Cogswell, Petrice M

Abstract Associations of Alzheimer’s disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier versus later an individual’s progression on plasma and PET Alzheimer’s disease biomarkers is associated with earlier versus later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed-effects models to estimate how much earlier versus later each individual progresses on plasma phosphorylated tau (p-tau)217, amyloid PET, tau PET and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cut-off points, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R = 0.38–0.47) in the MCSA and stronger (R = 0.74–0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET Alzheimer’s disease biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer’s disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer’s disease co-pathologies.

Abstract A workgroup assembled by the Alzheimer’s Association recently described a conceptual framework for Alzheimer’s disease biological staging based on amyloid and tau PET imaging. However, specific tau PET cut points were left to be determined, a step necessary prior to clinical application. We sought to operationalize and evaluate Alzheimer’s disease biological staging by identifying meaningful tau PET cut points to define the four biological stages in a well-characterized participant cohort and describe the features of individuals placed into the different biological stages. The primary analysis included 896 participants in the Mayo Clinic Study of Aging or the Mayo Clinic Alzheimer’s Disease Research Center longitudinal cohorts. A validation cohort consisted of 328 participants in the Alzheimer’s Disease Neuroimaging Initiative. Both cognitively normal and impaired individuals with positive amyloid PET and evaluable tau PET imaging were included. Tau PET cut points were identified with Gaussian mixture models to characterize Alzheimer’s disease biological stage in study participants with different clinical diagnoses and objective degrees of cognitive impairment as measured by Mini-Mental State Examination. A tau PET cut point in the medial temporal region and two cut points in the temporoparietal region were identified to produce, collectively, the four Alzheimer’s disease biological stages described in the revised criteria. Increasing stage was associated with greater likelihood of mild cognitive impairment and dementia diagnosis and worsening cognitive performance on Mini-Mental State Examination and Clinical Dementia Rating Sum of Boxes, a result that was reproduced in the independent Alzheimer’s Disease Neuroimaging Initiative cohort. This study provided empirical validation for the concept of using amyloid PET and tau PET to separate subjects with biomarker-proven Alzheimer’s disease into four biological stages with distinct characteristics.

Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia worldwide with rising prevalence, incidence and mortality. Despite many decades of research, there remains an unmet need for disease‐modifying treatment that can significantly alter the progression of disease. Recently, with United States Food and Drug Administration (FDA) drug approvals, there have been tremendous advances in this area, with agents demonstrating effects on cognition and biomarkers. Magnetic resonance imaging (MRI) plays an instrumental role in these trials. This review article aims to outline how MRI is used for screening eligibility, monitoring safety and measuring efficacy in clinical trials, leaning on the landscape of past and recent AD clinical trials that have used MRI as examples; further, insight on promising MRI biomarkers for future trials is provided.Level of Evidence1.Technical EfficacyStage 4.

Abstract Staging the severity of Alzheimer’s disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid and tau PET has face validity; however, this would be more practical with plasma biomarkers. Our objectives were, first, to examine approaches for staging amyloid and tau PET and, second, to examine prediction of amyloid and tau PET stages using plasma biomarkers. Participants (n = 1136) were enrolled in either the Mayo Clinic Study of Aging or the Alzheimer’s Disease Research Center; had a concurrent amyloid PET, tau PET and blood draw; and met clinical criteria for cognitively unimpaired (n = 864), mild cognitive impairment (n = 148) or Alzheimer’s clinical syndrome with dementia (n = 124). The latter two groups were combined into a cognitively impaired group (n = 272). We used multinomial regression models to estimate discrimination [concordance (C) statistics] among three amyloid PET stages (low, intermediate, high), four tau PET stages (Braak 0, 1–2, 3–4, 5–6) and a combined amyloid and tau PET stage (none/low versus intermediate/high severity) using plasma biomarkers as predictors separately within unimpaired and impaired individuals. Plasma analytes, p-tau181, Aβ1–42 and Aβ1–40 (analysed as the Aβ42/Aβ40 ratio), glial fibrillary acidic protein and neurofilament light chain were measured on the HD-X Simoa Quanterix platform. Plasma p-tau217 was also measured in a subset (n = 355) of cognitively unimpaired participants using the Lilly Meso Scale Discovery assay. Models with all Quanterix plasma analytes along with risk factors (age, sex and APOE) most often provided the best discrimination among amyloid PET stages (C = 0.78–0.82). Models with p-tau181 provided similar discrimination of tau PET stages to models with all four plasma analytes (C = 0.72–0.85 versus C = 0.73–0.86). Discriminating a PET proxy of intermediate/high from none/low Alzheimer’s disease neuropathological change with all four Quanterix plasma analytes was excellent but not better than p-tau181 only (C = 0.88 versus 0.87 for unimpaired and C = 0.91 versus 0.90 for impaired). Lilly p-tau217 outperformed the Quanterix p-tau181 assay for discriminating high versus intermediate amyloid (C = 0.85 versus 0.74) but did not improve over a model with all Quanterix plasma analytes and risk factors (C = 0.85 versus 0.83). Plasma analytes along with risk factors can discriminate between amyloid and tau PET stages and between a PET surrogate for intermediate/high versus none/low neuropathological change with accuracy in the acceptable to excellent range. Combinations of plasma analytes are better than single analytes for many staging predictions with the exception that Quanterix p-tau181 alone usually performed equivalently to combinations of Quanterix analytes for tau PET discrimination.

