15th International Conference on Parkinson’s and Alzheimer’s Diseases
dateMarch 9-14, 2021
The 15th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders, AD/PD™ 2021, will build on the well-earned reputation of the groundbreaking series of Alzheimer’s and Parkinson’s Diseases Conferences, which attract international medical and scientific professionals worldwide.
In light of the continuing uncertainty about the evolution of the COVID-19 pandemic and its impact on travel restrictions and physical distancing requirements throughout 2021, the AD/PD™ Organizing Committee has decided to transform this COVID crisis into a new opportunity and will hold the AD/PD™ 2021 conference as a fully online, virtual experience.
Quanterix will be sponsoring this important event with a virtual booth and lobby video.
Poster presentations featuring research facilitated by Simoa technology:
- P220 / #1487 J. Kaplow, et al
Theme A: ß-Amyloid Diseases / A4.c. Imaging, Biomarkers, Diagnostics: PET – amyloid
PERFORMANCE OF CSF AD BIOMARKERS IN PREDICTING AMYLOID PET POSITIVITY IN EARLY AD: DATA FROM EISAI’S MISSIONAD PROGRAM
2. P232 / #566 D. Alcolea, et al
Theme A: β-Amyloid Diseases / A4.h. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers
PLASMA BIOMARKERS IN THE AT(N) CATEGORIES FOR THE DETECTION OF ALZHEIMER’S DISEASE
3. P233 / #1264 E. Andersson, et al
Theme A: β-Amyloid Diseases / A4.h. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers CEREBROSPINAL FLUID AΒ42 AND AΒ40 AND THEIR RELATION TO SOLUBLE AND INSOLUBLE AΒ IN THE BRAIN IN ALZHEIMER’S DISEASE
4. P245 / #1259 A. Moscoso, et al
Theme A: β-Amyloid Diseases / A4.h. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers ASSOCIATION OF BLOOD PHOSPHORYLATED TAU181 AND NEUROFILAMENT LIGHT WITH PROGRESSIVE NEURODEGENERATION IN ALZHEIMER DISEASE
5. P254 / #1287 C. Rubel, et al
Theme A: β-Amyloid Diseases / A4.h. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers CROSS-PLATFORM EVALUATION OF HIGHLY SENSITIVE IMMUNOASSAY TECHNOLOGIES FOR SERUM MEASURES OF PTAU181: PERFORMANCE IN ALZHEIMER’S DISEASE
6. P255 / #1284 J. Simrén, et al
Theme A: β-Amyloid Diseases / A4.h. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers ALTERNATIVE PROTOCOLS TO SUPPORT BLOOD COLLECTION IN CHALLENGING PRE-ANALYTICAL CONDITIONS
7. P302 / #1436 C. Johansson, et al
Theme A: β-Amyloid Diseases / A6.a. Cell, Molecular and Systems Biology: APP, APLP, Abeta DIFFERENTIAL PLASMA BIOMARKER PROFILE IN FAMILIAL ALZHEIMER DISEASE
8. P384 / #934 K. Foster, et al
Theme B: Taupathies / B2.b. Therapeutic Targets, Mechanisms for Treatment: Immunotherapy
EVALUATION OF PNT001, A MONOCLONAL ANTIBODY DIRECTED TOWARD CIS-PT231 TAU, IN HUMAN TISSUE AND THE TG4510 TAU TRANSGENIC MOUSE
9. P391 / #659 T. Miyasaka, et al
Theme B: Taupathies / B2.m. Therapeutic Targets, Mechanisms for Treatment: Other
THE EXPRESSION OF MICROTUBULE ASSOCIATED PROTEIN TAU IN MICE PODOCYTE.
