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JOURNAL CLUB

By- Dr. Shubham


Samdarshi
Perceptor-

Dr. Abhijith R Rao (Senior Resident)


Dr. Avinash Chakravarthy – Consultant
PRODUCT OVERVIEW
CONTENTS

INTRODUCTION
REVIEW OF LITERATURE
JOURNAL PROPER
STATISTICAL ANALYSIS
RESULTS
DISCUSSION
INTRODUCTION
• Approximately 50 million people across the world are living with dementia.

• In India an estimated 7.4% of people aged 60 years and older lived with dementia (8.8 million
individuals).

• Dementia prevalence is higher among females than males (9.0% vs. 5.8%) and higher in rural than
in urban areas (8.4% vs. 5.3%)

• If prevalence stays the same, the number of people with dementia is projected to reach 16.9
million in 2036 .

• Alzheimer’s disease (AD) is the most common cause of dementia, contributing to an estimated
60–70% of all cases.

WHO / LASI
RISK FACTORS FOR ALZHEIMER DISEASE
 Female >Male
Age (>65 year )
 Family history

Inherited mutated gene –  Head trauma


•AAP gene ( 21)
 Physical inactivity
• presenilin1(14)
• presenilin 2 (1)  Smoking and alcohol
•ε4 allele of the APOE gene
 Social isolation

 Sleep disorders
HISTOPATHOL
OGY
Amyloid Plaques: Extracellular
deposits of amyloid-beta (Aβ) peptides

Neurofibrillary Tangles:Intracellular
aggregates of hyperphosphorylated tau
protein form neurofibrillary tangles
within neurons.
IMAGING IN AD

• MRI Brain - Medial temporal atrophy

• FDG-PET – distinct regions of hypometabolism

• SPECT – distinct regions of hypoperfusion

• Amyloid PET imaging-Amyloid lesion burden

• Tau PET imaging


CSF biomarkers used in AD
• Amyloid-beta 42 (Aβ42)

BIOMARK •Phosphorylated tau (p-tau)

ERS IN •Total tau (t-tau).


•Ratio of CSF Aβ42/40
AD In AD, there is decreased CSF Aβ42 and increased
tau isoforms (both p-tau and t-tau).
•Aβ42/Aβ40 Ratio
•p-tau181 and p-tau217
•Neurofilament Light Chain (NfL)
BLOOD •Glial Fibrillary Acidic Protein (GFAP)

BIOMARK •YKL-40

ER IN AD •Proteomics and Metabolomics


•MicroRNAs (miRNAs)
•Plasma Clusterin
•Exosomal Biomarkers
Three clinical phases of Alzheimer's disease may be defined:
(i) pre-symptomatic (or pre-clinical) AD, Molecular pathology of AD
present but not yet clinically expressed

(ii) pre-dementia phase of AD (compatible with the definition of


progressive, amnestic mild cognitive impairment).

iii) clinically defined dementia phase of AD, in which cognitive and


functional impairment is severe enough to surmount the dementia
threshold..

De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV. Alzheimer's disease. Subcell Biochem.
2012;65:329-52. doi: 10.1007/978-94-007-5416-4_14. PMID: 23225010.
Disease Modifying Therapies of AD