BackgroundFocally enlarged sulci (FES) are areas of proposed extraventricular fluid entrapment that may occur within idiopathic normal pressure hydrocephalus (iNPH) with radiographic evidence of disproportionately enlarged subarachnoid‐space hydrocephalus (DESH), and should be differentiated from atrophy.PurposeTo evaluate for change in FES size and pituitary height after shunt placement in iNPH.Study typeRetrospective.SubjectsA total of 125 iNPH patients who underwent shunt surgery and 40 age‐matched controls.Field Strength/Sequence1.5 T and 3 T. Axial T2w FLAIR, 3D T1w MPRAGE, 2D sagittal T1w.AssessmentFES were measured in three dimensions and volume was estimated by assuming an ellipsoid shape. Pituitary gland height was measured in the mid third of the gland in iNPH patients and controls.Statistical testsWilcoxon signed‐rank test for comparisons between MRI measurements; Wilcoxon rank sum test for comparison of cases/controls. Significance level was P < 0.05.ResultsFifty percent of the patients had FES. FES volume significantly decreased between the pre and first postshunt MRI by a median of 303 mm3 or 30.0%. Pituitary gland size significantly increased by 0.48 mm or 14.4%. FES decreased significantly by 190 mm3 or 23.1% and pituitary gland size increased significantly by 0.25 mm or 6% between the first and last postshunt MRI.Data ConclusionDecrease in size of FES after shunt placement provides further evidence that these regions are due to disordered cerebrospinal fluid (CSF) dynamics and should not be misinterpreted as atrophy. A relatively smaller pituitary gland in iNPH patients that normalizes after shunt is a less‐well recognized feature of altered CSF dynamics.Evidence Level3Technical EfficacyStage 2

BackgroundLocalized regions of left–right image intensity asymmetry (LRIA) were incidentally observed on T2‐weighted (T2‐w) and T1‐weighted (T1‐w) diagnostic magnetic resonance imaging (MRI) images. Suspicion of herpes encephalitis resulted in unnecessary follow‐up imaging. A nonbiological imaging artifact that can lead to diagnostic uncertainty was identified.PurposeTo investigate whether systematic LRIA exist for a range of scanner models and to determine if LRIA can introduce diagnostic uncertainty.Study TypeA retrospective study using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data base.SubjectsOne thousand seven hundred fifty‐three (median age: 72, males/females: 878/875) unique participants with longitudinal data were included.Field Strength3T.SequencesT1‐w three‐dimensional inversion‐recovery spoiled gradient‐echo (IR‐SPGR) or magnetization‐prepared rapid gradient‐echo (MP‐RAGE) and T2‐w fluid‐attenuated inversion recovery (FLAIR) long tau fast spin echo inversion recovery (LT‐FSE‐IR). Only General Electric, Philips, and Siemens' product sequences were used.AssessmentLRIA was calculated as the left–right percent difference with respect to the mean intensity from automated anatomical atlas segmented regions. Three neuroradiologists with 37 (**), 32 (**), and 3 (**) years of experience rated the clinical impact of 30 T2‐w three‐dimensional FLAIR exams with LRIA to determine the diagnostic uncertainty. Statistical comparisons between retrospective intensity normalized T1m and original T1‐w images were made.Statistical TestsFor each image type, a linear mixed effects model was fit using LRIA scores from all scanners, regions, and participants as the outcome and age and sex as predictors. Statistical significance was defined as having a P‐value <0.05.ResultsLRIA scores were significantly different from zero on most scanners. All clinicians were uncertain or recommended definite diagnostic follow‐up in 62.5% of cases with LRIA >10%. Individuals with acute brain pathology or focal neurologic deficits are not enrolled in ADNI; therefore, focal signal abnormalities were considered false positives.Data ConclusionLRIA is system specific, systematic, creates diagnostic uncertainty, and impacts IR‐SPGR, MP‐RAGE, and LT‐FSE‐IR product sequences.Level of Evidence: 2Technical Efficacy Stage: 3