10. P538 / #1227 S. Canaslan, et al
Theme C: α-Synucleinopathies / C4.f. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers DETECTION OF DIAGNOSTIC RELEVANT BIOMARKER PROTEINS IN PLASMA AND CSF OF ALPHA SYNUCLEINOPATHIES BY SINGLE MOLECULE ARRAY (SIMOA)
11. P369 / #683 N. Zhu, et al
Theme B: Taupathies / B1.j. Disease Mechanisms, Pathophysiology: Astroglia
PLASMA GLIAL FIBRILLARY ACIDIC PROTEIN AND NEUROFILAMENT, AND THEIR COMBINATION AS BIOMARKERS IN FRONTOTEMPORAL DEMENTIA
12. P240 / #893 M. Grothe, et al
Theme A: β-Amyloid Diseases / A4.h. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers
NEUROPATHOLOGIC CORRELATES OF ELECSYS-DERIVED CEREBROSPINAL FLUID BIOMARKERS OF ALZHEIMER’S DISEASE IN COMPARISON TO A NOVEL PLASMA-BASED P-TAU181 BIOMARKER
13. P482 / #1461 A. Pilotto, et al
Theme C: α-Synucleinopathies / C1.p. Disease Mechanisms, Pathophysiology: Modeling of disease progression
PLASMA INFLAMMATORY AND NEURODEGENERATION MARKERS AND DISEASE PROGRESSION IN LEWY BODIES DISORDERS
14. P540 / #417 K. Fraser, et al
Theme C: α-Synucleinopathies / C4.f. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers
EVALUATING SERUM NEUROFILAMENT LIGHT AS A MEASURE OF TREATMENT RESPONSE IN STANDARD SIZED PH2 PARKINSON’S DISEASE TRIALS
Poster presentation featuring research performed using the Uman NF-Light™ Assay:
P545 / #175 E. Papuć, et al
Theme C: α-Synucleinopathies / C4.f. Imaging, Biomarkers, Diagnostics: CSF, blood, body fluid biomarkers
INCREASED CSF NFL IN NON-DEMENTED PARKINSON’S DISEASE PATIENTS REFLECTS EARLY WHITE MATTER DAMAGE
Oral presentations featuring research facilitated by Simoa technology:
- BLOOD BIOMARKERS FOR ALZHEIMER’S DISEASE – THE PROMISE FOR SCREENING, DIAGNOSTICS AND THERAPY MONITORING
Lecture Time: 10:30 – 10:45 10.03.2021, Wednesday
Presenter: Kaj Blennow, Sweden
Recent studies showing that it is possible to accurately detect the core AD pathologies amyloid deposition (A), tau pathology (T), and neurodegeneration (N), using easily accessible blood tests.
For A, ultrasensitive immunoassays and immunoprecipitation – mass spectrometry (IP-MS) methods show very high concordance (up to >90%) with brain amyloidosis evaluated by PET. For T, several phosphorylated tau species (P-tau181, P-tau217) in blood, show a specific increase in AD, and high concordance with tau PET. Further, plasma P-tau is increased very early, in cognitively unimpaired elderly who have a positive amyloid PET scan. For N, blood NFL reflects axonal degeneration, with plasma levels being increased even in early stages of the disease, but also tracks neurodegeneration during the AD continuum. These biomarkers also show very low variation in longitudinal samples, and thus promise as a tool to monitor drug therapies, but we are still awaiting data on how these blood biomarkers perform in clinical trials on drugs showing clinical benefit.
Further work is needed to standardize these assays for clinical use, especially the development of Certified Reference Measurement Procedures (“Gold Standard methods”) and Certified Reference Materials (aliquoted plasma pools with known biomarker levels) to assure batch-to-batch stability and for harmonization across assays. We also need studies validating the diagnostic performance in prospective studies using pre-set cut-offs, with samples analysed week by week as they come to the lab.
These blood biomarkers show promise for being clinically useful, easily accessible and cheap, tools for screening and possibly also diagnostics.
2. BLOOD BIOMARKERS FOR ALZHEIMER’S DISEASE AND OTHER NEURODEGENERATIVE DISEASES – UTILITY IN CLINICAL TRIALS AND PRACTICE
Lecture Time: 10:45 – 11:00 10.03.2021, Wednesday
Presenter: Henrik Zetterberg, Sweden
Two blood-based biomarkers have been analytically and clinically validated as biomarkers for Alzheimer’s disease (AD) pathophysiology: the ratio of the 42 to 40 amino acid-long amyloid β as a marker of amyloid plaque pathology, and phosphorylated tau as a marker of AD-related tau phosphorylation and secretion. Additionally, serum neurofilament light (NfL) can be used as a general (non-specific) marker of neurodegeneration. Here, I give an updated account of the current state of the blood-based AD biomarker research field. I discuss how the new blood tests may be used in research studies, as well as in clinical trials and practice, and what role they may play in relation to more established diagnostic tests, such as cerebrospinal fluid biomarkers and amyloid and tau positron emission tomography, in the clinical work-up of patients with suspected AD.
