors: Gray Michelle , Paulson S. , Gills J.L. , Glenn J.M. , Madero E.N. , Myers J. , Campitelli A. , Jones M. , Vincenzo J. , Walter C.
Published: December 2021

Background

Cognitive impairment is associated with increased falls and fall risk among older adults. In fact, studies have significantly predicted falls between high and low cognitive functioning community‐dwelling older adults. However, many negative cognitive changes occur years before significant cognitive changes arise. Thus, the purpose of the present investigation was to determine the ability of falls to predict cognitive status using a digital Digit Symbol task (Neurotrack Technologies, Inc., Redwood City, CA).

Method

Sixty‐nine community‐dwelling older adults (80.7 ± 5.4 years) volunteered to complete a falls history questionnaire and a digital Digit Symbol task. Cognitive groups (High [HDS] and Low Digit Symbol [LDS] function) were determined based on age‐sex normative values. Logistic regression analysis was conducted predicting cognitive group placement using age, sex, education, and previous falls within previous 12 months.

Result

By knowing the four predictor variables (falls, age, sex, education), cognitive group (HDS vs. LDS) was predicted correctly 80% of the time. Sensitivity and specificity were 90% (37 of 41) and 64% (18 of 28), respectively. The addition of fall risk was not statistically significant; however, it increased sensitivity by 4% and specificity by 13%.

Conclusion

The results suggest that knowing falling status may help identify older adults with cognitive impairment, specifically deleterious changes in processing speed. While the mechanisms cannot be elucidated from the present investigation, others have suggested slower processing speed is associated with impaired balance; thus, leading to falls. Future research is needed to further examine the relationship between falls and cognitive performance in hopes that identifying fallers could lead to more extensive cognitive testing.
In silico differential gene expression analysis in tissue databases from patients with Alzheimer’s disease, to identify potential new biomarkers
Authors: del Carmen Silva‐Lucero Maria , Rivera‐Osorio Jared , Yogesh Muley Vijaykumar , Lopez‐Toledo Gustavo , Sanchez Cintia P. , del Carmen Cardenas‐Aguayo Maria
Published: December 2021

Background

Alzheimer's disease (AD) is a neurodegeneration that accounts for 60‐70% of dementia cases. Symptoms begin with mild memory difficulties and evolve towards cognitive impairment. The underlying risk factors remain largely unclear for this heterogeneous disorder. Discovery of AD biomarkers will allow early detection and the discovery of new treatments. Bioinformatics has become a relevant research tool which have led to the identification of several pathways related to AD.

Method

Open access databases of RNA microarrays of tissue from the medial temporal lobe (MTL) and peripheral blood of AD patient, were analyzed after background correction and data normalization, Limma package was used for DEA throw statistical R programming language. Data were corrected with the Benjamini and Hochberg approach and the genes with p values equal to or less than 0.05 were considered significant. The direction of the change in gene expression was determined by its variation in the "log2‐fold change" between controls and patients. We performed a functional enrichment analysis of GO using goana and topGO‐Limma (Smyth et al., 2016).

Result

With MTL brain tissue database (EMEXP 2280) we obtained 359 down regulated genes (DR) and 324 up regulated genes (UR), the UR pathways were: transcription, mitochondrial function and hydrolase activity, while DR were: gene expression and regulation of cell proliferation, nuclear alterations, transmembrane receptor signaling. Analysis with KEGGp showed that metabolic pathways were UR and cytokine pathways and their receptors were DR. The blood samples analysis (PBMC, E‐GEOD‐18309) showed 383 genes DR and 257 genes UR. Finally, the intersection of the differentially expressed genes in the two databases showed 34 genes shared between the brain and blood arrangements and TRIM58 matched in both databases.

Conclusion

Our in‐silico analysis of AD brain tissue identifies several UR genes related to mitochondria, function, transcription, and hydrolase activity, while gene expression, regulation of proliferation and nuclear alterations were DR. On the other hand, blood databases showed DEG such as TRIM58 (E3 ubiquitin ligase), that is involve in ubiquitination. Protein identified here could be valuable as possible new AD biomarkers.
Trajectories of cognitive activity from early to late life and risk of Alzheimer’s dementia in community‐dwelling older adults
Authors: Dhana Klodian , Rajan Kumar B , Zammit Andrea R , Wilson Robert S , Liu Xiaoran , Aggarwal Neelum T , Leurgans Sue E , Bennett David A , Barnes Lisa L
Published: December 2021

Background

We used a life‐course approach to investigate the relationship between trajectories of cognitive activity from early to late‐life with the risk of Alzheimer’s dementia and elucidate a critical age window during which cognitive activities may exert most of their favorable effects.