Aducanumab (Aduhelm)
 Approval: Approved by the FDA in June 2021.
 Mechanism: Aducanumab is a monoclonal antibody that targets amyloid-beta plaques in
the brain, helping to clear them.
 Clinical Data: Clinical trials (ENGAGE and EMERGE) showed that Aducanumab could
reduce amyloid plaques in the brain.
 However, the data on cognitive improvement were mixed, with one trial showing a
benefit and the other not achieving statistical significance. The approval was
controversial due to these mixed results .
Donanemab
•Approval: Approved by the FDA in July 2023.
•Mechanism: Donanemab is an antibody that targets a specific
form of amyloid-beta, known as N3pG amyloid, facilitating its
clearance from the brain.
•Clinical Data: The TRAILBLAZER-ALZ 2 trial showed that
Donanemab slowed cognitive decline by about 35% in patients with
early Alzheimer’s disease over 18 months
•The trial also showed a significant reduction in amyloid plaques and
tau pathology.
Lecanemab (Leqembi)
•Approval: Approved by the FDA under the Accelerated Approval pathway in
January 2023.
•Mechanism: Lecanemab is another monoclonal antibody that targets
soluble amyloid-beta protofibrils, aiming to reduce the buildup of amyloid
plaques.
•Clinical Data: In the CLARITY-AD trial, Lecanemab demonstrated a 27%
slowing of cognitive decline in patients with early Alzheimer’s over 18
months compared to placebo.
Other Drugs in Development
•Alzheon’s ALZ-801: An oral drug that inhibits the formation of amyloid
oligomers. It’s currently in Phase 3 trials.
•Eisai’s BAN2401: Similar to Lecanemab, BAN2401 is under investigation
and is showing promise in clearing amyloid plaques
REVIEW OF LITERA
Aim - Estimation of Tau and Phosphorylated Tau181 in Serum of
Alzheimer’s Disease and Mild Cognitive Impairment Patients
Methods - this case control study of 113 subjects; 39 patients with AD, 37 patients with
MCI and 37 elderly controls; were recruited from the Geriatric Medicine Memory Clinic and
Neurology OPD of AllMS, New Delhi, India
Result-concentrations (mean with SE) of Tau and p-Tau181 were significantly higher in AD
patients (Tau 47.39±1.34 ng/μL, p-Tau181 0.157±0.005 ng/μL) as compared to that of MCI
patients (Tau 39.27±1.38 ng/μL, p-Tau181 0.139±0.005 ng/μL) and elderly controls (Tau
35.02±1.31 ng/μL, p-Tau181 0.124±0.005 ng/μL).
ROC analysis revealed that area under curve (AUC) for Tau was 0.907 in case of AD vs
control
Conclusion - the serum Tau and p-Tau181 were capable of differentiating between elderly
controls from AD and MCI patients and also AD from MCI patients.
serum p-Tau181 can serve as a predictive protein marker for MCI and AD patients and can
also work as prognostic marker during follow up of patients in the future
Objective
The objective of the study was to evaluate the diagnostic performance of plasma
phosphorylated tau 217 (p-tau217) and phosphorylated tau 181 (p-tau181) as biomarkers
in distinguishing Alzheimer’s disease (AD) from frontotemporal lobar degeneration (FTLD)
and other neurodegenerative disorders.
Study Design: Retrospective diagnostic performance study.
Participants: Included individuals with clinically diagnosed AD, FTLD, other
neurodegenerative disorders, and cognitively normal controls.
Biomarker Measurement: Plasma levels of p-tau217 and p-tau181 were
measured using specific immunoassays.
Results -
p-tau217:AUC for distinguishing AD from FTLD: 0.98 (95% CI: 0.96-0.99)
Sensitivity: 96% ,Specificity: 93% •
p-tau181:AUC for distinguishing AD from FTLD: 0.89 (95% CI: 0.85-
0.93)Sensitivity: 85% ,Specificity: 82%
Comparison:p-tau217 showed superior diagnostic accuracy compared to p-
tau181.
p-tau217 had better performance in differentiating AD from non-AD conditions.
Conclusions-Plasma p-tau217:Demonstrated high diagnostic accuracy for
distinguishing AD from FTLD and other neurodegenerative disorders.
Plasma p-tau217 is a promising biomarker for the differential diagnosis of AD.
Objective - The study aimed to develop and validate a blood-
based diagnostic test for Alzheimer’s disease. This test
incorporates the plasma amyloid-beta (Aβ) 42/40 ratio, ApoE
proteotype, and age to accurately identify brain amyloid status,
which is crucial for diagnosing Alzheimer’s disease.
Methodology -The researchers conducted a multi-cohort analysis.
Plasma samples were collected from participants across different cohorts, and
the levels of Aβ42/40 were measured using immunoassays. Additionally, the
ApoE proteotype was determined, and the participants’ ages were recorded.
Statistical models were employed to evaluate the accuracy of the test in
identifying brain amyloid status compared to established diagnostic methods
like PET scans.
Results - The study found that the combined measurement of plasma Aβ42/40
ratio, ApoE proteotype, and age provided a highly accurate prediction of brain
amyloid status.
The blood-based test demonstrated a strong correlation with PET scan results,
indicating its potential as a reliable, less invasive diagnostic tool for
Alzheimer’s disease.
Conclusions -The findings suggest that the blood-based diagnostic test is a
viable alternative to more invasive methods like PET scans for identifying brain
amyloid status.
JOURNAL PROPER
NEED FOR THIS STUDY
Early Detection and Diagnosis:
Early detection is crucial for initiating interventions that can slow disease
progression.