3. PREDICTION OF ALZHEIMER’S DISEASE DEMENTIA USING PLASMA P-TAU217 IN COMBINATION WITH OTHER NON-INVASIVE MEASURES: LONGITUDINAL STUDY FROM THE BIOFINDER AND ADNI COHORTS
Lecture Time: 08:00 – 08:15 13.03.2021, Saturday
Presenter: Sebastian Palmqvist, Sweden
To examine the accuracy of plasma phospho-tau217 (P-tau217) for predicting Alzheimer’s disease dementia (AD) when combined with other non-invasive biomarkers. The accuracy was compared to the clinical diagnostic prediction
328 participants with subjective cognitive decline (SCD, n=155) or mild cognitive impairment (MCI, n=173) at baseline were included from the Swedish BioFINDER study. Plasma P-tau217, cognitive tests, demographics, plasma Aβ42/40, plasma neurofilament light (NfL), and MRI (AD-signature cortical thickness) were examined using logistic regression models with conversion to AD at 2, 4 and 6 years, respectively, as outcomes. Model selection and area under the ROC curve (AUC) were validated in 531 participants with SCD or MCI from the ADNI study using plasma P-tau181 instead of P-tau217.
Plasma P-tau217 predicted conversion to AD with an AUC of 0.78 (95%CI 0.72-0.85) at 2 years, 0.82 (0.77-0.88) at 4 years and 0.85 (0.80-0.90) at 6 years. 2-year prediction of AD was improved by adding MRI, memory, executive function, and gender to P-tau217 (0.88, 0.83-0.94). 4-year prediction was improved by adding MRI, memory, and executive function (0.90, 0.86-0.93). 6-year prediction was improved by adding plasma Aβ42/40 and NfL, MRI, and memory (0.91, 0.87-0.94). In ADNI, similar models were selected with similar accuracies. The diagnostic prediction of memory clinic physicians blinded to biomarker data were inferior to all models (AUCs 0.68-0.73).
Plasma P-tau can accurately predict future AD, better than a clinical diagnostic prediction. The accuracy can be improved further by adding brief cognitive tests and MRI, and to a lesser extent plasma Aβ42/40 and NfL.
4. PLASMA AMYLOID, P-TAU217, NFL, AND GFAP AS BIOMARKERS OF AMYLOID PATHOLOGY IN COGNITIVELY HEALTHY INDIVIDUALS
Lecture Time: 08:15 – 08:30 13.03.2021, Saturday
Presenter: Shorena Janelidze, Sweden
To study if the accuracy of blood amyloid-β (Aβ) to detect Alzheimer disease (AD) at early stages could be improved by other blood biomarkers including phospho-tau217 (P-tau217), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP).
We measured plasma Aβ42/Aβ40 (Araclon mass spectrometry [MS] or Euroimmun ELISA [EL]), Ptau-217 (Lilly assay), NfL (Simoa assay) and GFAP (Simoa assay) in cognitively unimpaired elderly from the Swedish BioFINDER-1 (n=242) and BioFINDER-2 (n=338) studies. In BioFINDER-1, out of 239 individuals followed longitudinally, 12 converted to AD dementia. CSF Aβ42/Aβ40 measures were available in all study participants, 568 individuals underwent Aβ-PET.
In BioFINDER-1, plasma Aβ42/Aβ40MS identified individuals with abnormal CSF Aβ status with AUC of 0.79 (AIC=260). We observed a better performance (higher AUC and lower AIC) for models including plasma Aβ42/Aβ40MS and P-tau217 (AUC=0.83, AIC=230) or plasma Aβ42/Aβ40MS, P-tau217 and GFAP (AUC=0.85, AIC=224). In BioFINDER-2, the model with plasma Aβ42/Aβ40EL and P-tau217 as predictors provided better fit (AUC=0.84, AIC=319) for CSF Aβ status than plasma Aβ42/Aβ40EL alone (AUC=0.74, AIC=354). The results when using Aβ-PET instead of CSF Aβ status were very similar. In BioFINDER-1, a combination of plasma Aβ42/Aβ40MS and P-tau217 (AUC=0.82, AIC=88) better modelled conversion to AD dementia than plasma Aβ42/Aβ40MS (AUC=0.79, AIC=90). There was no further improvement when adding plasma NfL to the models.
The accuracy of blood test to detect preclinical cerebral Aβ pathology could be improved by combining plasma measurements of Aβ42/Aβ40, Ptau-217 and potentially GFAP.