BackgroundA low‐cryogen, compact 3T (C3T) MRI scanner with high‐performance gradients capable of simultaneously achieving 80 mT/m gradient amplitude and 700 T/m/second slew rate has been in use to study research patients since March 2016 but has not been implemented in the clinical practice.PurposeTo compare head MRI examinations obtained with the C3T system and a conventional whole‐body 3T (WB3T) scanner in seven parameters across five commonly used brain imaging sequences.Study TypeProspective.SubjectsThirty patients with a clinically indicated head MRI.Sequence 3T; T1 FLAIR, T1 MP‐RAGE, 3D T2 FLAIR, T2 FSE, and DWI.AssessmentAll patients tolerated the scans well. Three board‐certified neuroradiologists scored the comparative quality of C3T and WB3T images in blinded fashion using a five‐point Likert scale in terms of: signal‐to‐noise ratio, lesion conspicuity, motion artifact, gray/white matter contrast, cerebellar folia, susceptibility artifact, and overall quality.Statistical TestLeft‐sided, right‐sided, and two‐sided Wilcoxon signed rank test; Fisher's method. A P value <0.05 was considered statistically significant.ResultsThe C3T system performed better than the WB3T in virtually all comparisons, except for motion artifacts for the T1 FLAIR and T1 MP‐RAGE sequences, where the WB3T system was deemed better. When combining all sequences together, the C3T system outperformed the WB3T system in all image quality parameters evaluated, except for motion artifact (P = 0.13).Data ConclusionThe C3T scanner provided better overall image quality for all sequences, and performed better in all individual categories, except for motion artifact on the T1 FLAIR and T1 MP‐RAGE.Level of Evidence2Technical Efficacy Stage1

BackgroundIntracranial vessel wall imaging (VWI) at a clinical field strength of 3T has become more widely available. However, how vessel measurements change with age and sex, over an age range spanning a typical lifespan, are needed.Purpose/HypothesisTo assess for identifiable changes in arterial wall thickness, outer vessel wall diameter, and lumen diameter with age cross‐sectionally in healthy controls without cerebrovascular disease risk factors at the spatial resolution afforded by currently recommended 3T VWI approaches.Study TypeProspective.Population/SubjectsHealthy subjects (n = 82; age = 8–79 years).Field Strength/Sequence3T intracranial VWI, angiography, and T1‐weighted anatomical imaging.AssessmentTwo readers measured lumen and outer wall diameters of the supraclinoid internal carotid artery (ICA) and distal basilar artery. Wall thickness and intraclass correlation coefficients (ICCs) were calculated.Statistical TestsSeparate linear regressions were performed to understand the relationship between wall measurements (lumen diameter, outer vessel wall diameter, and wall thickness) and age, gender, side (left or right); significance: two‐sided P < 0.05.ResultsReaders showed excellent agreement for lumen and outer wall diameters (ICC 0.83–094). Linear regression of supraclinoid ICA wall measurements showed a statistically significant increase in wall thickness (P = 0.00051) and outer vessel wall diameter (P = 0.030) with age. ICA lumen and outer vessel wall diameters were statistically greater in males vs. females (lumen diameter 3.69 ± 0.41 vs. 3.54 ± 0.35 mm, P = 0.026; outer wall diameter 5.78 ± 0.52 vs. 5.56 ± 0.44 mm, P = 0.0089) with a trend toward increase in wall thickness (1.05 ± 0.12 vs. 1.01 ± 0.10 mm, P = 0.055). No significant difference was found in basilar artery wall thickness (P = 0.45, P = 0.72), lumen diameter (P = 0.15, P = 0.42), or outer vessel wall diameter (P = 0.34, P = 0.41) with age or gender, respectively.Data ConclusionIntracranial vessel wall measurements were shown to be consistent between readers. At the available spatial resolution of 3T intracranial VWI sequences, supraclinoid ICA vessel wall thickness and outer vessel wall diameter appear to mildly increase with age. There was no detectable change in basilar artery vessel wall characteristics with age.Level of Evidence: 2Technical Efficacy: Stage 3J. Magn. Reson. Imaging 2019;50:1452–1460.