bluuebunny/crossref_metadata_2025 huggingface dataset:
TRAILBLAZER‐ALZ Study: Dynamics of amyloid reduction after donanemab treatment
Authors: Shcherbinin Sergey , Andersen Scott W. , Evans Cynthia Duggan , Lo Albert C. , Lu Ming , Navitsky Michael , Collins Emily C , Sims John R. , Brooks Dawn A. , Mintun Mark A
Published: December 2021

Background

Accumulation of amyloid‐β (Aβ) peptide in amyloid plaques is a pathological hallmark of Alzheimer’s disease (AD). Reduction of Aβ could slow the progression of AD. Donanemab is an antibody specific for the N‐terminal pyroglutamate Aβ epitope that is only present in mature brain amyloid plaques. In the TRAILBLAZER‐ALZ study, 67.8% (n=61) of donanemab‐treated participants became amyloid negative by 76 weeks. Here we further characterize amyloid reduction after donanemab treatment.

Method

Participants (placebo N=84, donanemab N=69) that completed 4 florbetapir scans in TRAILBLAZER‐ALZ were analyzed for amyloid reduction rate, measured in centiloids (CL). Donanemab dosing was 700mg every 4 weeks (Q4W) for the first 3 doses, then 1400mg Q4W, for up to 76 weeks. Planned blinded dose reduction evaluations occurred at 24 and 52 weeks creating three periods of time between florbetapir scans: baseline‐24wk, 24wk‐52wk, or 52wk‐76wk. ANOVA were performed to compare baseline parameters.

Result

At 24wk, 15 participants in the donanemab group were assigned to 700mg dose and 19 were assigned to placebo. At 52wk, 10 participants were assigned to 700mg dose and 8 were assigned to placebo. In the 17 participants that remained on 1400mg donanemab until the end of the trial, amyloid reduction rate decreased during baseline‐24wk, 24wk‐52wk, and 52wk‐76wk (mean (SD): ‐2.7(1.5), ‐1.0 (0.7), and ‐0.5 (0.5) CL/wk, respectively). At the end of the trial, 5 out of 17 participants that remained in the 1400mg group became amyloid negative. In the 15 participants that were assigned to 700mg at 24wk, plaque lowering rate decreased from an average of ‐3.0 (1.2) CL/wk over the first 24wk to an average of ‐0.4 (0.4) CL/wk over 24wk‐52wk. At the end of the trial, 13 participants assigned to 700mg donanemab Q4W at 24wk became amyloid negative. Patients that received placebo at 24wk‐76wk (n=19) or 52wk‐76wk (n=19), had no re‐accumulation (mean (SD): 0.0 (0.1) CL/wk and ‐0.1 (0.2) CL/wk, respectively). Participants that stayed on 1400mg until study end had higher baseline amyloid (p=0.0000) and tau (p=0.0488) and were younger (p=0.0472) than those assigned to 700mg or placebo at 24wk.

Conclusion

Donanemab treatment reduced amyloid plaques and resulted in no re‐accumulation of amyloid over 1 year.
Cross‐sectional associations between sleep quality reports and core Alzheimer’s disease biomarkers in cognitively unimpaired adults from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD LCS)
Authors: Stankeviciute Laura , Grau‐Rivera Oriol , Blackman Jonathan , Arenaza‐Urquijo Eider M , Suárez‐Calvet Marc , Sánchez‐Benavides Gonzalo , Vilor‐Tejedor Natalia , Minguillón Carolina , Iranzo Álex , Molinuevo Jose , Gispert Juan Domingo , Coulthard Elizabeth ,   EPAD Consortium
Published: December 2021

Background

Sleep disturbances are prevalent in Alzheimer’s disease (AD), with sleep quality having been reported to be already impaired at the preclinical stage of the disease. However, most results originate from studies with rather limited sample sizes. This research aimed to evaluate the association of subjective sleep measures with cerebrospinal fluid (CSF) AD biomarkers in cognitively unimpaired adults from the European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study (EPAD‐LCS).

Method

This cross‐sectional study included 1257 cognitively unimpaired adults [CDR(clinical dementia rating scale)=0] aged over 50 years who underwent CSF sampling and filled out the Pittsburgh sleep quality index (PSQI) questionnaire. The PSQI includes 7 components (scored 0‐3), which summed yield a total score ranging from 0 to 21. We used multivariate linear regressions to analyse associations between CSF biomarkers (i.e. Aβ42, p‐tau and t‐tau) and the following PSQI measures: total score, binarized score (poor sleep categorized as PSQI>5), sleep latency, duration, efficiency and disturbance. For sleep duration and disturbance, the two highest categories were collapsed into one due to an insufficient number of responses. We used separated models, with each biomarker as the dependent variable and each sleep measure as the predictor, and adjusted them by known potential confounders.

Result

Poor sleep quality (PSQI total>5) was associated with higher CSF levels of p‐tau (std. β=0.060, p=0.040) and t‐tau (std. β=0.066, p=0.019). Shorter sleep duration (6‐7 hours vs >7 hours) was associated with higher CSF levels of p‐tau (std. β=0.063, p=0.017) and t‐tau (std. β=0.054, p=0.037). A higher degree of sleep disturbance (1‐9 vs 0 and >9 vs 0) was associated with lower CSF levels of Aβ42 (std. β=‐0.106, p=0.016; std. β=‐0.091, p=0.046).