Non-Invasive Diagnostic Methods:


Current diagnostic methods for AD, CSF analysis and PET imaging are invasive,
expensive, and not widely accessible.
Blood biomarkers offer a non-invasive, cost-effective alternative that could be more
easily implemented in routine clinical practice.

Accessibility in Primary Care: Having reliable blood biomarkers can facilitate early
diagnosis at this initial point of contact, enabling timely referrals and interventions.
AIM OF THIS STUDY :
•Aim was to evaluate the diagnostic accuracy and effectiveness of
specific blood biomarkers (including plasma β-amyloid 42/40,
phosphorylated tau for detecting Alzheimer’s disease in both
primary care and secondary care settings.
•The study sought to determine whether these biomarkers could
serve as reliable, non-invasive tools for early detection and
diagnosis of Alzheimer’s disease across different healthcare
environments.
Primary Objective-
•Examine the ability of plasma percentage of p-tau217 alone and when
combined with the Aβ42:Aβ40 plasma ratio (the amyloid probability score 2
[APS2]) to detect Alzheimer disease pathology or clinical Alzheimer disease in
patients with cognitive symptoms using predefined cutoff values;
• Evaluate the diagnostic accuracy of blood biomarkers when analyzed in
batches prospectively (biweekly)
• Compare the diagnostic accuracy of blood biomarkers with the diagnostic
accuracy of primary care physicians or dementia specialists.
Secondary objective-
•Examine the performance at different cognitive stages
• Compare different cutoff value approaches for the blood test.
METHODOLOGY
The study included 2 cohorts from primary and secondary care
clinics at which the plasma samples were analyzed together at 1
time point in a single batch.
The study also included 2 cohorts from primary and secondary care
clinics at which the plasma samples were analyzed prospectively in
batches biweekly throughout the enrollment period.
Only 1 plasma sample per patient was analyzed.
PARTICIPANTS ( PRIMARY
CARE )
•The first segment of the BioFINDER-Primary Care study (plasma
analyzed in a single batch) consisted of participants examined
between February 2020 and October 2022
•the second segment (samples shipped and analyzed bi-weekly
throughout the study period) included participants examined from
October 2022 to October 2023 (no overlap with the first segment).
INCLUSION CRITERIA OF
BIOFINDER-PRIMARY CARE
STUDY
1) Patient seeks medical help in primary care because of cognitive
symptoms experienced by the patient and/or informant or the
primary care physician (PCP) suspects a progressive
neurodegenerative disorder including, but not limited to, AD, Lewy
body disease, frontotemporal lobar degeneration or subcortical
vascular cognitive impairment;
2) Age ≥40 years;
3) Cognitive impairment characterized as subjective cognitive
decline, mild cognitive impairment or mild dementia.
EXCLUSION CRITERIA
1. Already diagnosed dementia
2. Significant unstable systemic illness making it difficult to
participate in the study
3. Current significant alcohol or substance misuse
4. Refusing investigation at the Memory clinic
5. Cognitive impairment with acute onset due to stroke
6. The cognitive impairment can with high certainty, as assessed
by the PCP, be explained by another condition or disease such
as psychotic disorder, depression, alcohol abuse etc.
PARTICIPANTS
( SECONDARY CARE )
•Patients in the single-batch analysis in secondary care were
recruited at the Memory Clinic of Skåne University Hospital or the
