Weigand, Stephen D.

Abstract Primary four-repeat tauopathies are characterized by depositions of the four-repeat isoform of the microtubule binding protein, tau. The two most common sporadic four-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to four-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in four-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus post-mortem pathological diagnosis of a four-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy and mean diffusivity were modelled using linear regression with post-mortem tau lesion scores considered separately, based on cellular type (neuronal versus glial), or summed (total tau). Results showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P < 0.001), substantia nigra (P = 0.03) and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P < 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P < 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in four-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, whereas white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in four-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.

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

AbstractBackgroundDiagnosing Alzheimer’s disease (AD) with biomarkers requires evidence of abnormal beta‐amyloid (Aβ) and tau. Individuals that are Aβ‐positive, but tau‐negative, are considered to have AD neuropathologic change, or early AD. The objective of this study was to determine whether some Aβ‐positive but tau‐negative individuals remain tau‐negative 5‐years later and describe the characteristics of such individuals.MethodWe identified 45 individuals from ADNI who were Aβ‐positive but tau‐negative on PET more than five years after their first abnormal Aβ‐PET (Amyloid+ Low Tau, ALT group). For comparison, we identified 157 Aβ‐positive individuals that had abnormal tau‐PET within five years of their first abnormal Aβ‐PET (i.e. biomarker‐AD). Aβ‐positivity was determined by ADNI‐provided cut‐points of 1.11 for AV45 and 1.08 for florbetapir. A negative tau‐PET scan was defined using Gaussian mixture modeling.ResultThe ALT and biomarker‐AD groups were similar in terms of sex and age at the time of their first Aβ‐PET scan. However, the ALT group was characterized by a lower proportion of APOE ε4 carriers (31% versus 67%, p<0.001), a lower median centiloid (36 versus 85, p<0.001, Figure) and lower likelihood of having a dementia diagnosis at first Aβ PET (2% versus 22%, p<0.001) compared to the biomarker‐AD group. The ALT group also performed better on tests of general cognition and had larger hippocampal volume compared to biomarker‐AD (p<0.001 for all). APOE ε4 status, centiloid and hippocampal volume were all associated with increased odds of elevated tau within 5 years from baseline Aβ‐PET (Table). Within the ALT group, 19 (42%) had high centiloid (>40): these individuals did not differ from the <40 centiloid individuals in clinical diagnosis, but there was some indication of a higher APOE ε4 frequency (42% versus 23%; p=0.30).ConclusionAmyloid‐positive individuals can remain tau‐negative for at least five years, and without becoming demented. Baseline characteristics can help identify these ALT individuals that have a low risk of progression. These findings beg the question of whether more conservative Aβ cut‐points are required for diagnosis of individuals with a high risk of developing AD.

AbstractBackgroundThe apolipoprotein ε4 (APOE4) allele is the most common and well established risk factor for typical late‐onset amnestic Alzheimer’s dementia. Less is known about the role of APOE in patients with atypical clinical presentations of AD, with studies often disagreeing on APOE4 frequencies in these cohorts. We aimed to assess relationships between APOE genotype and age, amyloid‐beta (Aβ) deposition and clinical phenotype in Alzheimer’s disease.Method138 atypical AD patients (57 posterior cortical atrophy and 81 logopenic aphasia) were recruited by the Neurodegenerative Research Group at Mayo Clinic, and underwent APOE testing and Pittsburgh Compound B PET. 318 typical AD patients with APOE genotype and known onset age were identified from ADNI (121 had Aβ‐PET). Aβ‐PET was quantified using the centiloid scale. Logistic regression was used to estimate the proportion of APOE4 carriers by onset age and clinical group. Linear regression was used to estimate mean Aβ centiloid by age, APOE4 status, and clinical group in patients who were Aβ‐positive (centiloid≥19).ResultThe overall frequency of APOE4 carriers was lower in atypical AD (52%) compared to typical AD (66%), particularly for ε4ε4 homozygotes (9% vs 20%). APOE4 frequency increased with age in atypical AD, but showed a bell‐shaped curve in typical AD where highest frequencies were observed between 65‐70 years (Figure). Typical AD showed higher APOE4 frequencies than atypical AD only between the ages of 57 and 69 years. Aβ centiloid was higher in atypical AD compared to typical AD by approximately 16 centiloid units, but did not differ according to APOE4 status (Figure). Aβ centiloid stayed relatively flat with increasing age for both carriers and non‐carriers in atypical AD, but declines with increasing age in typical AD. Relationships between APOE4 and age, as well as centiloid, did not differ between the two atypical AD phenotypes.ConclusionAPOE4 frequency differs between atypical and typical AD but is highly dependent upon age, with higher APOE4 frequency in typical AD only observed between 57 and 69 years. The findings highlight the importance of age and clinical phenotype in understanding the effects of APOE genotype in Alzheimer’s disease.