Method

The investigation was based on 1,817 older persons without dementia participating in the Rush Memory and Aging Project, a community‐based clinical‐pathologic study. Participants underwent annual clinical evaluations including questions about cognitive activity over the life‐course. Latent class trajectory analyses were used to develop trajectories of cognitive activity from childhood (6‐12y), young adult (18y), middle‐adult‐life (30‐40y), to late‐life (>65y). Clinical diagnosis of Alzheimer’s dementia was determined using standard criteria. Multivariable adjusted Cox proportional hazard models were used to estimate the hazard ratio(HR) and 95% confidence interval (CI) of trajectories of cognitive activity and Alzheimer’s dementia.

Result

The average age of study participants was 80 years, 75% were women, and the mean education was 15 years. We identified three groups of participants with distinct trajectories of cognitive activity from early to late‐life. The largest group of individuals (n=1,614, 88.8%) showed steady cognitive activity levels over time – we named this group “stable‐high.” The second group comprised 131 (7.2%) individuals who experienced an increase in cognitive activities after the age of 40 years –‐ the “moderate‐progressive‐increase.” The third group included 72 (4%) individuals who initially engaged in high cognitive activities in early life but then experienced a substantial decrease during middle‐age – the “marked‐decrease” group. During 10 years of follow‐up, 358 (19.7%) of the participants were clinically diagnosed with Alzheimer’s dementia. Compared to individuals in the marked‐decrease group, the risk of Alzheimer’s dementia was 44% lower (HR 0.56, 95%CI 0.37‐0.86) among individuals in the stable‐high group and 53% lower (HR 0.47, 95%CI 0.27‐0.83) in those in the moderate‐progressive‐increase group.

Conclusion

Using the latent trajectory approach, we identified three distinct cognitive activity trajectories from early to late‐life. These trajectories were differently associated with the risk of Alzheimer’s dementia, suggesting that high cognitive activity starting in middle adult life is protective against Alzheimer’s dementia.
Sharper in the morning: Cognitive sundowning revealed with high‐frequency smartphone testing
Authors: Wilks Hannah M , Aschenbrenner Andrew J. , Gordon Brian A. , Balota David A. , Fagan Anne M. , Balls‐Berry Joyce E , Benzinger Tammie L.S. , Cruchaga Carlos , Morris John C. , Hassenstab Jason
Published: December 2021

Background

In Alzheimer’s disease (AD), patients and caregivers often report a pattern of increasing cognitive and behavioral difficulties in evening hours, known colloquially as “sundowning.” Here, we describe the first known attempt to capture circadian fluctuations in cognition in humans at risk for AD using a novel smartphone assessment that samples cognition rapidly and repeatedly over a 7‐day period. We hypothesized that cognitive sundowning would manifest among individuals with abnormal AD biomarkers, even in preclinical stages of AD.

Methods

Older adults (N=168, Ages 61‐94 years) were asked to complete 4 brief smartphone‐based testing sessions per day for 7 consecutive days at quasi random intervals throughout the day, from morning until evening. Tests included associate memory, processing speed, and visual working memory tasks (Figure 1). Cerebrospinal fluid biomarkers for beta amyloid (Ab42) and phosphorylated tau181 (ptau) were collected within ∼3 years of smartphone tests. Scores from morning hours (range ∼5am – 12pm) were averaged for comparison with averaged scores from evening hours (after 12pm). Mixed effect models evaluated time of day effects by CSF biomarker status and clinical status.

Results

Participant characteristics are provided in Table 1. Models with terms for age, gender, education, APOE e4 status, and Clinical Dementia Rating™ Sum of Boxes tested the interaction between time of day and CSF ptau/Ab42 ratio in predicting cognition (Figure 2). Compared to those with normal biomarkers, participants with abnormal CSF ptau/Aβ42 ratio had worse associate memory (p=0.03) and processing speed performance (p=0.026) in evening hours. On processing speed, participants with abnormal ptau/Aβ42 ratios were slower by an average of 700ms in the evening compared to those with normal ptau/Aβ42 ratios tested in morning hours. When models were run in cognitively normal participants only, a similar pattern was observed, confirming the hypothesis that increasing loads of AD pathology result in worse cognitive performance in evening hours prior to symptom onset.

Conclusion

Our results provide the first known evidence of cognitive sundowning in preclinical and early symptomatic AD and suggest that time of day is an important consideration for studies of cognition in AD populations.
SavaDx, a novel plasma biomarker to detect Alzheimer’s disease, confirms mechanism of action of simufilam
Authors: Wang Hoau‐Yan , Pei Zhe , Xu Qiang , Brunelle Lynn A , Burns Lindsay H. , Thornton George Ben
Published: December 2021

Background

The diagnosis and management of Alzheimer’s disease (AD) would be greatly aided by sensitive, accurate and scalable biomarkers. SavaDx is proposed as a novel plasma diagnostic/biomarker candidate for Alzheimer’s disease. SavaDx detects altered filamin A, a previously described proteopathy in AD. SavaDx was evaluated as an exploratory endpoint in a clinical trial of simufilam, a drug candidate for AD that targets and reverses altered filamin A, the proteopathy detected by SavaDx.

Method

SavaDx was evaluated in a multi‐center, randomized, controlled trial of simufilam completed in 2020. This Phase 2b study enrolled 64 patients with mild‐to‐moderate AD, MMSE 16 to 26 and CSF total tau/Aβ42 ratio ≥ 0.28. Patients were randomized (1:1:1) to placebo, 50 mg, or 100 mg b.i.d. oral simufilam for 28 days. CSF and blood samples were collected at baseline and Day 28. Plasma p‐tau181 was measured in duplicate by SIMOA®. Data with Coefficients of Variation >11% were repeated and excluded if >15% on repeat. Biomarker analyses were conducted blind to treatment. Day 1 and Day 28 samples for each patient were analyzed together. SavaDx, a non‐published investigational assay, was used to estimate altered filamin A levels in brain.

Result

This Phase 2b study met all co‐primary CSF biomarker endpoints, as previously reported. Simufilam 50 mg and 100 mg twice daily significantly improved eleven CSF biomarkers of AD pathology, neurodegeneration and neuroinflammation, baseline to Day 28 versus placebo. SavaDx values decreased 44% and 48% in the 50 and 100 mg arms, respectively, (p=0.02 and p=0.005 versus placebo) versus a 3% decrease in the placebo arm. Plasma p‐tau181 values decreased 15% and 17% in the 50 and 100 mg arms, respectively (both p<0.05), versus a 20% increase in placebo.

Conclusion

SavaDx detected treatment effects in a randomized, controlled trial of simufilam, a drug candidate that targets and reverses a critical proteopathy in AD. These data offer quantitative evidence of drug‐target engagement in patients, confirming simufilam’s mechanism of action. These data also suggest the use of the SavaDx assay to detect and monitor AD in plasma. This work was funded by NIA grants AG057329 and AG060878.
Forecasting progression of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) with digital twins
Authors: Bertolini Daniele , Loukianov Anton D. , Smith Aaron , Li‐Bland David , Pouliot Yannick , Walsh Jonathan R. , Fisher Charles K.
Published: December 2021

Background

Machine learning models can leverage historical data to forecast disease progression. These predictions can be integrated in clinical trial design to reduce sample size or increase power, speeding up the evaluation of new drugs. This is especially critical in AD where trials face challenges with enrollment and where no new therapies have emerged in 18 years. Recently, there has been a shift towards evaluating drugs in earlier stages of the disease using Clinical Dementia Rating Sum‐of‐Boxes (CDR‐SB) as the primary endpoint. We present a model that includes CDR‐SB and spans a broad range of baseline disease severity from MCI to mild‐to‐moderate AD.