Conclusion

Our results show that self‐reported sleep quality is associated with AD biomarkers in people without cognitive impairment. Specifically, overall poor sleep quality and shorter sleep duration are related to higher p‐tau and t‐tau levels, whilst more profound sleep disturbances are associated with lower Aβ42 levels. These results potentially support sleep impairment before cognitive symptom onset in AD. Future longitudinal studies using objective sleep quantification will more precisely illuminate the role of sleep in the early stages of the AD continuum.
Considerations for the real‐world management of ARIA from the aducanumab phase 3 studies EMERGE and ENGAGE
Authors: Burkett Patrick , Chalkias Spyros , Umans Kimberly , Castrillo‐Viguera Carmen , Purcell Derk D , Barakos Jerome , Fam Sami , Smirnakis Karen , Haeberlein Samantha Budd
Published: December 2021

Background

Amyloid‐related imaging abnormalities (ARIA), a spectrum of imaging findings detected on brain magnetic resonance imaging (MRI), are associated with the investigational use of amyloid‐targeting monoclonal antibodies, including aducanumab, in patients with Alzheimer’s disease (AD). EMERGE (NCT02484547) and ENGAGE (NCT02477800) were Phase 3 studies that evaluated the efficacy and safety of aducanumab in patients with early AD.

Methods

ARIA risk minimization included dose titration, routine brain MRI monitoring, ad hoc MRI testing as clinically indicated, and among patients who developed ARIA, possible dose suspension or permanent discontinuation. The criteria for dose suspension or discontinuation were based on the radiographic severity of ARIA and presentation of clinical symptoms. On detection of an ARIA episode, follow‐up MRIs were conducted approximately every 4 weeks to document radiographic resolution of ARIA‐edema (ARIA‐E) or stabilization of ARIA‐hemorrhage (ARIA‐H), which refers to brain microhemorrhages and localized superficial siderosis.

Results

The integrated data set from EMERGE and ENGAGE consisted of 3285 participants (aducanumab treated, n=2198; placebo treated, n=1087). In the 10‐mg/kg group (n=1029 with ≥1 postbaseline MRI), ARIA‐E was the most common adverse event (35.2%), with a higher incidence in apolipoprotein ε4 carriers compared with noncarriers (43.0% versus 20.3%, respectively). Radiographic severity of ARIA‐E was characterized as mild (30.1%), moderate (57.7%), or severe (12.2%). ARIA‐E typically occurred within the first 32 weeks of treatment with aducanumab and were mostly asymptomatic (74.0%). Among participants who reported symptoms in the setting of ARIA, the majority of symptoms during ARIA were characterized as mild (67.7%) or moderate (28.3); the most common symptoms were headache (46.6%), confusion (14.6%), dizziness (10.7%), and nausea (7.8%). ARIA‐E were transient but recurred in 10.6% of participants in the 10‐mg/kg group. ARIA‐H microhemorrhage and superficial siderosis were typically asymptomatic and more common in participants who had ARIA‐E (40.3% and 38.7%, respectively), compared with participants without ARIA‐E (7.6% and 1.6%, respectively). In participants with ARIA‐E and ARIA‐H, these events frequently overlapped temporally. There were no fatal events due to ARIA.

Conclusions

ARIA are mostly asymptomatic; evidence supports the use of routine brain MRI to monitor for events in clinical practice.
Machine learning for the prediction of amyloid positivity in amnestic mild cognitive impairment
Authors: Kang Sung Hoon , Jang Hyemin , Kim Hee Jin , Park Kyung Won , Noh Young , Lee Jin San , Ye Byoung Seok , Na Duk L. , Lee Hyejoo , Seo Sang Won
Published: December 2021

Background

Amnestic mild cognitive impairment (aMCI) patients with amyloid (Aβ) deposition have worse prognosis than those without Aβ deposition and are candidates for clinical trials of anti‐Aβ drugs. In this regard, Aβ evaluation in aMCI patients is important for predicting conversion to Alzheimer’s disease. However, Aβ evaluation through amyloid positron emission tomography (PET) is limited due to high cost and safety issues. We therefore aimed to develop and validate two different prediction models of Aβ positivity for aMCI using optimal interpretable machine learning (ML) approaches utilizing multimodal markers.

Method

We recruited 529 aMCI patients from multiple centres who underwent Aβ PET. We trained ML algorithms using a training cohort (324 aMCI from Samsung medical center) with two‐phase modelling: model 1 included age, gender, education, diabetes, hypertension, apolipoprotein E genotype, and neuropsychological test scores; model 2 included the same variables as model 1 with additional MRI features. We used four‐fold cross‐validation during the modelling and evaluated the model on an external validation cohort (187 aMCI from the other centres).

Result

Model 1 showed good accuracy (area under the receiver operating characteristic curve [AUROC] 0·837) in cross‐validation, and fair accuracy (AUROC 0·765) in external validation. The addition of MRI features to the model 1 to create model 2 led to improvements in the prediction performance. Consequently, model 2 showed good accuracy (AUROC 0·892) in cross validation. Apolipoprotein E genotype, delayed recall task scores, and interaction between cortical thickness in the temporal region and hippocampal volume were the most important predictors of Aβ positivity.

Conclusion

Our results suggest that ML models are effective in predicting Aβ positivity at the individual level and could help the biomarker‐guided diagnosis of prodromal AD.
Recent regulatory and scientific developments suggest a novel oral formulation (CoM pat. pend.) of HP‐alpha‐cyclodextrin as a safe (not ototoxic) and convenient (oral) drug against Alzheimer's disease
Authors: Wittkowski Knut M.
Published: December 2021

Background

There are no disease‐modifying treatments (DMTs) for Alzheimer's disease (AD). HP‐beta‐cyclodextrin (HPβCD) was effective in AD models and, in Feb 2021, clinical results were presented at a conference: a phase 1/2 trial of IV HPβCD qow for >8 h had shown reduction of CSF tau protein after 12 wk. HPβCD is known for its risk of cholesterol‐related ototoxicity, but hearing loss was only transient (Fig. 1) and the FDA accepted INDs for overnight IV HPβCD as a drug against NPC1 (phase 3) and AD (phase 2).