Memory Clinic of Ängelholm Hospital in Sweden as part of the
BioFINDER 2 study from January 2019 to November 2023.
•For the prospective, biweekly analysis in secondary care, patients
were recruited as part of the BioFINDER Memory Clinic study from
December 2022 to January 2024 at the Memory Clinic of Skåne
University Hospital.
Primary Outcome: Presence of Alzheimer Disease
Pathology
•- Defined by Aβ and tau positivity (csf)
•- Aβ positivity: Aβ42:Aβ40 ratio ≤0.072 (Lumipulse assay)
•- Tau positivity: p-tau217 level >11.42 pg/mL
•- Alternative for non-lumbar puncture: Positive [18F]flutemetamol PET scan
Secondary Outcomes:
1. Clinical Alzheimer Disease
- Defined by the International Working Group criteria
- Only analyzed in patients with mild cognitive impairment or
dementia
2. [18F]flutemetamol PET Scan Results
- Positivity: SUVR >1.033
3. Additional Biomarker Analyses
- CSF Aβ42 to p-tau181 ratio <15
Receiver operating characteristics
An ROC(ROC)
curve is curve
a graphical plot used to show the diagnostic ability
of a binary classifier system as its discrimination threshold is varied.
- overview of key concepts related to ROC Curve Analysis:
1.True Positive Rate (TPR): (sensitivity)it represents the proportion
of actual positives that are correctly identified by the model.
2.False Positive Rate (FPR): This measures the proportion of actual
negatives that are incorrectly identified as positives by the model.
3.ROC Curve: The ROC curve is created by plotting the TPR against
the FPR at various threshold settings. The area under the ROC curve
(AUC) provides an aggregate measure of performance across all
classification thresholds.
4.AUC (Area Under the Curve): This value ranges from 0 to 1 and
provides a single metric for comparing classifiers. An AUC of 0.5
suggests no discriminative ability (equivalent to random guessing),
while an AUC of 1 indicates perfect classification.
STATISTICAL ANALYSIS
Diagnostic Performance Metrics:
Sensitivity and specificity of the blood biomarkers were calculated to determine
their ability to correctly identify individuals with and without Alzheimer’s disease.
Positive predictive value (PPV) and negative predictive value (NPV) were also
calculated to assess the likelihood that individuals with positive or negative
biomarker results truly have or do not have the disease.
Receiver Operating Characteristic (ROC) Curve Analysis:
ROC curve analysis was performed to evaluate the diagnostic accuracy of the
blood biomarkers.
The area under the curve (AUC) was calculated for each biomarker and
combination of biomarkers to quantify their overall performance in distinguishing
between individuals with and without Alzheimer’s disease.
Comparison of Biomarkers:
Statistical tests such as the DeLong test were used to compare the AUCs
of different biomarkers to determine if one biomarker or combination of
biomarkers performed significantly better than others.
Pairwise comparisons of sensitivity and specificity were conducted to
evaluate the relative performance of biomarkers across primary and
secondary care settings.
Logistic Regression:
Multivariate logistic regression analysis was used to adjust for potential
confounders and to assess the independent predictive value of each
biomarker.
95% confidence intervals (CIs) were reported to indicate the strength of
association between biomarker levels and Alzheimer’s disease diagnosis.
The optimal cutoff at 90% specificity was 36 for the APS2 score and 3.26
for %p-tau217.