Method

We used nearly 7,000 clinical records from placebo arms of AD clinical trials (in the C‐Path Online Data Repository for AD) and from observational studies (in the AD Neuroimaging Initiative) to train Conditional Restricted Boltzmann Machines (CRBMs). A CRBM is a generative machine learning model that learns a multivariate distribution over the relevant variables, and is particularly suited to model clinical data. A CRBM generates Digital Twins ‐ synthetic clinical records with baseline characteristics matched to those of actual trial subjects describing their likely progression under standard‐of‐care (SOC) with/without placebo. These forecasts include all components of CDR‐SB, Alzheimer’s Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog11) and Mini Mental State Examination (MMSE), along with other variables including labs, vitals, and biomarker status. We evaluated Digital Twins on a held‐out portion of the dataset (not included in the training dataset), stratified by baseline ADAS‐Cog11. For each variable, the mean change from baseline +/‐ 95% confidence interval error at 3‐month intervals was estimated by drawing 100 Digital Twins for each subject and averaging over the population.

Result

CRBM‐generated predictions of ADAS‐Cog11, MMSE, and CDR‐SB progression up to 18 months were consistent within 95% confidence intervals with actual data across all scores, timepoints, and cohorts.

Conclusion

Digital Twins accurately model MCI and AD subjects’ progression on SOC with/without placebo across a broad range of baseline disease severity, and can be integrated into clinical trials as prognostic scores to increase power or reduce sample size required to achieve desired power.
In vivo detection of changes related to cortical columnar organization across the AD continuum
Authors: Torso Mario , Hardingham Ian , Schwarz Adam J. , Chance Steven A
Published: December 2021

Background

Recent studies have suggested intriguing biphasic trajectories of cortical structural changes in both sporadic and autosomal‐dominant Alzheimer’s disease (AD), namely decreased mean diffusivity (MD) and increased cortical thickness in cognitively normal, amyloid positive individuals, ahead of increases and decreases, respectively, in these parameters in cognitively impaired stages of the disease. To better understand these observations, we assessed novel diffusion tensor imaging (DTI) metrics that are correlated with disruption of cortical minicolumns ‐ the units of cortical microstructure. These have previously been shown to be associated with protein deposition and synaptic and neuronal loss. Such cytoarchitectural changes offer potential pathological markers before alterations at the macrostructural level.

Method

Twenty‐four amyloid‐negative controls (CN‐), 28 amyloid‐positive controls (CN+), 46 amyloid‐positive subjects with Mild cognitive Impairment (MCI+) and 22 amyloid‐positive subjects with Alzheimer’s disease from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used. 3DT1 and DTI scans at 2 timepoints (baseline and 24‐month follow‐up) were used to calculate the cortical MD and three novel cortical diffusivity measures, namely: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD), and the principal diffusion component parallel with the minicolumns (ParlPD). Mixed effect models were used to investigate cross‐sectional and longitudinal differences.

Result

At a whole‐brain level, the mixed effects models revealed a significant effect of diagnostic group in all the measures (all p‐values<0.001). The pairwise (Figure 1) comparisons showed AngleR differed between CN‐ and CN+ (p<0.005), between CN+ and MCI+ (p<0.005) and between CN+ and AD+ (p<0.001). PerpPD values were significantly different between CN‐ and MCI+ (p<0.05) and AD+ groups (p<0.001), CN+ and MCI+ (p<0.005) and AD+ groups (p<0.001) while differences between CN‐ and CN+ were not significant. No significant difference was found between the timepoints for any measures, although the direction of change indicated progression between the first and second assessments.

Conclusion

Cortical diffusivity parameters reflecting cortical minicolumnar organization may provide a more sensitive and biologically interpretable measurement of cortex quality and microstructure across the AD continuum.
Neuropsychological test performance in former college and professional American football players
Authors: Culhane Julia E , Barr William , Wethe Jennifer , Banks Sarah J , Miller Justin B , Adler Charles , Balcer Laura , Bernick Charles B. , Palmisano Joseph , Tripodis Yorghos , Cummings Jeffrey L. , Reiman Eric M. , Shenton Martha E , Stern Robert A , Alosco Michael L
Published: December 2021

Background

Repetitive head impacts from American football have been associated with long‐term cognitive symptoms. The late neuropsychological profiles of this population is not well‐characterized. Research has relied on retrospective informant reports and/or has been small samples of former professional players. We describe objective neuropsychological test performance in former college and professional American football players.

