Alzheimer’s disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline

For early detection of Alzheimer’s disease, it is important to find biomarkers with predictive value for disease progression and clinical manifestations, such as cognitive decline. Individuals can now be profiled based on their biomarker status for Aβ42 (A) or tau (T) deposition and neurodegeneration (N). The aim of this study was to compare the cerebrospinal fluid (CSF) and imaging (PET/MR) biomarkers in each ATN category and to assess their ability to predict longitudinal cognitive decline. A subset of 282 patients, who had had at the same time PET investigations with amyloid-β and tau tracers, CSF sampling, and structural MRI (18% within 13 months), was selected from the ADNI dataset. The participants were grouped by clinical diagnosis at that time: cognitively normal, subjective memory concern, early or late mild cognitive impairment, or AD. Agreement between CSF (amyloid-β-1-42(A), phosphorylated-Tau181(T), total-Tau(N)), and imaging (amyloid-β PET (florbetaben and florbetapir)(A), tau PET (flortaucipir)(T), hippocampal volume (MRI)(N)) positivity in ATN was assessed with Cohen’s Kappa. Linear mixed-effects models were used to predict decline in the episodic memory. There was moderate agreement between PET and CSF for A biomarkers (Kappa = 0.39–0.71), while only fair agreement for T biomarkers (Kappa ≤ 0.40, except AD) and discordance for N biomarkers across all groups (Kappa ≤ 0.14) was found. Baseline PET tau predicted longitudinal decline in episodic memory irrespective of CSF p-Tau181 positivity (p ≤ 0.02). Baseline PET tau and amyloid-β predicted decline in episodic memory (p ≤ 0.0001), but isolated PET amyloid-β did not. Isolated PET Tau positivity was only observed in 2 participants (0.71% of the sample). While results for amyloid-β were similar using CSF or imaging, CSF and imaging results for tau and neurodegeneration were not interchangeable. PET tau positivity was superior to CSF p-Tau181 and PET amyloid-β in predicting cognitive decline in the AD continuum within 3 years of follow-up.

Clinical, Imaging, and Pathologic Characteristics of Patients With Right Versus Left Hemisphere-Predominant Logopenic Progressive Aphasia

Objective:To assess and compare demographic, clinical, neuroimaging and pathologic characteristics of a cohort of patients with right versus left hemisphere-predominant logopenic progressive aphasia (LPA).Methods:This is a case-control study of patients with LPA who were prospectively followed at Mayo Clinic and underwent an [18F]-fluorodeoxyglucose (FDG)-PET scan. Patients were classified as rLPA if right temporal lobe metabolism was ≥1 standard deviation lower than left temporal lobe metabolism. Patients with rLPA were frequency-matched 3:1 to typical left-predominant LPA based on degree of asymmetry and severity of temporal lobe metabolism. Patients were compared on clinical, imaging (MRI, FDG-PET, amyloid-beta- and tau-PET) and pathologic characteristics.Results:Of 103 prospectively recruited LPA patients, 8 (4 females) were classified as rLPA (7.8%); all rLPA cases were right-handed. rLPA patients had milder aphasia based on the Western Aphasia Battery-Aphasia Quotient (p=0.04) and less frequent phonologic errors (p=0.015). rLPA had shorter survival compared to typical LPA: hazard ratio 4.0(1.2- 12.9), p=0.02. There were no other differences in demographics, handedness, genetics, neurological or neuropsychological tests. Compared to the 24 frequency-matched typical LPA patients, rLPA showed greater frontotemporal hypometabolism of the non-dominant hemisphere on FDG-PET and less atrophy in amygdala and hippocampus of the dominant hemisphere. Autopsy evaluation revealed a similar distribution of pathologic findings in both groups, with Alzheimer’s disease pathologic changes being the most frequent pathology.Conclusions:Right LPA is associated with less severe aphasia but has shorter survival from reported symptom onset than typical LPA, possibly related to greater involvement of the non-dominant hemisphere.

PET-Amyloid After Inconclusive Cerebrospinal Fluid Biomarkers in Clinical Practice. Is it Necessary to Duplicate Procedures?

Introduction: In the absence of a gold standard for in vivo Alzheimer disease (AD) diagnosis, AD biomarkers such as cerebrospinal fluid biomarkers (CSF-B) and PET-Amyloid are considered diagnostically useful in clinical practice guidelines and have consensual appropriate use criteria (AUC). However, little evidence has been published on their utilization in the clinical setting or on approaches to mismatched results. The objective of this work was to evaluate the use of AD biomarkers in clinical practice, focusing on the implementation of PET-Amyloid in cases of inconclusive CSF-B. Methods: This naturalistic, ambispective case series included patients fulfilling AUC for CSF-B and PET-Amyloid whose CSF-B results were non-diagnostic (target population), analyzing the diagnostic certainty, the treatment approach, and the relationship between CSF-B and PET-Amyloid results. Results: Out of 2373 eligible patients, AD biomarkers were studied in 417 (17.6%), most frequently due to cognitive impairment in under 65-year-olds, using CSF-B in 311 patients and PET-Amyloid in 150. CSF-B results were non-diagnostic for 44 patients (52.3% male; aged 60.9±6.6 years), who then underwent PET-Amyloid study, which was positive in 31. A ‘k’ coefficient of 0.108 was obtained between CSF-B and PET-amyloid (54.5% concordance). In multivariate regression analysis, Aβ42 was the only significant predictor (p= 0.018) of a positive PET-Amyloid result. In the target population, PETAmyloid increased diagnostic confidence by 53.7% (p <0.001) and modified the therapeutic approach in 36.4% of cases. Conclusion: These findings support the duplication of AD biomarkers and demonstrate that the implementation of PET-Amyloid provides an early and certain diagnosis to guide appropriate treatment.

Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-β positivity

Mismatch between CSF and PET amyloid-β biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer’s disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-β42 and [18F]Florbetapir PET assessments at baseline (n = 867) and at 2-year follow-up (n = 289). Longitudinal trajectories of amyloid-β positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (n = 289), we found that participants with normal CSF/PET amyloid-β biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (χ2(1) = 5.40; p < 0.05). Progression to CSF+/PET+ status was ten times more frequent in cases with discordant biomarkers, as compared to csf−/pet− cases (χ2(1) = 18.86; p < 0.001). Compared to the CSF+/pet− group, the csf−/PET+ group had lower APOE-ε4ε4 prevalence (χ2(6) = 197; p < 0.001; n = 867) and slower rate of brain amyloid-β accumulation (F(3,600) = 12.76; p < 0.001; n = 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-β accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-β biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways (“CSF-first” vs. “PET-first”) toward established amyloid-β pathology, characterized by different genetic profiles and rates of amyloid-β accumulation. In conclusion, CSF and PET amyloid-β biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials.