Cognitive Impact of TDP-43 Pathology in Alzheimer's Disease Patients Protocol
Phase 1: Patient Enrollment and Baseline Assessment (Days 1-30)
Participant Recruitment: Recruit AD patients (n=100, ages 55-85, NINCDS-ADRDA criteria) and cognitively normal age-matched controls (n=50) from memory clinics. Obtain written informed consent, IRB approval.
APOE Genotyping: Extract DNA from peripheral blood (saliva kit or blood draw). Genotype APOE (ε2/ε3/ε4) via PCR-RFLP or TaqMan assay. Stratify for APOE4 carrier status as covariant.
...Cognitive Impact of TDP-43 Pathology in Alzheimer's Disease Patients Protocol
Phase 1: Patient Enrollment and Baseline Assessment (Days 1-30)
Participant Recruitment: Recruit AD patients (n=100, ages 55-85, NINCDS-ADRDA criteria) and cognitively normal age-matched controls (n=50) from memory clinics. Obtain written informed consent, IRB approval.
APOE Genotyping: Extract DNA from peripheral blood (saliva kit or blood draw). Genotype APOE (ε2/ε3/ε4) via PCR-RFLP or TaqMan assay. Stratify for APOE4 carrier status as covariant.
Baseline Cognitive Testing: Administer comprehensive neuropsychological battery: (a) ADAS-Cog (Alzheimer's Disease Assessment Scale, cognitive subscale), (b) CDR (Clinical Dementia Rating sum of boxes), (c) MMSE (Mini-Mental State Examination), (d) Trail Making Test A/B, (e) Digit Span, (f) Logical Memory (WMS-R). Score locally and centralize for blind analysis.
Phase 2: TDP-43 Biomarker Assessment (Days 31-60)
CSF Collection: Perform lumbar puncture (25G Sprotte, 12 mL CSF) per standard protocol. Centrifuge within 1 hour (800×g, 10 min, 4°C). Aliquot 0.5 mL fractions, store at -80°C. Exclude sanguinolent samples (>500 RBC/μL).
TDP-43 Measurement: Assay total TDP-43 and phospho-TDP-43 (pS409/410) via ELISA (Fujirebio). Run in duplicate with QC standards. Technicians blinded to diagnosis and cognitive scores.
Statistical Stratification: Using median CSF phospho-TDP-43 as cutoff, stratify AD patients into TDP-43 high (n~50) and TDP-43 low (n~50) groups. Compare cognitive performance between groups controlling for age, education, and APOE4 status.
Phase 3: Longitudinal Cognitive Decline Assessment (Days 61-180)
Follow-up Testing: Repeat full neuropsychological battery at 12 and 24 months. Track change from baseline (ADAS-Cog, CDR sum of boxes, MMSE). Define decline endpoint as: (a) ≥4 point increase in ADAS-Cog, (b) ≥1 point increase in CDR, or (c) ≥3 point decrease in MMSE.
Neuroimaging: At 24-month endpoint, obtain 3T MRI (T1 MPRAGE, T2 FLAIR, tau-PET if available). Process via FreeSurfer for hippocampal volume, cortical thickness. Rate white matter hyperintensities.
Time-to-Event Analysis: Compare time to cognitive decline endpoint between TDP-43 high vs. low groups via Kaplan-Meier analysis and Cox proportional hazards regression (covariates: age, baseline cognition, APOE4, total tau).