Methods

Male (45‐74 years) former National Football League (n=107) and college football players (n=59) from the DIAGNOSE‐CTE Research Project completed a neuropsychological test battery, Functional Activities Questionnaire (FAQ) and Quick Dementia Rating Scale (QDRS). Neuropsychological test scores were converted to T‐scores using age, sex, and/or education‐adjusted normative data. T‐scores<35 defined impairment. Participants were enrolled across the spectrum of symptom severity (asymptomatic to dementia). Individuals without decisional capacity were excluded. Participants with missing data (n=4) and who scored <45 on Test of Memory Malingering Trial 2 (n=10) were excluded.

Results

108 (65.1%) identified as White and 53 (31.9%) as Black. Mean education years was 16.76 (SD=1.48). Fourteen (8.4%) and 6 (3.6%) reported diagnostic history of ADHD and learning disability, respectively. Average Montreal Cognitive Assessment score was 24.96 (SD=3.17); 85 (51.2%) scored <26. Impairment rates were highest for learning and episodic memory. On Neuropsychological Assessment Battery List Learning, 29.5% were impaired on Immediate recall, 36.1% on Short Delay, and 44.0% on Long Delay Recall. Impairment rates for Craft Story Immediate and Delayed Recall (Paraphrase) were 15.7% and 18.7%, respectively. 19.9% and 15.7% were impaired on learning and delayed recall of the Brief Visuospatial Memory Test‐Revised. Impairments were frequent on the Multilingual Naming Test (20.5%), Trail Making Test Parts B (19.3%) and A (18.1%), Animal Fluency (15.7%), and Number Span Backward (15.1%). Impairments were less common (<10%) for phonemic fluency, planning, basic attention, and visual‐perceptual abilities, Mean FAQ was 3.11 (SD=5.14); 23 (13.9%) had an FAQ >9. Based on QDRS scores, 66 (39.8%) had mild cognitive impairment, 44 (26.5%) mild dementia, and 6 (3.6%) moderate dementia.

Conclusions

In these former American football players, neuropsychological impairments were most frequent in episodic memory, followed by confrontation naming and executive function. Further research is needed to delineate this population’s unique neuropsychological profile.
Concordance between [18F] GTP1 PET and fluid tau biomarkers in the Tauriel phase II Study
Authors: Toth Balazs , Teng Edmond , Manser Paul T. , Bohorquez Sandra Sanabria , Schauer Stephen , Lee Julie , Blendstrup Mira , Pickthorn Karen , Wildsmith Kristin R.
Published: December 2021

Background

The Tauriel Study (NCT03289143) was a Phase 2 randomized, double‐blind, placebo‐controlled, parallel‐group clinical trial that assessed the safety and efficacy of semorinemab in patients with prodromal‐to‐mild Alzheimer’s disease. We examined the concordance of fluid tau biomarkers with Tau PET for the identification of patients with high tau burden at enrollment.

Method

Tau at baseline was assessed by [18F]GTP1 PET imaging and assays for multiple CSF and plasma tau indices, including pTau181 and mid‐domain tTau (Elecsys assays), tau peptides 2‐24 and 93‐105 (anti‐peptide capture mass‐spec assay), and phosphotau/unphosphorylated tau217 ratio (mass‐spec assay). The association between imaging and fluid tau levels were assessed with Spearman correlations. AUC, sensitivity and specificity are reported in the context of predicting tau burden with a single fluid biomarker, where ‘high tau’ is defined as GTP1 temporal meta‐ROI SUVR ≥1.3. Cutoffs were derived using Youden’s index.

Result

354 participants had both PET and plasma samples; 68 subjects had paired PET and CSF data. GTP1 significantly correlated with each fluid marker, highly with pT217 (r = 0.78), moderately with other CSF assays (r = 0.44 ‐ 0.56) and weakly with plasma tTau (r = 0.19) (Table 1). Discrimination was highest for CSF pTau217 ( AUC = 0.909). Specificity was 0.862 and 0.84 for pTau181 and pTau217 respectively, while sensitivity was 0.564 and 0.868 (Figure 1). Empirically defined cutoffs were 36.88 pg/mL for pTau181 and 0.052 for pT217.

