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Val J. Lowe

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22 papers

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YNIMG Journal 2025 Journal Article

Cardiorespiratory dynamics in the brain: Review on the significance of cardiovascular and respiratory correlates in functional MRI signal

Mahathi Kandimalla
Seokbeen Lim
Jay Thakkar
Sannidhi Dewan
Daehun Kang
Myung-Ho In
Hang Joon Jo
Dong Pyo Jang

Cardiorespiratory signals have long been treated as "noise" in functional magnetic resonance imaging (fMRI) research, with the goal of minimizing their impact to isolate neural activity. However, there is a growing recognition that these signals, once seen as confounding variables, provide valuable insights into brain function and overall health. This shift reflects the dynamic interaction between the cardiovascular, respiratory, and neural systems, which together support brain activity. In this review, we explore the role of cardiorespiratory dynamics-such as heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and changes in blood flow, oxygenation, and carbon dioxide levels-embedded within fMRI signals. These physiological signals reflect critical aspects of neurovascular coupling and are influenced by factors such as physiological stress, breathing patterns, and age-related changes. We also discuss the complexities of distinguishing these signals from neuronal activity in fMRI data, given their significant contribution to signal variability and interactions with cerebrospinal fluid (CSF). Recognizing the influence of these cardiorespiratory dynamics is crucial for improving the interpretation of fMRI data, shedding light on heart-brain and respiratory-brain connections, and enhancing our understanding of circulation, oxygen delivery, and waste elimination within the brain.

YNIMG Journal 2024 Journal Article

Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies

Neha Atulkumar Singh
Austin W. Goodrich
Jonathan Graff-Radford
Mary M. Machulda
Irene Sintini
Arenn F. Carlos
Carling G. Robinson
Robert I. Reid

F] fluorodeoxyglucose (FDG) PET. We assessed functional connectivity within and between 12 brain networks using rsfMRI and the CONN functional connectivity toolbox and calculated regional DTI metrics using the Johns Hopkins atlas. Multivariate linear-regression models corrected for multiple comparisons and adjusted for age and sex compared DTI metrics and within-network and between-network functional connectivity across groups. Regional gray-matter volumes and FDG-PET standard uptake value ratios (SUVRs) were calculated and analyzed at the voxel-level using SPM12. We used univariate linear-regression models to investigate the relationship between connectivity measures, gray-matter volume, and FDG-PET SUVR. On DTI, PCA showed degeneration in occipito-parietal white matter, posterior thalamic radiations, splenium of the corpus collosum and sagittal stratum compared to DLB and CU, with greater degeneration in the temporal white matter and the fornix compared to CU. We observed no white-matter degeneration in DLB compared to CU. On rsfMRI, reduced within-network connectivity was present in dorsal and ventral default mode networks (DMN) and the dorsal-attention network in PCA compared to DLB and CU, with reduced within-network connectivity in the visual and sensorimotor networks compared to CU. DLB showed reduced connectivity in the cerebellar network compared to CU. Between-network analysis showed increased connectivity in both cerebellar-to-sensorimotor and cerebellar-to-dorsal attention network connectivity in PCA and DLB. PCA showed reduced anterior DMN-to-cerebellar and dorsal attention-to-sensorimotor connectivity, while DLB showed reduced posterior DMN-to-sensorimotor connectivity compared to CU. PCA showed reduced dorsal DMN-to-visual connectivity compared to DLB. The multimodal analysis revealed weak associations between functional connectivity and volume in PCA, and between functional connectivity and metabolism in DLB. These findings suggest that PCA and DLB have unique connectivity alterations, with PCA showing more widespread disruptions in both structural and functional connectivity; yet some overlap was observed with both disorders showing increased connectivity from the cerebellum.