The two-cutoff approach at 95% sensitivity and 95% specificity yielded


cutoffs at 31 (lower) and 62 (upper) for the APS2 score and 3.93 (lower)
and 5.18 (upper) for %p-tau217.
Performance Comparison of the Blood Tests Using the 1 Cutoff-Value Approach Along With
Presence of Alzheimer Disease Pathology as an Outcome
o Primary care cohort o Secondary care cohort o Primary care cohort o Secondary care cohort
(single batch analysis) (single batch analysis) (prospective analysis) (prospective analysis)
 APS2:  APS2:  APS2:  APS2: 91%
• Accuracy: 92% • Accuracy: 88% • Accuracy: 89% • Accuracy: 90%
• PPV: 91% • PPV: 88% • PPV: 88% • PPV: 91%
• NPV: 92% • NPV: 87% • NPV: 90% • NPV: 91%
 p-tau217 Alone:
 p-tau217 Alone:  p-tau217 Alone:  p-tau217 Alone:
• Accuracy: 88%
• Accuracy: 91% • Accuracy: 90% • Accuracy: 90%
• PPV: 86%
• PPV: 89% • PPV: 86% • PPV: 86%
• NPV: 92%
• NPV: 92% • NPV: 94% • NPV: 95%
Performance Comparison of the Blood Tests Using the 2 Cutoff-Value Approach Along With
Presence of Alzheimer Disease Pathology as an Outcome
o Secondary care cohort o Secondary care cohort o Secondary care cohort o Secondary care cohort
(single batch analysis) (single batch analysis) (single batch analysis) (single batch analysis)
 APS2:  APS2:  APS2:  APS2:
• Accuracy: 93% • Accuracy: 93% • Accuracy: 93% • Accuracy: 93%
• PPV: 97% • PPV: 97% • PPV: 97% • PPV: 97%
• NPV: 89% • NPV: 89% • NPV: 89% • NPV: 89%
• Intermediate Zone: 12% • Intermediate Zone: 12% • Intermediate Zone: 12% • Intermediate Zone: 12%

 p-tau217 Alone:  p-tau217 Alone:  p-tau217 Alone:  p-tau217 Alone:


• Accuracy: 93% • Accuracy: 93% • Accuracy: 93% • Accuracy: 93%
• PPV: 96% • PPV: 96% • PPV: 96% • PPV: 96%
• NPV: 90% • NPV: 90% • NPV: 90% • NPV: 90%
• Intermediate Zone: 6% • Intermediate Zone: 6% • Intermediate Zone: 6% • Intermediate Zone: 6%
Comparison Between the Diagnostic Performance of the Physicians and the Blood Tests
Using the 1 Cutoff-Value Approach Along With Presence of Alzheimer Disease Pathology as
an Outcome
o Primary care cohort (prospective o Secondary care cohort (prospective
analysis) analysis)
 APS2:  APS2: 92%
• Accuracy: 89% • Accuracy: 90%
• PPV: 88% • PPV: 91%
• NPV: 90% • NPV: 91%
 p-tau217 Alone:  p-tau217 Alone:
• Accuracy: 90% • Accuracy: 91%
• PPV: 86% • PPV: 86%
• NPV: 94% • NPV: 95%
 Primary care physician  Dementia specialists
 Accuracy-58% • Accuracy-71%
Performance of the Blood Tests in Different Cognitive Stages in Pooled Data Along With
Alzheimer Disease Pathology as an Outcome
Receiver Operating Characteristic (ROC) Curve Analysis of the Blood Tests Along With
Alzheimer Disease Pathology as an Outcome
DISCUSSION
Performance Consistency: Despite differences in patient
demographics, the blood biomarkers performed consistently across
primary and secondary care settings. The APS2 surpassed the
diagnostic accuracy of dementia specialists and primary care
physicians, especially in patients with medical comorbidities.
Superior Diagnostic Accuracy: The APS2 and p-tau217 alone
achieved diagnostic accuracies of 89%-90% compared to 58% for
primary care physicians using current tools.
Clinical Utility: The blood test could improve diagnostic accuracy
in primary care, aiding in timely treatment initiation and
appropriate referrals to secondary care.
Comparison with Existing Methods: In secondary care, the blood test
had a higher diagnostic accuracy (91%) compared to dementia
specialists (73%) before reviewing cerebrospinal fluid results, suggesting
potential as a more accessible alternative to cerebrospinal fluid tests and
PET scans.

