SYMPOSIUM

AD DIAGNOSIS, EARLY PHASE AD, CLINICAL TRIALS (2)

Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Session Description
PLEASE JOIN US FOR THE LIVE DISCUSSION FOR THIS SESSION AT 15:30 VIA THE AUDITORIUM LOCATED IN THE MAIN LOBBY.

FOLLOWING THE LIVE DISCUSSION, THE RECORDING WILL BE AVAILABLE IN THE ON-DEMAND SECTION OF THE AUDITORIUM.

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On-Demand

ADJUDICATING MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE AS A NOVEL ENDPOINT EVENT IN THE TOMORROW STUDY

Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia B
Lecture Time
08:00 - 08:15
Presenter
  • Lon S. Schneider, United States of America
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On-Demand

Abstract

Aims

MCI onset is an essential outcomes event in Alzheimer prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an international AD prevention trial.

Methods

The TOMMORROW study (NCT01931566) selected cognitively normal participants at increased genetic risk for Alzheimer’s and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered a participant’s clinical information was randomly assigned to a 3-member panel of an independent adjudication committee. Determination of whether a participant reached MCI or AD proceeded through up to three review stages, requiring unanimous decision.

Results

Of 3494 participants randomized, 648 cases involving 386 participants were adjudicated, resulting in 92 MCI events and 4 AD dementia. A total of 235 (61%) participants required only one adjudication. Most cases, 485 (74.8%), were decided by blinded independent review (Stage 1); 14.0% required broader collaborative review (Stage 2); and 11.1% full committee discussion (Stage 3). Concordance between site investigators’ clinical diagnoses and the adjudication committee’s endpoint decisions increased from 50% to approximately 93% after around 100 cases and was maintained at that level.

Conclusions

These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between a trial’s success and failure.

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VALIDITY AND SENSITIVITY OF THE COGSTATE BRIEF BATTERY FOR IN-CLINIC AND AT-HOME COGNITIVE ASSESSMENT IN ADNI-3

Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia B
Lecture Time
08:15 - 08:30
Presenter
  • Chris J. Edgar, United Kingdom
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On-Demand

Abstract

Aims

The Cogstate Brief Battery (CBB) is a computerized cognitive assessment validated for Alzheimer’s disease (AD) and unsupervised use. The CBB assesses processing speed, attention, visual learning, and working memory. The CBB is offered to cognitively normal (CN) and mild cognitive impairment (MCI) participants in ADNI-3. In-clinic visits are completed annually for MCI and every other year for CN, with both groups completing unsupervised assessments at-home within 14 days of the first in-clinic visit and every 3 months.

Methods

CBB data were analyzed for eight outcome measures to evaluate sensitivity to disease status (CN, MCI), effect of setting (in-clinic, at-home), and change over time.

Results

Data were analyzed for 697 participants (459 CN, 222 MCI, 12 AD). Fewer participants completed a first at-home (n=365) versus a first in-clinic assessment (n=629). Statistically significant, small-moderate effect size differences between CN and MCI/AD (0.34 to 0.72) were evident at the first in-clinic visit. Effect size differences for in-clinic versus first at-home assessment, were small (<0.01 to 0.29) and non-significant, except for faster working memory reaction times at-home. Linear mixed models for participants completing 24 months (n=171), showed evidence for divergence between CN and MCI over time, a finding most evident on the learning and memory tests. Inclusion of amyloid status supported a predicted pattern of poorer cognition in amyloid positive participants.

Conclusions

Data from ADNI-3 support the validity and sensitivity of the CBB for unsupervised, at-home assessment, demonstrating known groups validity, equivalence between in-clinic and at-home assessment, and longitudinal sensitivity.

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CSF PROTEIN PANELS REFLECTING MULTIPLE PATHOPHYSIOLOGICAL MECHANISMS FOR EARLY AND SPECIFIC DIAGNOSIS OF ALZHEIMER’S DISEASE.

Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia B
Lecture Time
08:30 - 08:45
Presenter
  • Marta Del Campo, Spain
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On-Demand

Abstract

Aims

Development of disease-modifying therapies against Alzheimer’s disease (AD) requires early and specific diagnostic biomarkers that depict the molecular complexity of AD, whose clinicopathological features overlap with other common forms of dementia. Here we aimed to identify panels of cerebrospinal fluid (CSF) proteins covering different molecular pathways for early and specific diagnosis of AD.