AbstractBackgroundAlzheimer’s disease biomarkers of tau pathology may be assessed by both CSF and PET. Cross‐sectional associations between CSF phosphorylated tau (p‐tau) and tau PET have been studied and regional tau PET SUVR has been shown to have similar diagnostic performance as CSF p‐tau. The association between CSF p‐tau and longitudinal tau PET has not been studied. CSF measures may be thought of as a result of the imbalance of influx vs efflux of soluble tau, whereas, tau PET reflects total tau accumulation into insoluble aggregates to date. We therefore hypothesize that baseline CSF p‐tau may be a leading indicator of future tau PET accumulation.MethodWe identified Mayo Clinic Study of Aging (MCSA) and Mayo Alzheimer’s Disease Research Center (ADRC) participants with diagnoses of cognitively unimpaired, mild cognitive impairment, and amnestic dementia who had CSF p‐tau (Elecsys p‐tau [181P]) and subsequent serial tau PET (flortaucipir) exams. The first tau PET scan was within 3 years of the CSF p‐tau collection. A longitudinal pipeline with two‐compartment partial volume correction was used to measure change in tau PET in a temporal‐lobe meta‐ROI (amygdala, fusiform, middle/inferior temporal, entorhinal, and parahippocampal regions) with a composite reference region (eroded supratentorial white matter, pons, and whole cerebellum). Spearman correlation was used to assess the association between CSF p‐tau and annual percent change in tau PET. A linear mixed effects model was fit to assess the association adjusting for age and sex.ResultThe study included 143 participants (76% cognitively unimpaired) (). CSF p‐tau was significantly associated with annual percent change in tau PET overall (Spearman R=0.19, p=0.023) () and after adjusting for age and sex (p<0.001) (). There was nonlinearity in the CSF p‐tau effect, with higher values (>20 pg/mL) having a greater association with annual change in tau PET than lower values.ConclusionIn a group of cognitively unimpaired and impaired participants, CSF p‐tau predicted subsequent tau PET accumulation rate. A threshold effect is suggested with subsequent tau PET accumulation primarily in participants with elevated CSF p‐tau levels near the Mayo threshold of 22 pg/mL.

AbstractBackgroundThe Mayo Clinic Study of Aging and Alzheimer’s Disease Research Center used GE scanners exclusively for MRI from 2005‐2017, employing consistent imaging parameters throughout. In 2017 the MRI protocol was updated and migrated to Siemens Prisma scanners; 113 participants were scanned with each configuration. The GE protocol included a 2D FLAIR. The Siemens protocol includes 3D FLAIR and T2‐weighted images. Both vendor protocols included a 3D T1. Experience with multi‐center trials suggests such changes may introduce systematic variations.MethodsGE scanning was carried out on 3T scanners with 12 channel phased array head coils. Siemens Prisma scanning was carried out with 64 channel head/neck coils. Imaging sequences and parameters are given in Table 1. We used the MCALT template and priors to perform standard six‐class segmentation on T1‐weighted (T1w) images. SPM12 unified segmentation supports the simultaneous use of multiple input contrasts; segmentation of multi‐contrast inputs was done using eight tissue classes including deep grey and white matter hyperintensity (WMH) priors. For a given MRI study (either GE or Siemens) all images were registered and resampled to the study’s T1w image. Two‐channel (T1+FLAIR) segmentation was performed on GE scans. Two and three‐channel segmentations were performed on Siemens scans. Comparisons included total intracranial volume, total tissue volume and total grey matter volumes, as well as hippocampal volumes and grey matter volume in a temporal lobe meta‐ROI.ResultsFour participants were excluded for poor image quality: one poor GE T1w quality, one poor Siemens T1, T2 and FLAIR quality, and two poor Siemens T2 quality. Comparisons were made among 109 participants aged 34–97 (Table 2). By visual assessment, adding T2‐weighted images always improved intracranial volume correctness. Using the combination of single‐channel GE and three‐channel Siemens generally improved cross‐vendor agreement on grey matter volumes with the exceptions of hippocampal and intracranial volume estimates.ConclusionRequiring multiple input channels increases the likelihood that the result of a study being excluded. Combining T1w, FLAIR and T2w images allows the delineation of WMH and deep grey matter probability outputs but may introduce differences in GM volumes.