Method

To test whether one could avoid ototoxicity and chaining patients to the bed overnight, we conducted a human PK/PD study of a novel (non‐covalent) clathrate of HPαCD and a milk/coconut oil medium‐chain fatty acid. HPαCD alone, co‐administered with, and as a clathrate with decanoate (both 2:1 molar) were administered orally before bedtime. HPαCD and phospholipids (PLs) were measured by FPLC in morning urine. We also conducted animal studies in breast cancer and movement disorders, where high levels of endocytosis are known to “derail” the endocytosis‐lysosome‐autophagy (ELA) axis.

Result

In the absence of dietary milkfat, no HPαCD was excreted into urine. With C10 added, some HPαCD and small increases in PLs were seen, but twice as much with the clathrate (Fig. 2). Animal studies showed IP HPαCD as more effective than HPβCD in breast cancer (reducing endocytosis and inflammation, Fig. 3) and also effective in movement disorders (not shown).

Conclusion

Intermittent fasting (IF) and the IF mimetic HPαCD (too small to fit cholesterol) were previously shown to be more effective than HPβCD in lysosomal storage diseases and in cancer, where endocytosis is also involved, albeit with manifestations in destinations different from AD (Fig. 4). With the new results showing that (a) the HPαCD clathrate ASD‐005 is intestinally absorbed, safe, and has systemic effects in other ELA axis diseases, including cancer (Ancidoni 2021, Alzheimers Res Ther 13:96), and (b) HP‐CDs are active across the blood‐brain barrier, two barriers against a more convenient, safer, and potentially more effective DMT for AD, as well as regulatory hurdles against cyclodextrins accepted as drugs were overcome in Feb 2021.
Characterizing brain age in the Alzheimer's disease connectome project using a deep neural network pre‐trained on the UK Biobank
Authors: Adluru Nagesh , Nair Veena A. , Prabhakaran Vivek , Bashyam Vishnu , Li Shi‐Jiang , Okonkwo Ozioma C. , Davidson Richard J. , Alexander Andrew L. , Bendlin Barbara B.
Published: December 2021

Background

Overall age of an individual is commonly measured in chronological time. With the advent of in vivo imaging and reliable predictive modeling, a finer gradation of the age into many internal biological scales such as cellular, tissue, organ and cognitive aging etc. can be estimated. Accurate estimation of the age of the in vivo brain can offer insights into its differential aging patterns and accelerated excess aging due to the burden of disease processes eventually leading to dementia. Modern machine learning algorithms have allowed for accurate estimation of “brain age” using MRI data. The purpose of this study was to evaluate the applicability of a 3D fully‐convolutional neural network (FCNN), pre‐trained on a large dataset of over ten thousand T1‐weighted (T1‐w) MR images from the UK Biobank to data from the Alzheimer’s disease connectome project.

Method

T1‐w data acquired from 152 participants were minimally pre‐processed (brain masking, B1 bias reduction, and linear registration to MNI) and input to the pre‐trained FCNN to predict their brain age. A linear regression between calendar age and brain age gap was used to correct the bias in each of the predicted brain age.

Result

The brain age predictions before and after bias correction, mean and spread of the calendar ages, mean absolute error of prediction for each group and sex are shown in Fig. 1. The quantiles of the excess brain aging are shown in Fig. 2.

Conclusion

With a minimal pre‐processing of T1w‐MRI, the UK Biobank pre‐trained deep neural network (DNN), along with a linear bias correction, provided an estimate of the age of the brain in ADCP with excellent approximation. The analysis revealed that the median gap between the brain age and calendar age is about a year in the AD group, and about half‐a‐year in the MCI group and none in the CU group, when averaged over the sexes. This provides preliminary evidence of accelerated aging of the brain in the cognitively impaired groups (MCI/AD). Future analysis involves examining excess brain and cognitive aging due to amyloid and tau burden. Future work entails developing DNNs to improve generalization, standardization, and individualized precision of such predictive models.
Amyloid aggregation in temporal regions is associated with longitudinal memory decline in cognitively unimpaired Apoe‐ε4 carriers
Authors: Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , Cacciaglia Raffaele , Salvadó Gemma , Collij Lyduine E. , Buckley Christopher , Van Berckel Bary N.M. , Perissinotti Andrés , Niñerola‐Baizán Aida , Milà‐Alomà Marta , Operto Grégory , Falcon Carles , Kollmorgen Gwendlyn , Suridjan Ivonne , Minguillón Carolina , Fauria Karine , Molinuevo Jose , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   for the ALFA Study
Published: December 2021

Background

Evidence shows that APOE‐ε4 is associated with amyloid‐beta (Aβ) aggregation in the medial temporal lobe (MTL), a crucial region supporting episodic memory (EM), early in the AD continuum. However, the impact of Aβ aggregation in the MTL of cognitively unimpaired (CU) APOE‐ε4 carriers has not been explored. We determine whether abnormal Aβ in the MTL of CU individuals APOE‐ε4 carriers has an impact on EM change.