Conclusion

Baseline Tau PET is shown to be prognostic for future cognitive decline and thus could be included in enrollment criteria for future clinical studies in AD. Alternative approaches include the use of fluid biomarkers for tau. While pTau181 and n‐terminal tau indices can only be optimized for either high specificity or high sensitivity, both can be concurrently optimized using pTau217, thus positioning it as a potential alternative marker for Tau pathology. Additional CSF and plasma tau indices are pending similar analyses.
Cognitive testing for early detection of Alzheimer's disease in people with Down syndrome: A systematic review and meta‐analysis
Authors: Nadeau Patricia Alves , Boller Benjamin
Published: December 2021

Background

Improved health care for people with Down syndrome (DS) has resulted in an increase in their life expectancy therefore increasing comorbidities associated with age related problems in this population, the most frequent being Alzheimer's disease (AD). The development of brain lesions appears years before AD. Through this progressive neuronal loss, patients can firstly begin to have a perception of cognitive difficulties, i.e., a subjective cognitive decline (SCD). This preclinical phase ends with the onset of mild cognitive impairment (MCI) which is characterized by a set of cognitive symptoms. Knowing that people with DS have already pre‐existing cognitive deficits, screening at the preclinical and clinical stages of AD therefore cannot be done through traditional cognitive tests. The aim of this systematic review is to synthesis cognitive assessment for the diagnosis of AD, MCI or SCD in people with DS.

Method

A meta‐analysis is in development. Articles were collected from Pubmed and Psychinfo databases through keywords related to three categories: 1) DS, 2) AD and 3) assessment. The inclusion criteria are studies 1) with participants over 18 years old with DS, 2) which assess cognitive abilities in the context of screening for AD or its early stages, 3) presenting the effect sizes or data allowing their calculation.

Result

Eighteen articles met the inclusion criteria. Fifty cognitive tests for the diagnosis of AD, MCI or SCD were found. From these tests, fourteen evaluated cognition through an informant questionnaire and thirty‐six directly evaluated the patient’s cognitive abilities.

Conclusion

Theoretical and practical implications of these results are discussed.
Clinical subtypes of frontotemporal dementia show different patterns of cortical atrophy
Authors: Fonov Vladimir S , Dadar Mahsa , Manera Ana Laura , Ducharme Simon , Collins Louis
Published: December 2021

Background

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder associated with atrophy of the frontal and/or anterior temporal lobes, it is highly heterogeneous and represents about 5% of all cases of dementia and it is one of the most common causes of early‐onset dementia (Onyike and Diehl‐Schmid, 2013). FTD syndromes can be divided into three major groups: the behavioral variant (bvFTD) characterised by prominent early behavioral and personality changes, and the two language variants: the semantic variant (svFTD) and the non‐fluent primary progressive aphasia (pnfaFTD).

Method

In our study we used MRI scans from a frontotemporal lobar degeneration neuroimaging initiative (FTLDNI) database: 133 age and sex matched controls, 70 bvFTD, 36 svFTD and 30 pnfaFTD. Each scan was pre‐processed (Intensity normalization, N3, linear registration, brain masking); tissue classification was performed using BISON (Dadar 2020). All scans were then processed using FALCON (Fonov 2020) to extract its cortical surface anc calculate thickness. Statistical analysis was performed on vertex level.

Result

Figure 1 shows relative cortical difference between groups relative to controls, Figure 2 shows areas of significant differences (FDR 1%): the decrease of cortical thickness in the bvFTD group was located in frontal lobes, bilaterally as well as the temporal poles (specially in medial frontal and dorsolateral prefrontal areas). In svFTD, however, cortical thinning is limited to the anterior and lateral temporal lobe, predominantly on the left side. Finally, pnfaFTD shows left sided cortical thinning in prefrontal and Broca’s areas.

Conclusion

The identification of predicted patterns of atrophy in each FTD subtype supports the validity of FALCON as an accurate tool to measure cortical changes in neurodegenerative disease. FALCON could be a useful tool for the development of the biomarkers associated with disease and improve understanding of disease progression.
Development of culturally appropriate clinical research education materials in Alzheimer’s disease and related dementias (ADRD) for Hispanic/Latino caregivers and at‐risk individuals
Authors: Shakur Mujaahida , Massett Holly A , McGowan Melissa , Gallop‐Goodman Gerda , Mitchell Alexandra K , Simoneau Elizabeth , Rehberg Kathryn , Burke Panne , Bui Elise
Published: December 2021

Background

Though Hispanics/Latinos (H/L) comprise 18% of the U.S. population and are 1.5 times at greater risk for Alzheimer’s and related dementias (AD/ADRD) than non‐Hispanic Whites, a median of only 2% of participants in NIH‐funded AD/ADRD clinical trials are H/L. Reasons abound for this inequity; key documented impediments to enrollment of Latinos are too few researchers offering studies and limited materials that provide culturally and linguistically relevant information. This abstract presents findings from focus groups conducted by the National Institute on Aging (NIA) to identify salient, culturally appropriate message concepts that raise awareness, address barriers, and motivate H/L to consider participation in AD/ADRD studies.