AbstractBackgroundOptimizing software to measure Flortaucipir (AV‐1451) tau PET SUVR change‐over‐time is crucial for longitudinal observational studies and potential trials of anti‐tau agents. Ideal measurements should have good repeatability (low noise), and should clearly separate clinical cognitive groups.MethodWe compared 456 software methods varying in their use of: two major packages, each with cross‐sectional and longitudinal variants (FreeSurfer and an in‐house pipeline using SPM12, MCALT, and ANTs); three temporal‐lobe target regions (each with/without adjacent WM); seven reference regions; five PVC methods; and two statistics (mean vs. median). We used linear mixed‐effects models to compare methods using scans from 88 Mayo Clinic participants (46 cognitively impaired, 42 impaired, excluding those with symptoms inconsistent with the AD pathology imaged by Flortaucipir), each with three visits with PET and MRI. From these models, we calculated two criteria for each pipeline: relative measurement error (residual from the linear mixed model), and the t‐statistic for testing differences in group‐wise rates of change (which has a Cohen’s d interpretation of effect size for longitudinal data). We plotted both criteria orthogonally, then ranked methods overall according to the average of their ranks on both individual criteria.ResultMethods using the entorhinal cortex target region performed poorly in both criteria (Figure 1). The top 10 methods by the combined criteria (top‐left in Figure 2) all used the Mayo SPM12‐based pipeline with an eroded supratentorial WM (eSWM) or composite (eSWM + pons + cerebellum) reference region. Among them, 9/10 used the longitudinal variant, 8/10 used 2‐compartment PVC, and 7/10 used median. Altogether, our results favored SUVR methods with a longitudinal design (simultaneously calculating all time‐points), a temporal‐lobe meta‐ROI including adjacent WM, a composite reference region, 2‐class voxel‐based (Meltzer) PVC, and median statistics. Methods using GTM‐Tau PVC (Baker et al., Data in Brief, 2017) had the highest group separation but relatively large measurement error, giving them ranks 197 and 199 out of 456 with the joint (average rank) criteria.ConclusionCompared with popular FreeSurfer‐based methods (ranks 176, 258; Figure 2), our top‐ranked approaches approximately halved error in SUVR measurements while maintaining or improving group separation.

AbstractBackgroundMagnetic resonance brainstem measurements are useful structural biomarkers in the Richardson's syndrome variant of progressive supranuclear palsy (PSP). However, it is unclear how these biomarkers differ across the phenotypic spectrum of PSP and how they relate to underlying pathology.ObjectiveThe aim of this study was to compare brainstem imaging measures across clinical variants of PSP and determine sensitivity and specificity based on pathologically diagnosed cases.MethodsA total of 153 patients with PSP who represented eight clinical variants were recruited at Mayo Clinic (Rochester, MN, USA) and underwent structural magnetic resonance imaging (MRI). Midbrain and pons area and superior and middle cerebellar peduncle width measurements were performed, and midbrain/pons ratio and Magnetic Resonance Parkinsonism Index (MRPI) were calculated. Among the 43 patients who later died, PSP pathology was confirmed in 29, whereas 14 had other pathology.ResultsBrainstem measurements varied across PSP clinical variants and were most abnormal in PSP‐Richardson's syndrome and frontal variants, followed by PSP‐corticobasal, PSP‐speech/language, and PSP‐parkinsonism variants. All these variants showed abnormalities compared with controls. The PSP‐gait freezing variant and patients with prominent corticospinal tract signs showed normal brainstem measures. Among cases with confirmed PSP pathology, the midbrain area, midbrain/pons ratio, and MRPI were all more abnormal compared to those with other pathologies, with best differentiation obtained with the MRPI (sensitivity = 83%; specificity = 85%).ConclusionsMRI brainstem measures show utility as diagnostic biomarkers across PSP clinical variants and have the potential to be useful in predicting underlying pathology. © 2021 International Parkinson and Movement Disorder Society

ABSTRACTBackgroundApathy and depression commonly occur in patients with progressive supranuclear palsy (PSP)‐Richardson's syndrome variant; depression often requiring treatment. Little is known, however, about apathy and depression among other PSP variants.MethodsWe prospectively studied 97 newly diagnosed PSP patients. All were classified into a PSP variant using the 2017 Movement Disorder Society‐PSP criteria and administered the Geriatric Depression and Apathy Evaluation Scales. Differences in apathy and depression frequency and severity across six variants, and secondarily across PSP‐Richardson's syndrome, PSP‐Cortical and PSP‐Subcortical, were analyzed using ANCOVA and linear regression adjusting for disease severity.ResultsDepression (55%) was more common than apathy (12%). PSP‐Speech/Language (PSP‐SL) variant had the lowest depression frequency (13%) and lower depression scores than the other variants. No differences in apathy frequency/severity were identified.ConclusionPSP‐SL patients may have less depression compared to PSP‐Richardson's syndrome and other PSP variants.