YNICL Journal 2024 Journal Article

Assessing network degeneration and phenotypic heterogeneity in genetic frontotemporal lobar degeneration by decoding FDG-PET

Nick Corriveau-Lecavalier
Leland R. Barnard
Scott A. Przybelski
Venkatsampath Gogineni
Hugo Botha
Jonathan Graff-Radford
Vijay K. Ramanan
Leah K. Forsberg

Fluorodeoxyglucose-positron emission tomography (FDG-PET) data from 39 patients with genetic FTLD, including 11 carrying the C9orf72 hexanucleotide expansion, 16 carrying a MAPT mutation and 12 carrying a GRN mutation. We performed a spectral covariance decomposition analysis between FDG-PET images to yield unbiased latent patterns reflective of whole brain patterns of metabolism ("eigenbrains" or EBs). We then conducted linear discriminant analyses (LDAs) to perform EB-based predictions of genetic mutation and predominant clinical phenotype (i.e., behavior/personality, language, asymptomatic). Five EBs were significant and explained 58.52 % of the covariance between FDG-PET images. EBs indicative of hypometabolism in left frontotemporal and temporo-parietal areas distinguished GRN mutation carriers from other genetic mutations and were associated with predominant language phenotypes. EBs indicative of hypometabolism in prefrontal and temporopolar areas with a right hemispheric predominance were mostly associated with predominant behavioral phenotypes and distinguished MAPT mutation carriers from other genetic mutations. The LDAs yielded accuracies of 79.5 % and 76.9 % in predicting genetic status and predominant clinical phenotype, respectively. A small number of EBs explained a high proportion of covariance in patterns of network degeneration across FTLD-related genetic mutations. These EBs contained biological information relevant to the variability in the pathophysiological and clinical aspects of genetic FTLD, and for offering valuable guidance in complex clinical decision-making, such as decisions related to genetic testing.

YNICL Journal 2024 Journal Article

Complex relationships of socioeconomic status with vascular and Alzheimer’s pathways on cognition

Dror Shir
Jonathan Graff-Radford
Angela J. Fought
Timothy G. Lesnick
Scott A. Przybelski
Maria Vassilaki
Val J. Lowe
David S. Knopman

INTRODUCTION: AD and CVD, which frequently co-occur, are leading causes of age-related cognitive decline. We assessed how demographic factors, socioeconomic status (SES) as indicated by education and occupation, vascular risk factors, and a range of biomarkers associated with both CVD (including white matter hyperintensities [WMH], diffusion MRI abnormalities, infarctions, and microbleeds) and AD (comprising amyloid-PET and tau-PET) collectively influence cognitive function. METHODS: In this cross-sectional population study, structural equation models were utilized to understand these associations in 449 participants (mean age (SD) = 74.5 (8.4) years; 56% male; 7.5% cognitively impaired). RESULTS: (1) Higher SES had a protective effect on cognition with mediation through the vascular pathway. (2) The effect of amyloid directly on cognition and through tau was 11-fold larger than the indirect effect of amyloid on cognition through WMH. (3) There is a significant effect of vascular risk on tau deposition. DISCUSSION: The utilized biomarkers captured the impact of CVD and AD on cognition. The overall effect of vascular risk and SES on these biomarkers are complex and need further investigation.

YNIMG Journal 2024 Journal Article

Direct comparison between 18F-Flortaucipir tau PET and quantitative susceptibility mapping in progressive supranuclear palsy

Ryota Satoh
Farwa Ali
Hugo Botha
Val J. Lowe
Keith A. Josephs
Jennifer L. Whitwell

PURPOSE: The pattern of flortaucipir tau PET uptake is topographically similar to the pattern of magnetic susceptibility in progressive supranuclear palsy (PSP); both with increased signal in subcortical structures such as the basal ganglia and midbrain, suggesting that they may be closely related. However, their relationship remains unknown since no studies have directly compared these two modalities in the same PSP cohort. We hypothesized that some flortaucipir uptake in PSP is associated with magnetic susceptibility, and hence iron deposition. The aim of this study was to evaluate the regional relationship between flortaucipir uptake and magnetic susceptibility and to examine the effects of susceptibility on flortaucipir uptake in PSP. METHODS: Fifty PSP patients and 67 cognitively normal controls were prospectively recruited and underwent three Tesla MRI and flortaucipir tau PET scans. Quantitative susceptibility maps were reconstructed from multi-echo gradient-echo MRI images. Region of interest (ROI) analysis was performed to obtain flortaucipir and susceptibility values in the subcortical regions. Relationships between flortaucipir and susceptibility signals were evaluated using partial correlation analysis in the subcortical ROIs and voxel-based analysis in the whole brain. The effects of susceptibility on flortaucipir uptake were examined by using the framework of mediation analysis. RESULTS: Both flortaucipir and susceptibility were greater in PSP compared to controls in the putamen, pallidum, subthalamic nucleus, red nucleus, and cerebellar dentate (p<0.05). The ROI-based and voxel-based analyses showed that these two signals were positively correlated in these five regions (r = 0.36-0.59, p<0.05). Mediation analysis showed that greater flortaucipir uptake was partially explained by susceptibility in the putamen, pallidum, subthalamic nucleus, and red nucleus, and fully explained in the cerebellar dentate. CONCLUSIONS: These results suggest that some of the flortaucipir uptake in subcortical regions in PSP is related to iron deposition. These findings will contribute to our understanding of the mechanisms underlying flortaucipir tau PET findings in PSP and other neurodegenerative diseases.

YNICL Journal 2024 Journal Article

Speech-language within and between network disruptions in primary progressive aphasia variants

Neha Singh-Reilly
Hugo Botha
Joseph R. Duffy
Heather M. Clark
Rene L. Utianski
Mary M. Machulda
Jonathan Graff-Radford
Christopher G. Schwarz

Primary progressive aphasia (PPA) variants present with distinct disruptions in speech-language functions with little known about the interplay between affected and spared regions within the speech-language network and their interaction with other functional networks. The Neurodegenerative Research Group, Mayo Clinic, recruited 123 patients with PPA (55 logopenic (lvPPA), 44 non-fluent (nfvPPA) and 24 semantic (svPPA)) who were matched to 60 healthy controls. We investigated functional connectivity disruptions between regions within the left-speech-language network (Broca, Wernicke, anterior middle temporal gyrus (aMTG), supplementary motor area (SMA), planum temporale (PT) and parietal operculum (PO)), and disruptions to other networks (visual association, dorsal-attention, frontoparietal and default mode networks (DMN)). Within the speech-language network, multivariate linear regression models showed reduced aMTG-Broca connectivity in all variants, with lvPPA and nfvPPA findings remaining significant after Bonferroni correction. Additional loss in Wernicke-Broca connectivity in nfvPPA, Wernicke-PT connectivity in lvPPA and greater aMTG-PT connectivity in svPPA were also noted. Between-network connectivity findings in all variants showed reduced aMTG-DMN and increased aMTG-dorsal-attention connectivity, with additional disruptions between aMTG-visual association in both lvPPA and svPPA, aMTG-frontoparietal in lvPPA, and Wernicke-DMN breakdown in svPPA. These findings suggest that aMTG connectivity breakdown is a shared feature in all PPA variants, with lvPPA showing more extensive connectivity disruptions with other networks.