Method

The study included 352 CU ALFA+ study individuals (age 45‐70) who completed a baseline cognitive assessment with valid T1w MRI, [18F]‐flutemetamol Aβ PET, CSF, and APOE genotyping, and also had a second cognitive assessment after 3 years. [18F]‐flutemetamol scans were visually assessed globally to rate the scan as positive or negative and regionally. CSF p‐tau, Aβ‐40 and Aβ‐42 concentrations were determined using the exploratory Roche NeuroToolKit assays, a panel of automated robust prototype immunoassays, and Elecsys® immunoassays (both Roche Diagnostics International Ltd). Hippocampal volumes (HV) were obtained from the T1w MRIs with Freesurfer 6.0. EM was assessed by the Memory and Binding Tests subscore Total Paired Recall (TPR). Annualized memory change was the dependent variable in linear models using regional or global visual read (VR), CSF biomarkers and HV as predictors, and age, sex, education and APOE‐ε4 as covariates. Interaction terms with APOE‐ε4 *VR were also modeled.

Result

57 (16.2%) participants were global VR amyloid‐positive and 41 (71.9%) were APOE‐ε4 carriers. For annualized change in memory, we found that APOE‐ε4 carriership modified the association between temporal VR and annualized change (p=0.02) (Figure 1). 29 (5.4%) were amyloid‐positive in temporal VR, of them 19 (65.5%) APOE‐ε4 carriers. This interaction remained significant after adjusting by CSF Aβ42/Aβ40 and ptau/Aβ42 ratios, and HV (Table 1). No significant interaction was found with global VR.

Conclusion

APOE‐ε4 carriers with a positive temporal VR exhibited a decline in EM. This result shows the effects on cognition of previous findings showing the association between APOE‐ε4 and Aβ aggregation in the MTL for any given level of soluble Aβ alterations. Moreover, this work supports that regional VRs can detect early Aβ pathology with relevant effects on cognition.
Mayo Test Drive: Reliability and construct validity of the Stricker Learning Span and Symbols Test on a self‐administered web‐based testing platform optimized for smartphone
Authors: Karstens Aimee J , Stricker John L , Geske Jennifer , Hassenstab Jason , Fields Julie A. , Mielke Michelle M. , Stricker Nikki H.
Published: December 2021

Background

Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for remote self‐administered assessment for novel (Stricker Learning Span; SLS) and open access (Symbols Test) cognitive measures. The SLS is a computer adaptive word‐list memory test that matches test difficulty to user performance. The SLS visually presents words for learning exposures and 4‐choice recognition to test encoding across 5 trials. Symbols is a measure of processing speed being used in many remote assessment studies and typically employs a burst design; in MTD participants complete 4 trials (12‐items each). We examine validity and reliability of the SLS and Symbols via MTD.

Method

Forty‐five women enrolled in an ongoing study of the Sex‐Specific Effects of Endocrine Disruption on Aging and Alzheimer’s Disease were recruited via email or phone. The Auditory Verbal Learning Test (AVLT) and Digit Symbol Coding (Coding), administered in person within the past 2 years (Mean=11 months), were used to establish construct validity. Participants (91.3% White, Mean age=66.2 years, Mean education=15.3 years) were emailed a link to complete the SLS and Symbols remotely at their convenience on their own device and emailed to repeat testing after approximately 1 week. Pearson correlations (n=45) and 2‐way mixed intraclass correlation coefficients (ICC; n=42) determined construct validity and test‐retest reliability, respectively. Significance was set at p<.05.

Result

Across all test sessions initiated, 97% were successfully completed. Most were completed at home (92.6%; vs. at work or in a public space), and device type varied (48% smartphone, 2% tablet, 50% PC). Median session completion time was 15 minutes. SLS learning scores (max span, total correct trials 1‐5) significantly correlated with AVLT 1‐5 total (r’s .37‐.39) and AVLT Trial 5 (r’s .51‐.52). SLS delay significantly correlated with AVLT delay (r=0.45) and recognition (r=0.61). Symbols time‐based scores averaged across trials were significantly correlated with Coding (r’s=‐.48‐(‐).50). Test‐retest reliabilities across 2 sessions were high for SLS (ICC’s=.80‐.88) and Symbols (ICC’s=.81‐.82).

Conclusion

SLS and Symbols are valid and reliable self‐administered remote tests in older females. Future work will examine effects of Alzheimer’s disease neuroimaging biomarkers and risk factors on these tests.
Alcohol consumption and cognitive impairment among Chinese older adults: 8‐year follow‐up of Chinese Longitudinal Healthy Longevity Study
Authors: Zhao Ziyi , Li Bingyu , Wei Chang , Sha Feng
Published: December 2021

Background

This is the first study examining the association between alcohol consumption and risk of cognitive impairment (CI) among Chinese older adults (65‐79 years).

Method

The study included 5,894 participants between 65 and 79 years from 2002‐2008 Chinese Longitudinal Healthy Longevity Study (CLHLS). The CI was assessed by Chinese version of Mini‐Mental State Examination (MMSE) . The self‐reported alcohol type and consumption were assessed and converted into pure alcohol consumption in gram. The adjusted cox proportional hazard model was implemented with age as time scale. With abstainers as the reference, hazard ratio (HR) for cognitive impairment was calculated for five levels of alcohol consumption (former drinker, 0.1‐175.0 g for male/0.1‐105.0 g for female per week, 175.1‐350.0 g for male/105.1‐210.0g for female per week, 350.1‐525.0 g for male/210.1‐315.0 g per week, >525.0 g for male/>315.0 g for female per week).