5. DIAGNOSTIC PERFORMANCE OF BLOOD BIOMARKERS FOR ALZHEIMER’S DISEASE IN AN UNSELECTED MEMORY CLINIC COHORT
Lecture Time: 09:45 – 10:00 13.03.2021, Saturday
Presenter: Agathe Vrillon, France
To compare the diagnostic performance of plasma biomarkers for Alzheimer’s disease (AD) diagnosis in a diverse memory clinic setting.
We compared two recently developed plasma p-tau Single molecule array assays (p-tau181 and p-tau231), plasma neurofilament light (NfL) and plasma amyloid ratio (Aβ42/40) in diagnosing AD and identifying amyloid positivity, in 310 subjects: 32 controls, 60 with AD related mild cognitive impairment (MCI) and 104 with AD-dementia, 31 non-AD dementia’s (Lewy body dementia, frontotemporal dementia and vascular dementia), and 83 with non-AD related MCI. Patients were recruited in a memory clinic setting (Hospital Lariboisière, Paris, France).
P-tau181, p-tau231 and NfL demonstrated high accuracy in identifying AD compared to controls (p-tau181: AUC=88.7%; p-tau231: AUC=85.4%; NFL: AUC=84.4%), performing better than amyloid ratio (AUC=70.2%). P-tau231 and p-tau181 also distinguished AD-MCI from controls (p-tau181: AUC=78.6%; p-tau231: AUC=78.4%). Both tau biomarkers separated amyloid+ from amyloid– patients (p-tau181: AUC=80.48%; p-tau231: AUC=80.31%), with higher accuracy than NfL (AUC=65.8%) and amyloid ratio (67.8%). P-tau181 and p-tau231 also distinguished AD from non-AD dementia (p-tau231: AUC=82.72%; p-tau181: AUC=81.22%), as opposed to NfL (AUC=57.78%).
Plasma p-tau181 and p-tau231 accurately identified AD at MCI and dementia stages of the disease, and efficiently distinguished AD dementia from non-AD dementia in a clinical setting. These could be simple and accessible tests for AD screening and diagnosis.
6. NOVEL TOTAL TAU ASSAYS: EXPLORING TAU FRAGMENTS IN ALZHEIMER’S DISEASE AND OTHER NEUROLOGICAL DISORDERS
Lecture Time: 12:45 – 13:00 14.03.2021, Sunday
Presenter: Anniina Snellman, Sweden
Cerebrospinal fluid (CSF) total tau (t-tau) is an established Alzheimer’s disease (AD) biomarker, while plasma t-tau only shows a marginal change. This may be due to a rapid metabolism and fragmentation of tau in plasma. We aimed to develop alternative immunoassays targeting different N-terminal and mid-region tau fragments and to investigate their performance in AD and other neurological conditions.
Three ultrasensitive immunoassays targeting mid-region and N-terminal tau fragments were developed using Single molecule array (Simoa) technology. The pilot cohort consisted of paired CSF (35μl/assay) and plasma (70μl/assay) samples defined as AD (N=22) or controls (N=22) based on core AD CSF biomarkers. Samples were additionally analysed with the commercially available Simoa t-tau kit (Human Total Tau 2.0, Quanterix).
In CSF, all N-terminal and mid-region tau fragments were increased in AD patients compared with controls (p<0.001 for all assays, Figure 1). ROC analysis showed that the mid-region and N-terminal A fragments were able to separate the groups with an AUC of 88% (95% CI: 77-100% and 75-100%), performing slightly better than the commercial assay (AUC 83%; 95% CI: 70-96%, Figure 2). However, no difference between groups was seen in plasma (p=0.48-0.68; AUC 54-57% for all assays).
All t-tau assays detected significantly increased CSF tau levels in AD; however, plasma t-tau had limited value as a biomarker for AD pathology. Future experiments aim to investigate the presence and temporal course of different CSF tau fragments in larger cohorts including AD, and other neurological disorders, such as Creutzfeldt-Jakob disease and stroke.
7. NOVEL PLASMA P-TAU231 IN ALZHEIMER’ DISEASE: EARLY INCREASE INDICATES UTILITY FOR PREVENTIVE TRIAL SELECTION
Lecture Time: 13:15 – 13:30 10.03.2021, Wednesday
Presenter: Nicholas J. Ashton, Sweden
Plasma p-tau181 and p-tau217 have shown excellent utility in the differential diagnosis of dementia patients. However, increases at the preclinical stage are subtle and may not be optimal for detecting preclinical pathology. Our recent work in cerebrospinal fluid (CSF) indicates p-tau231 to be a preclinical biomarker for AD pathology, which motivated us to develop a novel molecule array (Simoa) to detect p-tau231 in plasma.