Methods

We analyzed 979 proteins in CSF samples from patients with mild cognitive impairment with amyloid pathology (MCI-Aβ+;n=50), AD (n=230), non-AD dementias (n=322) and non-demented controls (n=195) using proximity ligation-based multiplex immunoassays

Results

CSF proteins were strongly dysregulated in MCI-Aβ+ (110 proteins) or AD (281 proteins) compared to controls as well as between AD and non-AD dementias (455 proteins). Proteins dysregulated in early AD stages were primarily related to oxidative stress and energy metabolism, while those dysregulated in later stages were related to cell remodeling, vascular function and immune system. We identified practicable CSF protein panels (<10 proteins) with a strong power to discriminate between MCI-Aβ+ or AD and controls (AUC: 0.99 and 0.95 respectively) or between AD and non-AD dementias (AUC: 0.87). The CSF panel discriminating AD from non-demented controls was validated in an independent cohort (n=62, AUC: 0.94). The selected proteins were linked to multiple AD-related mechanisms including energy/glucose metabolism, lysosomal function, vascular and immune system.

Conclusions

In this unprecedent large CSF study we identified and validated protein panels reflecting the specific molecular fingerprint of AD with high accuracy, which can be translated into customized assays for widespread validation and potential use in routine diagnosis or clinical trials.

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THE MEDIATING ROLE OF CSF AMYLOID BETA 1-40 ON WHITE MATTER HYPERINTENSITIES IN EARLY-STAGE SPORADIC ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia B
Lecture Time
08:45 - 09:00
Presenter
  • Lene Pålhaugen, Norway
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On-Demand

Abstract

Aims

Amyloid beta 1-40 (Aβ40) in CSF is a promising biomarker for cerebral amyloid angiopathy (CAA)1. Here we assess the mediating effect of CSF Aβ40 on the increase in global and regional white matter hyperintensities (WMHs) in early-stage sporadic Alzheimer’s disease (AD).

Methods

221 controls and cases with subjective cognitive decline or mild cognitive impairment were included from the longitudinal Norwegian Dementia Disease Initiation (DDI) multi-site study. We stratified on CSF Aβ42 pathology (Aβ42+/-), using an amyloid-PET verified cutoff. Global and regional WMH volumes on FLAIR MRI were determined using a novel automated algorithm, and were normalized to global or regional brain volumes, respectively. Mediation analysis was performed to find the indirect effect of CSF Aβ40 on the association between Aβ42 status and WMHs, correcting for age, sex, pulse pressure and scanners.

Results

We found that 23% of the increase in global WMHs and 17-33 % of the increase in regional WMHs in Aβ42+ individuals was mediated by CSF Aβ40 levels, with the largest indirect effect in the occipital lobe. There were significant direct effects of Aβ42+ status on global, parietal and temporal WMH loads.

plot_mediation_analysis.jpg

Conclusions

These results suggest that increased WMH load in early-stage sporadic AD is partially mediated by CAA, but also support the hypothesis that WMHs are a core feature in AD.

1. Van Etten ES et al. β-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy. Neurology 2017

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TIMING AND ORDER OF PATHOLOGICAL EVENTS IN ALZHEIMER'S DISEASE: FOCUS ON THE TRAJECTORY OF THE AWARENESS OF COGNITIVE DECLINE

Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia B
Lecture Time
09:00 - 09:15
Presenter
  • Federica Cacciamani, France
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On-Demand

Abstract

Aims

We built an Alzheimer’s disease (AD) Course Map depicting the timing and order of the pathological events occurring during AD progression, with a particular focus on the evolution of the awareness of cognitive decline (ACD).

Methods

We included 373 ADNI participants with positive markers of amyloid and tau (A+T+), and 145 A-T- cognitively-normal controls.

The AD Course Map was built by including measures of global cognition (MMSE), episodic memory (RAVLT), autonomy (FAQ), self- and informant-reported ratings of cognitive functioning (E-Cog), brain metabolism, hippocampal volume. An Awareness of Cognitive Decline Index (ACDI) was computed as the subject-informant discrepancy in the E-Cog score. All measures were normalized between 0 (normal) and 1 (abnormal). We used a non-linear Bayesian mixed-effects model in the Leaspy software (https://gitlab.com/icm-institute/aramislab/leaspy/).

Results

Our model identified the following temporal sequence of events in AD (see Figure): the episodic memory was the first measure to become abnormal in A+T+ subjects (i.e. different from controls), followed by autonomy, study-partner’s E-Cog score, brain metabolism and MMSE, hippocampal volume, and finally subject’s E-Cog score (this letter occurring around 3 years after the diagnosis of dementia).

The ACDI had a non-linear evolution: the subject initially experiences cognitive complaints but his/her ACD soon decreases, eventually constituting a clear anosognosia.

figure.png

Conclusions

The study of ACD in AD is a piece of the larger understanding of the pre-dementia phases. The presence of an informant is useful to identify the first signs of the disease and anticipate the diagnosis.

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BRAIN DARK MATTER – A NEW BIOMARKER FOR EARLY DETECTION OF ALZHEIMER DISEASE

Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia B
Lecture Time
09:15 - 09:30
Presenter
  • Satya VVN Kothapalli, United States of America
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On-Demand

Abstract

Aims

Brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer Disease (AD). However, postmortem studies show that loss of memory is related to loss of neurons that in AD exceeds volumetric loss of tissue. Thus, in vivo detection of neuronal loss prior to detectable atrophy is essential for early AD diagnosis.