Result

837 (14.2%) participants developed CI in the follow‐up waves with mean follow‐up of 7.9 (SD 4.6, range 0.17‐17.3) years. There was no evidence that low‐to‐moderate alcohol consumption (0.1‐175.0 g for male/0.1‐105.0 g for female per week) was associated with increased risk of CI (HR: 1.25, 95% CI: 0.91‐1.74); however, heavy alcohol use (>525.0 g for male/>315.0 g for female per week) was associated with increased risk of CI (HR: 1.37, 95% CI: 1.01‐1.84). Compared with abstainers, former drinkers had higher risk of cognitive impairment (HR: 1.50, 95% CI: 1.17‐1.92). In addition, among former drinkers, previous consumption of alcohol above 175.0 g/week for male and 105.0 g/week for female was associated with higher incidence of dementia (HR: 1.61, 95% CI: 1.22‐2.11).

Conclusion

Excess alcohol consumption in men (>525.0 g/week) and in women (>315.0 g/week) are both significantly associated with increased risk of CI. There is no evidence that low‐to‐moderate alcohol drinking had protective effect against CI. Among former drinkers, heavy drinkers have higher risk of CI compared to non‐drinkers, suggesting heavy consumption of alcohol negatively influences one’s cognitive health in later life even after abstinence. Further investigation is required to determine whether these relationships are mediated by specific environmental or genetic factors.
Plasma and CSF biomarkers for Alzheimer’s disease among Caribbean Hispanics
Authors: Honig Lawrence S. , Kang Min Suk , Reyes‐Dumeyer Dolly , Lantigua Rafael A. , Zerlin‐Esteves Marielba , Piriz Angel , Criollo Brian , Dominguez Zoraida , Recio Patricia , Rivera Diones , Medrano Martin , Mayeux Richard
Published: December 2021

Background

Biomarkers provide earlier and more accurate diagnoses of Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) biomarkers have proven highly specific and sensitive in research studies (e.g. ADNI, BIOFINDER), although often including mostly well‐educated, white non‐Hispanics without co‐morbidities. CSF testing also requires lumbar puncture, so blood testing would be of great value. Here we examined a Caribbean Hispanic cohort, with measurements of both plasma and CSF biomarkers of amyloid (Aβ42, Aβ40), tau (p‐tau181), and neurodegeneration (t‐tau, NfL).

Method

Study cohort included individuals of Caribbean Hispanic ancestry (N = 123; 45 [37%] men, 78 [63%] women) enrolled in the Dominican Republic or New York City, who underwent venipuncture, lumbar puncture, and neurological assessments. Average age was 69.5 yr (sd 8.0; range 45‐91); APOE e4 genotypes were 50% without e4, 30.2 % e4 heterozygous, and 19.8% e4 homozygous. Clinical diagnoses included non‐demented (54%), mild cognitive impairment (MCI, 21%), and dementia (25%). No individuals had non‐AD dementias, so MCI and dementia were combined as “AD” (46%). Samples were stored at ‐80C, and assayed in duplicate (average coefficients of variation 4‐7%) on the Simoa SR‐X platform (Quanterix), using Neurology 3‐Plex A kits for Aβ42, Aβ40, and t‐tau, and separate assay kits for p‐tau181 and NfL. Ratios of Aβ42/Aβ40, t‐tau/Aβ42, and p‐tau181/Aβ42 were also calculated. Regression and ROC analyses were performed, including models adjusting for age, gender, and number of APOE e4 alleles, using IBM SPSS 27.

Result

Overall, individuals with AD showed elevated levels of both plasma and CSF t‐tau, p‐tau181, and NfL. There was significant correlations between plasma and CSF for p‐tau181 (r=0.45, p<0.0001), for NfL (r=0.62, p<0.0001), and for plasma ratios Aβ42/Aβ40 (r=0.33, P<0.001), t‐tau/Aβ42(r=0.34, p<0.001) and p‐tau181/Aβ42 (r=0.39, p<0.0001) but not for plasma Aβ40, Aβ42, or t‐tau individually. Plasma analytes performed moderately well, especially p‐tau181 and NfL, better than CSF, in classifying persons with cognitive impairment, with ROC areas under the curve (AUC) of 74.4% and 73.2% respectively. Plasma ratios of Aβ42/Aβ40, t‐tau/Aβ42, and p‐tau181/Aβ42 did not perform as well.

Conclusion

Plasma p‐tau181 and NfL biomarkers performed well in classifying AD, in comparison to CSF biomarkers, in this Caribbean Hispanic cohort.
Connectome‐based predictive modeling of cognitive reserve
Authors: Boyle Rory , Connaughton Michael , McGlinchey Eimear , Knight Silvin P. , De Looze Celine , Carey Daniel , Stern Yaakov , Robertson Ian H. , Kenny Rose Anne , Whelan Robert
Published: December 2021

Background

Cognitive reserve (CR) enables individuals to maintain cognitive function despite the presence of pathology or atrophy. CR may be most directly measured using functional neuroimaging. Connectome‐based predictive modeling can develop measures of cognitive phenotypes using task‐fMRI that can be applied to resting‐state fMRI, which is easier to collect and unaffected by task‐related confounds. We aimed to develop and validate a CR measure that could be applied to resting‐state fMRI data.

Method

Paper Folding task‐fMRI scans from 220 participants of the Cognitive Reserve/Reference Ability Neural Network studies formed a training set. Resting‐state fMRI scans from 294 participants from The Irish Longitudinal Study on Ageing formed a test set. fMRI data were preprocessed, motion‐corrected and parcellated into 205 nodes using the Shen atlas, excluding 63 brainstem and cerebellar nodes due to incomplete coverage. Functional connectivity matrices were calculated via Fisher z‐normalised correlations between the mean time series of each node‐pair.

Connectome‐based predictive modeling with leave‐one‐out cross‐validation was used to predict a CR residual from task‐based functional connectivity in the training set (Fig. 1). This generated three network‐strength predicted CR measures. We established the validity of these measures via a positive correlation with a CR proxy (NART scores) and global cognition, independent of brain structure. We then applied the model to the test set and assessed the validity of the resulting network‐strength measures.

Result

The three network‐strength measures accurately predicted the CR residuals of unseen participants (Fig. 2) and demonstrated validity as they were positively correlated with NART scores (Fig. 3) and global cognition, independent of brain structure. However, application of the model to the resting‐state data in the test set did not generate accurate predictions of the CR residual (Fig. 4) and the resulting measures did not correlate with NART scores nor global cognition (Fig. 5).

Conclusion

Validated measures of CR were generated using task‐based fMRI data but these measures did not generalise to resting‐state fMRI from an independent dataset. The inability to generalise may be because CR involves a reorganisation of connectivity in response to task demands or that the data here excluded the cerebellum.
No evidence for amyloid in the retina of Alzheimer's disease patients
Authors: den Haan Jurre , de Ruyter Frederique Jasmine Hart , Lochocki Ben , Kroon Maurice A.G.M. , Kemper Marleen , Scheltens Philip , Verbraak Frank , de Boer Johannes , Bouwman Femke H.
Published: December 2021

Background

The retina is increasingly recognized as a promising target to identify early changes associated with Alzheimer’s disease (AD). Previous studies showed presence of retinal amyloid in AD patients in‐vivo as well as in post‐mortem retinal tissue of AD patients. The objective of this study is to non‐invasively discriminate AD patients from controls with fluorescent retinal imaging, using curcumin as labeling fluorophore.

Method

26 AD patients (age 66(+9), MMSE≥18) and 14 controls (age 71(+12)) were enrolled from a tertiary memory clinic. Subjects were confirmed amyloid positive or negative based on CSF analysis and/or amyloid PET. We used three curcumin formulations: Longvida (10 days 4000 mg), Theracurmin (5 days 180 mg) and Novasol (4 days 300 mg). Plasma levels of curcumin and its derivatives were determined. Baseline and follow up scans of 2‐6 retinal regions were performed with blue autofluorescence imaging (λ = 486nm). Retinal images were visually assessed in a multidisciplinary setting. In addition a selection of retinal scans of participants receiving Longvida and Novasol were quantitatively analyzed.

Result

Plasma analysis yielded mean curcumin levels of 198.7 (±143.4) with Longvida, 576.6 nM, (±211.5) with Theracurmin and 1605.8 nM (±524.6) with Novasol. Visual analysis of baseline images showed no focal hyperfluorescence or other changes in AD‐patients compared to controls. Also, no differences were found when comparing pre‐and post‐curcumin images within AD patients and controls. Quantitative analyses confirmed a similar amount of focal hyperfluorescent spots in AD patients and controls. In addition no difference in increase of focal hyperfluorescence after curcumin intake could discriminate between AD patients and controls.

Conclusion

We found no focal retinal hyperfluorescence in AD patients or controls pre‐and post curcumin, even when using curcumin formulations that yielded higher plasma levels than Longvida, a formulation previously successfully used for this purpose. Implication: More and more initiatives are taken to assess retinal amyloid in AD patients and currently even commercial scans are brought to the market. We could not confirm that retinal changes described in previous studies represent retinal amyloid, and we were unable to replicate previous work discriminating AD patients from controls based on retinal amyloid visualization.
Is item response theory superior to classical test theory in scoring A‐IADL?
Authors: Negash Selam , Liu Cong , Randolph Christopher
Published: December 2021

Background

The Amsterdam IADL Questionnaire (A‐IADL‐Q) is increasingly being used in Alzheimer disease (AD) trials to assess activities of daily living. The authors of this scale (Sikkes et al., 2012) originally proposed an Item Response Theory (IRT) based scoring. While such an approach has some potential advantages, it requires a complex model, assumptions about population score distributions, and can be difficult to interpret clinically. An alternative to IRT scoring is the Classical Test Theory (CTT) method, which is relatively simple and easier to interpret. The present study compared IRT and CTT for scoring A‐IADL as a function of global cognition in healthy older adults and patients with mild‐to‐moderate AD.

Method

Aggregated data from three multinational clinical trials including subjects at the preclinical, early symptomatic, and moderate dementia phase of AD were analyzed. A‐IADL and CDR assessments at initial visits were evaluated and participants were classified into three groups based on CDR Global Scores: 0, 0.5, and 1. For IRT scoring, Graded Response Model (GRM) was used to estimate individual’s latent score. For CTT method, scaled average of scored responses were calculated. ROC analysis was conducted to evaluate the utility of each method in distinguishing between CDR groups.

Result

There were a total of 2,694 A‐IADL assessments across the three CDR groups. There was a very high correlation between CTT and IRT estimates of A‐IADL total score (r = 0.996, p < 0.05). As CDR Global Score increased, A‐IADL scores declined for both methods. In IRT scoring, the Item Characteristics Curve showed an overlap for most item responses, and the test information curve was narrow with a peak to the right of theta 0. Importantly, the ROC curve showed slightly better performance for CTT [AUC: 0.829 (0.812‐0.847)] compared to IRT [AUC: 0.809 (0.788‐0.830)].

Conclusion

The current study found that CTT scoring of A‐IADL performed slightly better in distinguishing AD populations as a function of global cognition/function. Given the procedural complexities and required assumptions for IRT scoring, the CTT method, which has the advantages of being more straightforward and familiar to clinicians, represents a better choice for most applications of this instrument.
EEG power bifurcation in the transition zone beta to gamma — from motor function to cognition — in Alzheimer and long COVID patients versus healthy controls revealed by quantitative EEG time series analysis of lateral EEG data
Authors: Wirner Frank , Fritsch Thomas , Scheuplein Sebastian , Dazian Dieter
Published: December 2021

Background

Similar EEG abnormalities suggest a nexus from Long COVID (LC) to Alzheimer‘s (AD) and probably to Parkinson‘s disease (PD). Symptoms like memory loss hint to a common cause. Ranasinghe (2020) showed EEG alpha slowing and hyper‐ and hyposynchrony for AD. In LC generalized EEG slowing (Antony, 2020) was reported. There is evidence that switching between brain hemispheres is necessary for scenery and object processing (Brincat, 2021), being disturbed in AD (Maass, 2020). However, explicitly lateral EEG for AD is rarely investigated. We calculate frontal asymmetry index (FAI) for F4/F3 EEG electrodes, which is normally used at alpha frequency for assessing emotional states in major depression (Davidson, 1998), not only for alpha but for further frequencies of AD patients. This possibly yields new biomarkers for AD and LC.

Method

FAI := logarithm of quotient between F4/F3 power, calculated for frequencies up to 120Hz of AD data taken from (Valladolid, Abasolo, 2017) and (Naples, Babiloni, 2018). AD and healthy control (HC) resting state EEG data from Valladolid were semi‐automatically artifact‐corrected and subdivided into 5s‐epochs. For AD patients and HCs the average of all 5s‐epochs was used for FAI. We recently determined power spectra and FAI from full‐length 10min resting‐state EEG for an LC patient, suffering from tremor. EEG power was calculated by averaged 5s‐epochs of raw‐data for F4/F3 for frequencies up to 100Hz.

Result

In Fig. 1 (Valladolid) FAI for F4/F3 is shown. A definite bifurcation occurs at 30Hz distinguishing AD group from HC. The power spectrum of an LC patient shows also at 30Hz frequency (Fig. 2) a significant increase, revealing high Beta EEG power conforming with severity of PD‐symptoms (O’Keeffe, 2020). Changing sign of asymmetry (i.e. FAI ∼ 0.3) can be observed at 30Hz (Fig. 3).

Conclusion

The application of FAI in the full frequency range shall further be investigated as a new biomarker for AD and LC. The EEG frequency range from 25Hz to 35Hz appears to be an important transition zone from motor function to cognition. Abnormalities in this frequency range might be linked to AD, PD and LC and could open a new diagnostic window.
Development of a site readiness framework to improve health system preparedness for potential new Alzheimer’s disease therapies
Authors: Geldmacher David S. , Christopher Roni , Anderson Misty , Bero Adam W. , Rubino Ivana
Published: December 2021

Background

The growing Alzheimer’s disease (AD) population, the continued emergence of AD biomarkers, and the potential approval of therapies that target the underlying pathophysiology of AD have the potential to transform the diagnosis, treatment, and monitoring of AD within health systems. Transformation of the AD patient care pathway will present significant challenges, and resources are needed to help health systems prepare to integrate potential new AD therapies into patient care.

Methods

Premier Applied Sciences developed a “Site Readiness Framework” for a new paradigm of AD care, with input from key medical experts in AD and select U.S. health systems, as well as financial support and input from Biogen. The development process involved interprofessional contributions from neurology, geriatrics, neuropsychology, psychiatry, radiology, infusion, memory disorders program coordination, and formulary management. Stakeholder interviews were conducted to illuminate the myriad challenges that potential new AD therapies may pose for health systems and guide the development of resources aimed to address those challenges.

Results

Key components of the Site Readiness Framework for AD include a program self‐assessment to help health systems identify gaps in preparedness for new AD therapies, and tools for mapping key considerations, such as purposeful referral of patients from primary care to a specialist, biomarker assessment, preparing for infusion therapy, and care coordination. An overview of the resources available within the Site Readiness Framework for AD, as well as a description of their potential application within a large academic health system, will be reported.

Conclusions

The approval of a disease‐modifying therapy for AD will require a transformation of the AD patient care pathway. The Site Readiness Framework for AD may help health systems prepare to integrate potential new therapies.
On gaps of clinical diagnosis of dementia subtypes: A study of Alzheimer's disease and Lewy body disease
Authors: Wei Hui , Masurkar Arjun V , Razavian Narges
Published: December 2021

Background

Alzheimer’s disease (AD) and Lewy body disease (LBD) are most common dementias, and can occur concurrently (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation could be difficult. Yet it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectrums and demographic variables. We aimed to compare clinical diagnosis and post‐mortem autopsy‐confirmed pathological results to assess the clinical subtype diagnosis quality across these factors.

Method

Participants were selected from the National Alzheimer’s Coordinating Center dataset, with autopsy‐confirmed AD and/or LBD results, and initial visits with Clinical Dementia Rating (CDR) of 0, 0.5, or 1.0. We analyzed the clinical AD and/or LBD diagnosis in first visits at each CDR stage. This analysis included precision (PPV), sensitivity and specificity of the clinical diagnosis, and disparities in these metrics by sex, race/ethnicity, age and education. If autopsy‐confirmed AD, LBD, or AD+LBD was missed in the clinic, the alternative clinical diagnosis was analyzed.