Method

Twelve remote focus groups (N=72) were conducted among two H/L audiences: 1) those at risk for AD/ADRD; and 2) those caring for a family member or friend with AD/ADRD. Messages were designed to motivate H/L to learn more about AD/ADRD clinical studies. Sessions explored participants’ knowledge, attitudes, and beliefs regarding AD/ADRD and clinical studies. Participants reviewed and provided feedback on messaging designed to motivate them to seek more information about AD/ADRD clinical studies.

Result

Message concepts that resonated strongly were those that 1) framed clinical studies as one step to finding a cure for AD/ADRD and 2) connected participation with helping their family members’ future health. Concepts were more acceptable if they represented multi‐generational families, emphasized the importance of family support, and promoted diversity and inclusivity (showing a diversity of age, gender, skin tone). Participants requested that concepts offered more opportunities to learn about Alzheimer’s and local clinical studies. Trusted concepts are those that clearly identified the document’s source and avoided the terms “trial” and “dementia,” as both had negative connotations in the Spanish language.

Conclusion

The data from these focus groups improve our understanding of message concepts that motivate H/L to consider participating in AD/ADRD clinical research. They also provide insights to develop, finalize and make available to the research community a suite of culturally appropriate, well‐tested materials for H/L populations in both English and Spanish that can be used to increase awareness of AD/ADRD and clinical research.
Serum immunoglobulins and biomarkers of dementia: A population‐based study
Authors: Yaqub Amber , Khan Samer R. , Wolters Frank J. , Vernooij Meike W. , Dalm Virgil A.S.H. , Ikram M. Arfan , Chaker Layal
Published: December 2021

Background

Dementia is a complex syndrome with multiple interacting pathways leading to brain damage and ultimately the clinical manifestation. In recent years, studies have identified the immune response as a novel contributing process to the aetiology of dementia, but it remains unclear how this links to established biomarkers of dementia, for instance those measured in plasma or on neuroimaging. We studied the association of serum immunoglobulins, markers of the adaptive immune response, with biomarkers of dementia.

Method

Between 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in 8,768 participants of the population‐based Rotterdam Study (median age 62.2 years, 57.0% women). Plasma biomarkers of dementia (total tau, neurofilament light chain (NfL), amyloid‐β40 (Aβ‐40), amyloid‐β42 (Aβ‐42)) were measured in a random sample of 3,455 participants. Neuroimaging was performed for 3,139 participants to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. We used linear regression models to determine cross‐sectional associations of IgA, IgG, IgM and biomarkers of dementia in plasma and on neuroimaging, while adjusting for age, sex, cohort, education, cardiovascular risk factors and stratifying for APOE‐ε4 carriership. Plasma biomarkers were log2 transformed and neuroimaging markers were standardized to facilitate comparison.

Result

Higher levels of IgA corresponded to higher log2 plasma levels of NfL (β=0.019, p=0.031), and a lower or higher tau and Aβ burden, depending on carriership of the APOE‐ε4 allele. Higher IgM was consistent with lower levels of all plasma biomarkers, particularly among no carriers of the APOE‐ε4 allele. No significant associations were found between IgG levels and plasma biomarkers, although associations were moderately driven by APOE‐ε4 allele carriership. Subsequently, higher serum immunoglobulin levels and in particular IgA, generally amounted to more brain atrophy (total brain volume (β=‐0.013, p=0.032), gray matter volume (β=‐0.026, p=0.009), decreased white matter integrity and increase of cerebral small vessel disease markers (white matter hyperintensities (β=0.041, p=0.008)).

Conclusion

The associations between serum immunoglobulins and biomarkers of dementia in plasma partly depend on APOE‐ε4 carriership. Higher serum immunoglobulins generally correspond to more brain atrophy, diminished white matter integrity and more cerebral small vessel disease.