Welcome to the AD/PD™ 2022 Interactive Program

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Displaying One Session

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134

BIOMARKER MODELING OF ALZHEIMER'S DISEASE USING IN VIVO BRAAK STAGING

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134
Lecture Time
02:45 PM - 03:00 PM

Abstract

Aims

Alzheimer’s disease (AD) is the leading cause of dementia worldwide and can be detected in vivo using biomarkers of amyloid-b and tau. Gold standard diagnostic methods for AD rely on staging systems to measure disease severity, which have not yet been incorporated into the in vivo biological research framework for AD. The topographical information conferred by tau-PET offers the potential to translate the gold standard histopathological Braak staging system to living individuals.

Methods

Using [18F]MK6240 tau-PET, we applied the Braak staging model to 345 individuals. We measured amyloid-PET, cerebrospinal fluid (CSF) and plasma phosphorylated tau (pTau) epitopes, neurodegeneration and neuropsychological function in relation to in vivo Braak stage. ANOVA assessed relationships between Braak stage with biomarker and clinical changes. Progression of in vivo Braak stage was assessed in 163 individuals with follow-up [18F]MK6240 scans.

Results

Advancing in vivo Braak stage was associated rising plasma pTau species, as well as rise and plateau of amyloid-PET & CSF pTau species. Early Braak stages were associated with isolated memory impairment, while later Braak stages were closely associated with the severity of dementia. Follow up tau-PET scans indicated sequential progression of in vivo Braak stages over time, with substantially higher rates of progression in amyloid-β+ individuals.

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Conclusions

In vivo Braak stages had stage-specific associations with the severity of amyloid-b deposition, CSF measures of pTau and clinical function. In vivo Braak staging contributes to the understanding of the natural history of biological AD and provides a framework to measure AD severity in living humans.

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A MODEL COMBINING TAU PET, BASELINE COGNITION AND NEUROFILAMENT LIGHT OPTIMALLY PREDICTS COGNITIVE DECLINE OVER 24 MONTHS IN AMNESTIC MILD COGNITIVE IMPAIRMENT AND DEMENTIA

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134
Lecture Time
03:00 PM - 03:15 PM

Abstract

Aims

To determine the best combination of tau-PET, MRI, cognition, APOE status, as well as phosphorylated tau (p-tau217), neurofilament light (NfL), Ab42/Ab40 measured in plasma and cerebrospinal fluid (CSF) for predicting cognitive decline.

Methods

Eighty-two participants with amnestic MCI or mild dementia were recruited. Participants were assessed at baseline with blood and CSF sampling, MRI, [18F]RO948 (tau)-PET, and cognitive testing. Linear regression models (adjusted for age, sex, education and baseline MMSE) were used to assess the ability of biomarkers (individually and in combination) to predict cognitive decline in MMSE over two years.

Results

Baseline tau-PET combined with plasma (or CSF) NfL and a composite baseline cognitive score provided the best model fits for predicting cognitive decline (plasma:R2=0.51, AIC=-37.9; CSF:R2=0.51, AIC=-37.7, versus demographics only model R2=0.16). The combination of tau-PET, NfL and baseline cognition predicted cognitive decline with high AUCs (0.87[95% C.I.=0.78-0.96] using CSF-NfL; and 0.85[95% C.I.=0.74-0.97] using plasma-NfL. Further, using these models to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. These models also enriched for Ab-positive cases (68% were Ab-positive in the unselected population, and 93% in the top 50%). The model was implemented as a publicly available online tool for individual prediction of cognitive decline.

Conclusions

A model including tau-PET, NfL and baseline cognition provided the best prediction of change in MMSE over 2 years in patients with amnestic MCI or mild dementia. Participant selection using this model significantly reduced the number of participants needed in clinical trials with cognition as the primary endpoint.

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SHORT-TERM PSYCHOLOGICAL IMPACT OF PRECLINICAL AΒ PET DISCLOSURE: PRELIMINARY FINDINGS FROM THE WISCONSIN REGISTRY FOR ALZHEIMER’S PREVENTION

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134
Lecture Time
03:15 PM - 03:30 PM

Abstract

Aims

Efforts towards earlier detection of Alzheimer’s disease (AD) together with improved accessibility of biomarker tests means more adults may learn their preclinical biomarker results. While Aβ-PET result disclosure has been safe so far, additional samples and research on utility of learning results are needed. The Wisconsin Registry for Alzheimer’s Prevention recently began disclosing Aβ-PET results to assess its impact on psychological well-being, health behaviors, and long-term planning.