We developed and validated a novel plasma p-tau231 in-house Simoa assays at the Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Sweden, in 541 participants of 3 independent cohorts.
In the discovery cohort (n=38), plasma p-tau231 demonstrated high accuracy to predict AD (AUC=0.941). In the validation cohort (n=313), plasma p-tau231 had high accuracy in determining AD from young (AUC=0.951), Aβ- elderly (AUC=0.915), Aβ- MCI (AUC=0.883) and other neurodegenerative disorders (AUC=0.923). In addition, plasma p-tau231 showed remarkable accuracy for the identification of tau PET and Aβ PET positivity (AUC=0.93). Comparing Aβ- elderly and Aβ+ elderly individuals without cognitive decline, p-tau231 had a high accuracy (AUC=0.884) to detect preclinical Aβ pathology, which was superior to plasma p-tau181 (AUC=0.771). Plasma p-tau231 predicted longitudinal cognitive decline (P=0.02) and correlated with Aβ PET, tau PET and CSF p-tau231 (r>0.610).
Our results indicate that plasma p-tau231 might be a superior marker for identifying preclinical AD. Thus, plasma p-tau231 has the potential to provide an invaluable contribution as a biomarker of both screening of preclinical AD and AD dementia diagnosis for the use in clinical practice and trials.
8. PLASMA GFAP INDICATES AMYLOID PATHOLOGY IN THE ALZHEIMER’S DISEASE SPECTRUM.
Lecture Time: 13:45 – 14:00 10.03.2021, Wednesday
Presenter: Andrea L. Benedet, Sweden
To evaluate how plasma glial fibrillary acidic protein (GFAP) associates with core PET, CSF and plasma biomarkers of the Alzheimer’s disease (AD) pathophysiology.
Plasma GFAP was quantified using a commercial Simoa assay on 330 participants of the Translational biomarker in aging and dementia (TRIAD) cohort (36 young individuals (<30 years old), 168 cognitively unimpaired (CU), 62 mild cognitive impairment (MCI), 45 AD, and 12 frontotemporal dementia (FTD) patients). These participants had also [18F]AZD4694 and [18F]MK6240 PET imaging data. Participants had also quantified CSF Ab42/40, p-tau181 and t-tau on the Lumipulse platform. In addition, CSF and plasma neurofilament (NfL) light and plasma p-tau181 were quantified with in house assays on the Simoa platform. The distribution of plasma GFAP concentration was compared across groups using linear regression models adjusting for age and sex. In addition, Spearman rank correlations were employed between biomarkers. Finally, mediation analyses were used to further evaluate the relationship between plasma GFAP and amyloid and tau pathologies in this context.
Plasma GFAP was found to progressively increase with age (P=3.4×10-9) and disease severity (P=4.6×10-11), showing its lowest concentration levels in young participants and the highest in AD patients (Figure 1). Plasma GFAP was also highly correlated with amyloid pathology, neurodegeneration biomarkers and tau pathology. Interestingly, mediation analysis indicated that the associations with t-tau, p-tau181 and tau PET biomarkers are dependent on amyloid pathology levels.
Plasma GFAP is a biomarker that reflects amyloid pathology in the AD spectrum.
9. PLASMA GLIAL FIBRILLARY ACIDIC PROTEIN PREDICTS AMYLOID STATUS AND FUTURE CONVERSION TO ALZHEIMER’S DISEASE IN A MILD COGNITIVE IMPAIRMENT LONGITUDINAL COHORT
Lecture Time: 12:30 – 12:45 12.03.2021, Friday
Presenter: Claudia Cicognola, Sweden
Astrogliosis in response to amyloid-beta (Aβ) plaques is an early feature of Alzheimer’s disease (AD). Glial fibrillary acidic protein (GFAP) is expressed in astrocytes and is increased in CSF in AD. Studies on plasma GFAP as AD biomarker are few and not longitudinal. Our aim was to evaluate plasma GFAP as potential biomarker for Aβ status and for future development of AD dementia.
161 subjects with a baseline clinical diagnosis of mild cognitive impairment (MCI) were included, genotyped for APOE, followed for 4.7 years (average) and assessed for conversion to AD at follow-up. Plasma was collected at baseline and follow-up. GFAP was measured with Simoa GFAP Discovery kit for SR-X (Quanterix). Aß positivity (Aß+) was defined as CSF Aβ42/40 <0.07 (cut-off calculated with Youden index within the cohort).
Baseline GFAP was increased in Aβ+ MCI patients (p<0.0001). Plasma GFAP could predict Aβ+ status (p<0.0001, AIC=184.3, AUC=0.787, sensitivity=73%, specificity=75%). Accuracy was increased by combining plasma GFAP and APOE genotype (p<0.0001, AIC 154.7, AUC=0.859). Plasma GFAP could also predict subsequent development of AD dementia (p<0.0001, AIC=154.4, AUC=0.836, sensitivity=72%, specificity=85%). Predictive accuracy of future AD dementia was improved by combining plasma GFAP with APOE genotype and age (p<0.0001, AIC=140, AUC=0.864). Longitudinal slopes showed a significant increase of plasma GFAP over time in Aβ+ MCI compared to Aβ- (p<0.0001) and in subjects later diagnosed with AD compared to those that remained clinically stable (stable Aβ-:p<0.0001; stable Aβ+:p=0.049).
Plasma GFAP is strongly associated to Aβ status and is a good predictor of clinical evolution to AD.
10. NEUROFILAMENT LIGHT PREDICTS WORSE NONMOTOR SYMPTOMS, DEPRESSION AND ANXIETY IN PARKINSON’S DISEASE
Lecture Time: 11:15 – 11:30 11.03.2021, Thursday
Presenter: Daniele D. Urso, United Kingdom
The relationship between neurofilament light (NfL) and the burden of non-motor symptoms (NMS) in Parkinson’s disease (PD) is unclear. The aim of this study is to investigate whether NfL levels are associated with worsening NMS burden in PD.
Baseline and longitudinal NfL levels were measured in the cerebrospinal fluid (CSF) and serum in a large cohort of PD patients and healthy controls from the Parkinson’s Progression Marker Initiative. NMS were assessed using composite measures from the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part I, the Geriatric Depression Scale (GDS) and the State-Trait Anxiety Inventory (STAI). We compared CSF and serum NfL between patients and controls and assessed their relationship with baseline and longitudinal NMS with correlations or linear mixed effects models. In all analyses, NfL levels were adjusted for potential confounders.
Serum NfL levels were higher at baseline (p=0.043) and showed significant longitudinal increases (p<0.001) in PD patients compared to controls. Baseline and longitudinal serum and CSF NfL predicted worse MDS-UPDRS-I and depression (GDS) scores over time in PD (p<0.01). Furthermore, longitudinal changes in serum and CSF NfL were associated with worse longitudinal anxiety (STAI) scores in PD (p<0.05). These results were similar after adjusting for cognitive and motor deficits.
Our findings suggest that serum NfL levels are elevated in PD and that both serum and CSF NfL are associated with worse NMS. Serum NfL could potentially be used in the clinic as a non-invasive marker of NMS progression for PD patients.
11. EVALUATION OF CEREBROSPINAL FLUID LEVELS OF THE SYNAPTIC PROTEIN, VAMP-2, IN LEWY BODY DEMENTIA PATIENTS
Lecture Time: 13:00 – 13:15 12.03.2021, Friday
Presenter: Olivia Belbin, Spain
To compare cerebrospinal fluid (CSF) levels of the synaptic protein, VAMP-2, in Lewy body dementia (LBD) and Alzheimer’s disease (AD) patients.
We quantified VAMP-2 using a Single Molecular Array (ADx NeuroSciences) in aged cognitively normal controls (n=68) and patients from the Sant Pau Initiative for Neurodegeneration cohort clinically diagnosed with mild cognitive impairment/dementia due to LBD (n=47) or AD (n=119). LBD with AD co-pathology (LBD+AD n=28) was distinguished from pure LBD (n=19) using our validated CSF p-tau/Aβ42 cut-off. Regression analyses were controlled for age and APOE E4 status.
Compared to controls, mean CSF VAMP-2 levels were lower in pure LBD (0.86-fold, p=.005) but elevated in LBD+AD (1.58-fold, p=.009) and AD (1.25-fold, p=.04).The CSF p-tau/Aβ42 ratio*LBD diagnosis interaction term contributed more to VAMP-2 levels (t=7.0, p<.0001) than either variable alone (t=5.6, p<.0001 and t=-4.4, p<.0001, respectively).
CSF VAMP-2 is not a surrogate marker of neurodegeneration. Low CSF VAMP-2 levels may reflect reduced synapse density in LBD patients, an effect that may be masked by AD pathology. Synuclein and AD pathologies may have a synergistic effect on CSF VAMP-2 levels.