Methods

We used quantitative Gradient Recalled Echo (qGRE) MRI for in vivo evaluation of neuronal loss in human hippocampus. Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy Controls (HC, Clinical Dementia Rating® [CDR®]=0, amyloidβ [Aβ]-negative, n=34); Preclinical (PC, CDR=0, Aβ-positive, n=19); and mild AD (CDR=0.5 or 1, Aβ-positive, n=17).

Results

qGRE identified two types of regions: one, practically devoid of neurons, we designate as “Dark Matter”, the other, with relatively preserved neurons, “Viable Tissue”. Hippocampal Dark Matter (Figure1) showed: (i) significant group differences among all groups - HC, PC and mild AD, while Total tissue volume did not differentiate PC from HC; (ii) greater neuronal loss (~37%) than volume loss (~15%) in the mild AD group compared with the healthy control group. Direct neuronal count from histopathological study of a participant who underwent in vivo qGRE 14 months prior to expiration showed a significant association with the hypointense R2t* signal (Figure2) that defines Dark Matter.

Conclusions

qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by morphological measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.

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REMOTE MOBILE APP-BASED MEMORY ASSESSMENTS REFLECT TRADITIONAL MEMORY MEASURES AND ARE SENSITIVE TO MEASURES OF TAU PATHOLOGY

Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia B
Lecture Time
09:30 - 09:45
Presenter
  • David Berron, Sweden
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On-Demand

Abstract

Aims

The medial temporal lobe is particularly affected by AD pathology. One of the earliest anatomical sites where tau pathology can be detected is the transentorhinal region which has been associated with mnemonic discrimination of similar objects. Recent studies showed that object mnemonic discrimination was associated with fluid and imaging measures of tau pathology. Here we set out to evaluate the relationship of an adaptation of this memory task for mobile devices in an unsupervised setting with neuropsychological measures and biomarkers of tau pathology.

Methods

59 non-demented individuals of the Swedish BioFINDER study (34% β-amyloid positive, mean age 62yrs, 59% female) participated in on-site memory assessments and underwent MRI and [18F]RO948 tau-PET scans. In addition, participants completed up to 12 remote memory tests using their own mobile devices. Here we report memory performance as a mean estimate across the first two remote sessions.

Results

Remote memory assessments correlated with computerized on-site assessments using a similar task for object-and-scene memory (Berron et al., 2018) (r=0.72,p<.001) as well as with delayed word recall performance (r=-0.57,p<.001). Remote object but not scene memory showed a significant relationship with tau-PET SUVr in the transentorhinal region (β=-0.11,SE=0.05,p=.039) and plasma pTau217 levels (β=-0.04,SE=0.017,p=.047). Finally, remote object memory was lower in individuals with thinner cortex in the transentorhinal region (β=0.31,SE=0.11,p=.009).

Conclusions

Our results demonstrate that remote and unsupervised memory assessments via mobile devices are (i) comparable to supervised computerized on-site testing, (ii) show a relationship with traditional neuropsychological measures for memory, and (iii) are sensitive to underlying tau pathology.

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ENGAGEMENT AND ADHERENCE TO REMOTE TESTING IN MIDDLE-AGED ADULTS AT RISK OF DEMENTIA

Session Type
SYMPOSIUM
Date
12.03.2021, Friday
Session Time
08:00 - 10:00
Room
On Demand Symposia B
Lecture Time
09:45 - 10:00
Presenter
  • Emily A. Thorp, United Kingdom
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On-Demand

Abstract

Aims

The COVID-19 pandemic has accelerated the need for digital solutions to allow Alzheimer’s research to continue, albeit in a modified form. Online platforms are powerful tools that can enable rapid, cost-effective assessments to be conducted remotely. However, the extent to which valid and high-quality data can be obtained, and the extent to which participant motivation is related to engagement and adherence rates remains unclear. Using data collected through the Healthy Brain Project, an online study of at-risk middle-aged adults, we aimed to describe demographic, motivational and adherence characteristics of participants who completed the CANTAB PAL assessments.

Methods

CANTAB PAL assessments were delivered using Cambridge Cognition’s secure web-based testing application via the Healthy Brain Project platform (healthybrainproject.org.au). To reduce participant burden, a 6-month window around an annual assessment was allowed. The average time between assessments was calculated for participants, who were then grouped by this time to investigate adherence to the assessment schedule.

Results

570 participants completed CANTAB PAL at multiple timepoints. 59% of participants adhered to protocol and completed the assessments yearly. However, results also showed that 14% of participants completed assessments on average less than 30 days post previous visit. This subgroup had higher errors on PAL at baseline and a higher mean age (58.6 years) compared to the group who completed the assessments at the correct intervals (56.2 years).

Conclusions

Participants appear engaged to improve their performance. Next steps include examining stability of performance to understand whether short follow-up relates to level of impairment.

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