Methods

Cognitively unimpaired participants learned their Aβ-PET results (n=40,mean age=70.9±4.6). We examined depressive (PHQ-9) and anxiety (GAS-10) symptoms as a function of Aβ, study visit, and their interaction using linear mixed effects modeling. We assessed between-group differences on test-related distress measures (INI-AD, IES) post-disclosure using Mann-Whitney U-tests.adpd_sampletable.png

Results

Neither depressive nor anxiety symptoms showed trends varying by Aβ result, suggesting symptom changes did not significantly differ between Aβ-elevated (n=28) and Aβ-non-elevated individuals (n=12). phq_adpd.pnggas_adpd.pngBoth distress measures significantly differed by Aβ-result, with Aβ-elevated individuals reporting more test-related distress directly following disclosure (INI:r=0.38,W=817,p=0.003;IES:r=0.26,W=392,p=0.02).distressspaplots.png Neither group reported depressive, anxiety, or distress symptoms at clinically-significant levels. Occasionally (n=3), despite passing psychological screening, upon interviewing at the disclosure visit, the clinician and participant decided jointly not to proceed with disclosure. To date, no participants have reported intention to harm themselves upon learning they had an increased risk for AD.

Conclusions

These results are encouraging and contribute to the growing consensus that disclosing preclinical AD biomarkers is safe and well-tolerated. As data collection continues, we will assess the safety, efficacy, and utility of disclosure for lifestyle and long-term care planning.

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PREVALENCE AND LONGITUDINAL COGNITIVE OUTCOMES OF NEGATIVE, MODERATE, AND ADVANCED 18F-FLORTAUCIPIR PET VISUAL PATTERNS IN AGING AND ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134
Lecture Time
03:30 PM - 03:45 PM

Abstract

Aims

The advent of positron emission tomography (PET) imaging with tracers such as 18F-flortaucipir (FTP) has allowed in-vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed and approved by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal outcomes of the different AD-associated visual patterns have not been investigated systematically.

Methods

We included cognitively normal, mild cognitive impairment, and AD dementia participants from five cohorts — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort— who had FTP PET scans available. Seven readers, blinded to clinical and imaging information, will evaluate each FTP PET image, and a patient’s FTP uptake pattern will be interpreted as negative, moderate, or advanced based on the majority read interpretation of the seven readers.

Results

A total of 1897 participants had FTP PET scans available. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β-amyloid status. Further, in the subset of participants with available longitudinal cognitive data, we will explore how the different FTP patterns associate with rates of cognitive decline across the aforementioned clinical groups.

Conclusions

Our study will contribute to elucidating the clinical relevance of FTP visual patterns in the early stages of AD, potentially promoting its use in patient assessment and in clinical prevention trials.

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HYPERSPECTRAL RETINAL IMAGING IN ALZHEIMER’S DISEASE: EVALUATION OF ITS SPECIFICITY AND ADDED VALUE IN A MULTIMODAL RETINAL IMAGING APPROACH FOR DIAGNOSIS OF DISEASE

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134
Lecture Time
03:45 PM - 04:00 PM

Abstract

Aims

Despite decades of intensive research, adequate diagnosis and treatment for AD are still unmet medical needs. The lack of techniques for patient screening and early diagnosis is believed to be one of the major reasons for this. By utilizing the retina as the most accessible portion of the central nervous system, the ADMIRE (Alzheimer’s disease Detection using Multimodal Imaging of the Retina) project aims to address the need for a novel, cost-effective, non-invasive, and widely available biomarker for AD, for identifying people at risk of AD who require additional neurological examinations, for longitudinal disease monitoring, and for (pre)clinical research in the pursuit of more effective treatments.

Methods

Our approach is based on the accumulating evidence for specific deterioration in retinal structure in AD patients and animal models, and the emerging evidence highlighting the potential for in vivo retinal hyperspectral imaging (HSRI) to serve as a biomarker for brain amyloid-β accumulation.

Results

By combining multimodal retinal measurements through HSRI and optical coherence tomography, we have quantified Aβ protein accumulation and neurodegeneration in the retina and established a classification model to differentiate individuals with AD from those without. In a next step, we are evaluating the specificity of HSRI by exploring HSRI signatures in different proteinopathies.

Conclusions

Preclinical research in different mouse models of neurodegenerative proteinopathies indicates distinct HSRI signatures for amyloid, tau and alpha-synuclein. These findings are now being further validated in patients with AD, Parkinson’s disease, frontotemporal dementia and dementia with Lewy bodies.

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SERUM GFAP DIFFERENTIATES ALZHEIMER´S DISEASE FROM FRONTOTEMPORAL DEMENTIA AND PREDICTS MCI TO DEMENTIA CONVERSION

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134
Lecture Time
04:00 PM - 04:15 PM

Abstract

Aims

Reactive astrogliosis is a hallmark of Alzheimer´s disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. In this multicenter study including 610 individuals, we investigated whether serum levels of the astroglial marker GFAP are different in patients with AD dementia, MCI-AD and behavioural variant FTD (bvFTD).