12. EFFECT OF BIOLOGICAL SEX ON CLINICAL, BIOCHEMICAL AND NEUROIMAGING BIOMARKERS OF ALZHEIMER’S DISEASE IN ADULTS WITH DOWN SYNDROME: A CROSS-SECTIONAL STUDY
Lecture Time:09:30 – 09:45 14.03.2021, Sunday
Presenter: M. Florencia Iulita, Spain
Biological sex is increasingly recognized as a modifier of Alzheimer’s disease (AD) pathophysiology and disease progression. We aimed to assess the effect of sex on cognitive and biomarker measures of AD in adults with Down syndrome, who have an ultra-high risk for developing AD dementia.
Cross-sectional study of 494 adults with Down syndrome recruited from two sites. We compared clinical characteristics and AD biomarkers between men (n=268) and women (n=226). Participants had at least one biomarker assessment among plasma NfL, Aβ1-42/1-40, p-Tau-181, tau and NfL in CSF, PET with amyloid tracers or 18F-fluorodeoxyglucose and/or MRI. We compared age at symptom onset and used within-group local regression models with confidence intervals to compare the trajectory of biomarker changes with age.
The mean age at which women were diagnosed with dementia was 53 years vs. 53.6 for men (p=0.46). Women with Down syndrome showed earlier decreases in CSF Aß1-42, however no differences were found when comparing the Aß1-42/Aß1-40 ratio. The biomarker trajectories of plasma NfL and CSF NfL, p-Tau-181 and tau were similar across ages between men and women. Women had smaller head sizes and hippocampal volumes, but there were no differences in hippocampal volumes when adjusted for differences in head size. There were no differences in age-associated changes in cerebral amyloid deposition (Centiloid) or glucose metabolism (FDG-PET).
In adults with Down syndrome, sex does not modify the age at diagnosis of dementia or the trajectories of plasma, CSF and imaging biomarkers. Reporting of negative results is important to avoid publication bias.
13. THE BIOMARKER SEARCH FOR SCA3
Lecture Time 09:30 – 09:45 14.03.2021, Sunday
Presenter: Zbigniew K. Wszolek, United States of America
Mayo Clinic Florida (MCF) Ataxia Center of Excellence was established in 2017. The Center’s aims are to deliver an excellent care and to provide the support for clinical and basic research studies on genetic forms of spinocerebellar ataxias (SCA).
On research side, MCF Ataxia Center of Excellence collects biomarker specimens including urine, blood, skin, and cerebrospinal fluid (CSF). As of writing this abstract (September of 2020), MCF Ataxia Center of Excellence personnel either directly or through the collaborative efforts were able to collect biospecimens from 130 SCA patients and controls. The collection contains specimens from patients with SCA1, SCA2, SCA3, SCA5-SCA8, SCA12, and others. Our sample collection includes 139 blood specimens, 91 urine samples, 78 CSF specimens, and 124 skin fibroblast cultures. Since earlier this year, a longitudinal component has been implemented to track disease progression by re-enrolling participants every two years. As of today, ten patients have returned to partake in the longitudinal arm of the study.
This unique collection allowed us to develop an immunoassay to measure polyQ ATXN3 proteins in biological fluids that can be used as a pharmacodynamic marker specific for SCA3 patients. This discovery will be presented during the meeting.
MCF Ataxia Center of Excellence is rapidly growing and will attract even more patients with SCA who will contribute to further discoveries in ataxia field. A discovery of a pharmacodynamics marker for SCA3 is of paramount importance for future planning of medication trials. Perhaps, it will allow the monitoring of the response to the experimental therapy.
14. THE ASSOCIATION OF AGE WITH AΒ, NEUROINFLAMMATION, AND TAU PATHOLOGY USING PET AND PLASMA BIOMARKERS IN LATE-ONSET ALZHEIMER’S DISEASE
Lecture Time: 09:15 – 09:30 12.03.2021, Friday
Presenter: Julie Ottoy, Canada
With the advent of disease-modifying therapeutic trials in early stages of Alzheimer’s disease (AD), disentangling normal age-related biomarker changes from AD-related pathological changes will be crucial to unravel therapy effectiveness in trial populations. Here, we aim to investigate the effects of age, the greatest risk factor of AD, on markers of amyloid-β (Aβ), tau, and neuroinflammation PET in late-onset AD.