Result

1887 qualified participants (Table 1) from September 1, 2005 to August 20, 2019 were included. Clinical AD+LBD diagnosis had poor sensitivity from 3% (CDR 0.5) to 6% (CDR 2.0). Over 60% of participants with autopsy‐confirmed AD+LBD were diagnosed clinically as AD (Table 2). Clinical AD diagnosis had low sensitivities at early dementia stage (57%) and low specificities at all stages (Table 3). Among participants clinically diagnosed as AD, over 33% had autopsy‐confirmed concurrent LBD neuropathology. Clinical LBD diagnosis had poor PPVs from mild cognitive impairment (22%) to severe dementia (20%). Within participants clinically diagnosed as LBD, 32% to 54% revealed autopsy‐confirmed AD+LBD pathology. When clinicians missed these three subtypes, “No cognitive impairment”, “Undecided” and “Primary progressive aphasia or behavioral variant frontotemporal dementia” were the leading alternative clinical diagnosis. With increasing dementia stages, the difference in clinical diagnosis accuracy significantly increased between White and Black/African‐American participants, and diagnosis quality significantly improved for males but not for females.

Conclusion

Our findings demonstrates that the clinical diagnosis of AD, LBD and AD+LBD are inaccurate and harbor significant disparities based on race and sex at all dementia stages.
ACD856: A novel positive allosteric modulator of Trk‐signaling in clinical development for the treatment of Alzheimer’s disease
Authors: Nordvall Gunnar , Madjid Nather , Backlund Maria , Halldin Magnus , Rother Matthias , Nilsson Boel , Sandin Johan , Forsell Pontus
Published: December 2021

Background

Neurotrophin pathways, such as those mediated by NGF and BDNF, have in numerous studies been shown to be important for neuronal cell function, communication and cell survival in brain areas vital for cognitive function. Therefore, enhancers of NGF and BDNF signaling through positive allosteric modulation of the TrkA and TrkB receptors may be a valuable new option for the treatment of cognitive decline in various disease states. The aim of this study was to identify and characterize compounds that potently stimulate neurotrophin signaling by binding to the Trk‐receptors and to investigate the effects of such a compound in various preclinical model. Moreover, the aim was also to assess its safety and tolerability in both animals and man.

Method

All binding studies were performed using a Biacore instrument. The effects of ACD856 were investigated in different preclinical in vivo behavioural models to assess its effect on cognitive function. Safety and toxicology studies were subsequently conducted in line with regulatory requirements before a microdosing study in humans was performed to evaluate the pharmacokinetics, safety and tolerability in man.

Result

A binding site on the intracellular domain of TrkA was observed for the compound ACD856 using surface plasmon resonance experiments. In an in vitro kinase assay using human full‐length TrkA, ACD856 could significantly increase the apparent maximal velocity (Vmax(app)) of TrkA. ACD856 also demonstrated potent pro‐cognitive effects in vivo, with a favorable PK profile. The compound was shown to be safe and well tolerated in the preclinical toxicological studies. Micodosing results in man showed that ACD856 had a profile suitable for further clinical develoment.

Conclusion

The in vitro results suggests that ACD856 binds directly to the TrkA receptor to increase the number of catalytic cycles per timepoint. This mechanism of action is a probably a likely cause for the observed in vivo effects with respect to improved cognitive performance. These data suggest that ACD856 may have a beneficial effect on cognition in patients with cognitive dysfunction and the compound is currently in clinical development for the treatment of cognitive dysfunction in Alzheimer’s disease.
Polygenic risk scores predict cognitive impairment as measured by the Preclinical Alzheimer Cognitive Composite (PACC) score in the ADNI cohort
Authors: Pither Richard , Daunt Paula , Davidson Greg , Gibson Alex , Gao Qian , Oshota Olusegun
Published: December 2021

Background

The development of diagnostic tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of Polygenic Risk Scores (PRS) is gaining increasing attention for generating an individual genetic risk profile and subsequent estimation of future disease risk in Alzheimer’s Disease. We have previously reported on the performance of our PRS to differentiate Alzheimer Disease cases from healthy controls in the ADNI cohort and also cognitive decline using ADAS‐Cog13 and CDR‐SB scales. In this work we have analysed whether the PRS is able to predict more subtle changes in cognition by using PACC scores of ADNI cohort participants. The aim being to demonstrate the utility of PRS approaches in longitudinal studies and future clinical practice.

Method

This study explored the performance of the Cytox genoSCORE™ PRS algorithm as measured using a receiver operating characteristic curve (ROC) curve to predict a PACC score of <‐1, as measured upon entry into the study. 724 subjects who entered the study as either cognitively normal, or with a diagnosis of mild cognitive impairment are included in the analysis based on availability of PACC scores and of genetic data in the ADNI database. Further analyses to predict longitudinal changes in PACC have also been performed.

Result

In a population of 724 individuals genoSCORE™ has an accuracy as measured by area under the curve (AUC) of 65.6% in predicting those individuals with cognitive impairment as measured by the PACC scale (threshold <‐1). A similar analysis performed using age as the predictor in the same group showed no discernible correlation with lower PACC scores.

Conclusion

Identifying individuals of higher risk for cognitive decline due to Alzheimer’s Disease irrespective of their baseline cognitive performance will allow clinical trialists to enrich their studies with more appropriate patients. In addition, use of such risk evaluation techniques in clinical practice will enable clinicians to make more informed decisions on how to manage their patients. Cytox is able to provide a robust end‐to‐end process to provide this comprehensive genetic risk assessment.