Methods

The study included serum samples from patients diagnosed with AD dementia (n=230), mild cognitive impairment due to AD (MCI-AD, n=111), bvFTD (n=140) and controls (n= 129). A sub-group of MCI-AD (n=32) patients was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, pTau181 and NfL were measured by Simoa (Quanterix) and Ella (ProteinSimple).

Results

In total, samples from 610 individuals from four clinical centers where investigated in this study. Serum GFAP levels in AD dementia were increased (median 375pg/mL, IQR 276-505pg/mL) compared with controls (167pg/mL, IQR 108-234pg/mL) and bvFTD (190pg/mL, IQR 134-298pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300pg/mL, IQR 232-433pg/mL, p<0.001) and was higher in MCI-AD patients who developed dementia during follow-up (360pg/mL, IQR 253-414pg/mL vs. 215pg/mL, IQR 111-266pg/mL, p<0.01, AUC=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%).

Conclusions

Our data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.

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Α-SYNUCLEIN CONFORMATIONS AS NOVEL BIOMARKERS IN BLOOD OF PD PATIENTS

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134
Lecture Time
04:15 PM - 04:30 PM

Abstract

Aims

Until recently, a presumed key player in Parkinson’s disease (PD), the α-Synuclein protein (αSYN), has been considered to exist as an “unfolded” monomer. Increasing evidence however, suggested, that native αSYN exists in different conformations, i.e. monomers and multimers in blood and brain tissue. We already showed that destabilization of αSYN multimers is associated with familial Parkinson’s disease due to SNCA mutations. In addition, we could demonstrate a brain-region specific alteration of αSYN multimers in idiopathic PD (iPD) patients according to the classical Braak spreading theory. Thus, the proposed project addresses the question whether physiological, aggregation-resistant αSYN multimers are also decreased in blood from iPD patients.

Methods

The detection of αSYN multimers is based on an in vitro crosslinking protocol of frozen EDTA blood samples. Samples were depleted of Hemoglobin and crosslinked using the the aminolinker disuccinimidyl glutarate. αSYN multimers and momoners are visualized via SDS-Page and Western blotting.

Results

We assessed the αSYN tetramer/monomer ratios in asymptomatic G51D carriers, idiopathic PD patients and healthy controls. Interestingly, the αSYN tetramer/monomer ratio is already decreased in the asymptomatic G51D carriers being at risk to develop PD. This supports the hypothesis that αSYN multimer destabilization precedes the development of clinical PD. We were also able to detect a significant decrease in αSYN tetramer/monomer ratios in idiopathic PD patients compared to controls.

Conclusions

According to our data, an ultrasensitive assay with antibodies directed against αSYN multimers in blood might help to detect slight and early changes in this possible novel PD biomarker.

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PRE-RECORDED: VIDEO-BASED GAIT ANALYSIS

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
ONSITE: 133-134
Lecture Time
04:30 PM - 04:45 PM

Abstract

Abstract Body

Background and Objective: Clinician-based rating scales or questionnaires for gait are subjective and sensor-based analysis is limited in accessibility. To develop an easily accessible and objective tool to evaluate gait, we analyzed gait from a single 2-dimensional (2D) video.

Methods: We prospectively recorded 2D videos of PD patients (n=16) and healthy controls (n=15) performing the timed up and go test (TUG). The gait was simultaneously evaluated with a pressure-sensor (GAITRite). We estimated the 3D position of toes and heels with a deep-learning based pose-estimation algorithm and calculated gait parameters including step/stride length, step/stride time, gait velocity, cadence and variability for step/stride length and step/stride time which was validated with the GAITRite. Then, we applied the algorithm to previously recorded and archived videos of PD patients (n=32) performing the TUG.

Results: From the validation experiment, gait parameters (step length, step time, stride length, stride time, gait velocity, cadence) derived from video tracking were in excellent agreement with the parameters obtained with the GAITRite. (Intraclass correlation coefficient > 0.9). The variability for step/stride length and step/stride time were in moderate agreement (Intraclass correlation coefficient > 0.6) with the GAITRite. From the analysis with the archived videos, step/stride length, gait velocity was significantly correlated (Absolute R > 0.4, p < 0.005) with the Freezing of gait questionnaire, Unified PD Rating scale part III total score, HY stage and postural instability. Furthermore, the video-based tracking objectively measured improvement of step/stride length, gait velocity with antiparkinsonian medication.

Conclusion: 2D video-based tracking could objectively evaluate gait.

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