PPV and NPV: The test achieved PPVs of 97%-99% in patients with
cognitive impairment, crucial for confirming Alzheimer’s disease
pathology before antiamyloid treatment.

Implications for Clinical Practice: The APS2 and p-tau217 alone


showed robust performance, emphasizing the need for interpretation in a
clinical context due to the potential for asymptomatic Alzheimer’s
pathology and coexisting conditions.
STRENGTH OF THIS
STUDY
Large and Diverse Cohort: The study included participants from both
primary and secondary care settings, ensuring a diverse and
representative sample.
Comprehensive Biomarker Analysis: The study evaluated multiple
blood biomarkers (plasma β-amyloid 42/40, phosphorylated tau p.
High Diagnostic Accuracy: The study demonstrated high sensitivity
and specificity for the biomarkers in detecting Alzheimer’s disease.
Non-Invasive and Cost-Effective: Blood-based biomarkers offer a
non-invasive and more cost-effective alternative to traditional
diagnostic methods like PET imaging and cerebrospinal fluid analysis,
making early detection more accessible.
Applicability in Primary Care: By including primary care settings, the
study addresses the need for diagnostic tools that can be used at the
initial point of contact with the healthcare system. This can facilitate
earlier diagnosis and intervention.
Statistical Rigor: The study employed robust statistical methods,
including ROC curve analysis, logistic regression, and validation
techniques, to ensure the reliability and accuracy of the results.
Clinical Relevance: The findings have significant implications for
clinical practice.
Future Implications: The study paves the way for further research and
development of blood biomarkers as standard diagnostic tools for AD,
encouraging advancements in non-invasive diagnostics.
Potential for Widespread Implementation: Given the non-invasive
nature and the high accuracy of the biomarkers, their use could be easily
implemented in various healthcare settings.
LIMITATION OF THIS
STUDY
Cross-Sectional Design:
Comparative Analysis: The study might not have included a direct comparison
with other established diagnostic methods, such as PET & CSF analysis .
Potential Selection Bias: Patients in secondary care are often referred due to
more severe or confirmed symptoms, which might not represent the broader
primary care population.
Confounding Variables: There may be unaccounted confounding variables,
such as comorbid conditions, medications, and lifestyle factors, that could
influence biomarker levels and affect the results.
Validation in Diverse Populations: The study’s findings may need further
validation in more diverse populations, including different ethnicities, geographic
locations, and socioeconomic statuses, to ensure the biomarkers’ applicability
across various
CONCLUSION
•The study concludes that specific blood biomarkers, including
plasma β-amyloid 42/40, phosphorylated tau (p-tau)are effective in
detecting Alzheimer's disease.
•The biomarkers demonstrated high sensitivity and specificity in
both primary and secondary care settings, making them reliable
tools for early diagnosis.
•These findings support the potential of blood-based biomarkers as
non-invasive, cost-effective diagnostic methods that can be widely
implemented in clinical practice, facilitating early intervention and
improving patient outcomes.
CRITICAL APPRAISAL Yes No

1. Did the study address a clearly focused issue? ✔

2. Was the cohort recruited in an acceptable way? ✔

3. Was the exposure accurately measured to minimise bias? ✔

4. Was the outcome accurately measured to minimise bias? ✔

5. Have the authors identified all important confounding factors? ✔

6.Have they taken account of the confounding factors in the design and/or ✔
analysis?
7. Was the follow up of subjects complete enough? ✔

8. Was the follow up of subjects long enough? ✔

9. Do you believe the results? ✔

10. Can the results be applied to the local population? ✔

11. Do the results of this study fit with other available evidence? ✔
THANK YOU

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