238 participants (120 amyloid- and tau-negative [A-] and 118 amyloid-positive [A+]) from the TRIAD cohort underwent 18F-AZD4694 amyloid-PET and 18F-MK620 tau-PET. A subset also underwent 11C-PBR28 neuroinflammation-PET, plasma Ptau181 and Aβ1-42/Aβ1-40 concentration measures, and 1-year follow-up tau-PET. We investigated the association between age and all PET modalities as well as between age and plasma concentrations using linear regression models, adjusting for sex, education, APOE-ε4, and the remaining PET or plasma variables. In addition, we investigated whether there is a significant difference in these associations between the A- and A+ groups (i.e., interaction-effect age*Aβ-status on PET/plasma biomarkers).
Younger A+ subjects showed increased plasma Ptau181 and tau-PET in Braak3and4 predominant areas at baseline as well as increased tau-PET SUVR changes in Braak1and2 predominant areas after 1-year follow-up compared to older A+ individuals, while there was no age-effect on tau-PET in A-. Second, while we detected a significant main effect of age on neocortical Aβ and orbitofrontal neuroinflammation SUVR, the effect of age on both markers did not significantly differ between A+ and A-.
Future clinical trials should consider age as an important stratification factor particularly when targeting tau in late-onset AD.
15. PLASMA P-TAU 181, P-TAU 217 AND OTHER BLOOD-BASED ALZHEIMER’S DISEASE BIOMARKERS IN A MULTI-ETHNIC, COMMUNITY STUDY
Lecture Time 08:45 – 09:00 13.03.2021, Saturday
Presenter: Adam M. Brickman, United States of America
Blood-based Alzheimer’s disease (AD) biomarkers provide opportunities for community studies and across ethnic groups.We investigated blood biomarker concentrations in the Washington Heights, Inwood, Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia. The goal was to determine the effectiveness of state-of-the-art AD related plasma biomarkers, including Aβ40 and ββ42 as markers of amyloid pathology, total tau and neurofilament light chain (NfL) as markers of eurodegeneration, and phospho-tau (P-tau) 181 and 217 as markers of tau pathology. We compared plasma biomarker concentrations between clinically- and pathologically-defined diagnostic groups and examined differences by race/ethnicity groups.
We measured plasma Aβ40, Aβ42,T-tau, P-tau181 and P-tau217, and neurofilament light chain (NfL) in 113 autopsied participants, (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD.
P-tau181, P-tau217 and NfL concentrations were elevated in pathologically diagnosed AD and to a lesser extent in clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased P-tau217 and P-tau181 were associated with subsequent AD diagnosis in a follow-up of previously unaffected individuals.
Blood-based AD biomarker concentrations of the Aβ42/Aβ40 ratio, P-tau217 and P-tau181 are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies.
16. PLASMA BIOMARKERS OF ALZHEIMER’S DISEASE PREDICT FUTURE COGNITIVE STATUS IN THE COGNITIVELY UNIMPAIRED ELDERLY
Lecture Time09:30 – 09:45 13.03.2021, Saturday
Presenter:Antoine Leuzy, Sweden
Plasma biomarkers of amyloid-β (Aβ), tau, and neurodegeneration can accurately predict the risk of developing Alzheimer’s disease (AD) dementia in individuals with mild cognitive impairment (MCI), but their effectiveness in the cognitively unimpaired (CU) elderly population is unknown.
A total of 435 CU individuals were analyzed from the Swedish BioFINDER study with an average age of 72.5 years (range = [60, 88]). We tested the combined ability of plasma Aβ42/Aβ40, tau phosphorylated at threonine 217 (P-tau217), and neurofilament light (NfL) to predict (a) continuous four-year decline in Mini Mental State Examination (MMSE) scores, (b) which individuals remained cognitively stable (< 2 points decline). Plasma biomarkers were compared to a basic model which included only age, sex, and education.
Adding plasma biomarkers to a basic demographics model significantly improved the prediction of continuous four-year MMSE decline (P=0.001) with P-tau217 and NfL having a significant effect (P=0.013 and 0.008, respectively). Adding plasma biomarkers also significantly improved prediction of cognitively stable individuals (P=0.0004), with P-tau217 and NfL again both having a significant effect (P=0.015 and 0.036, respectively). Figure 1 shows the relationship between biomarker levels and four-year change in MMSE (shown as baseline MMSE – four-year MMSE; positive values indicate worsening cognition).
Plasma biomarkers of AD add significant prognostic information for the future cognitive status of elderly individuals without cognitive impairment, particularly for individuals at highest risk of cognitive decline. This further motivates their use in a screening context.
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