YNICL Journal 2023 Journal Article

Effects of de-facing software mri_reface on utility of imaging biomarkers used in Alzheimer’s disease research

Christopher G. Schwarz
Walter K. Kremers
Stephen D. Weigand
Carl M. Prakaashana
Matthew L. Senjem
Scott A. Przybelski
Val J. Lowe
Jeffrey L. Gunter

Brain imaging research studies increasingly use "de-facing" software to remove or replace facial imagery before public data sharing. Several works have studied the effects of de-facing software on brain imaging biomarkers by directly comparing automated measurements from unmodified vs de-faced images, but most research brain images are used in analyses of correlations with cognitive measurements or clinical statuses, and the effects of de-facing on these types of imaging-to-cognition correlations has not been measured. In this work, we focused on brain imaging measures of amyloid (A), tau (T), neurodegeneration (N), and vascular (V) measures used in Alzheimer's Disease (AD) research. We created a retrospective sample of participants from three age- and sex-matched clinical groups (cognitively unimpaired, mild cognitive impairment, and AD dementia, and we performed region- and voxel-wise analyses of: hippocampal volume (N), white matter hyperintensity volume (V), amyloid PET (A), and tau PET (T) measures, each from multiple software pipelines, on their ability to separate cognitively defined groups and their degrees of correlation with age and Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB). We performed each of these analyses twice: once with unmodified images and once with images de-faced with leading de-facing software mri_reface, and we directly compared the findings and their statistical strengths between the original vs. the de-faced images. Analyses with original and with de-faced images had very high agreement. There were no significant differences between any voxel-wise comparisons. Among region-wise comparisons, only three out of 55 correlations were significantly different between original and de-faced images, and these were not significant after correction for multiple comparisons. Overall, the statistical power of the imaging data for AD biomarkers was almost identical between unmodified and de-faced images, and their analyses results were extremely consistent.

YNICL Journal 2022 Journal Article

Distinct brain iron profiles associated with logopenic progressive aphasia and posterior cortical atrophy

Neha Atulkumar Singh
Arvin Arani
Jonathan Graff-Radford
Matthew L. Senjem
Peter R. Martin
Mary M. Machulda
Christopher G. Schwarz
Yunhong Shu

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer's disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

YNIMG Journal 2022 Journal Article

Face recognition from research brain PET: An unexpected PET problem

Christopher G. Schwarz
Walter K. Kremers
Val J. Lowe
Marios Savvides
Jeffrey L. Gunter
Matthew L. Senjem
Prashanthi Vemuri
Kejal Kantarci

It is well known that de-identified research brain images from MRI and CT can potentially be re-identified using face recognition; however, this has not been examined for PET images. We generated face reconstruction images of 182 volunteers using amyloid, tau, and FDG PET scans, and we measured how accurately commercial face recognition software (Microsoft Azure's Face API) automatically matched them with the individual participants' face photographs. We then compared this accuracy with the same experiments using participants' CT and MRI. Face reconstructions from PET images from PET/CT scanners were correctly matched at rates of 42% (FDG), 35% (tau), and 32% (amyloid), while CT were matched at 78% and MRI at 97-98%. We propose that these recognition rates are high enough that research studies should consider using face de-identification ("de-facing") software on PET images, in addition to CT and structural MRI, before data sharing. We also updated our mri_reface de-identification software with extended functionality to replace face imagery in PET and CT images. Rates of face recognition on de-faced images were reduced to 0-4% for PET, 5% for CT, and 8% for MRI. We measured the effects of de-facing on regional amyloid PET measurements from two different measurement pipelines (PETSurfer/FreeSurfer 6.0, and one in-house method based on SPM12 and ANTs), and these effects were small: ICC values between de-faced and original images were > 0.98, biases were <2%, and median relative errors were < 2%. Effects on global amyloid PET SUVR measurements were even smaller: ICC values were 1.00, biases were <0.5%, and median relative errors were also <0.5%.

YNIMG Journal 2021 Journal Article

Associations of quantitative susceptibility mapping with Alzheimer's disease clinical and imaging markers

Petrice M. Cogswell
Heather J. Wiste
Matthew L. Senjem
Jeffrey L. Gunter
Stephen D. Weigand
Christopher G. Schwarz
Arvin Arani
Terry M. Therneau

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34-97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM.

YNICL Journal 2021 Journal Article

FDG PET metabolic signatures distinguishing prodromal DLB and prodromal AD

Kejal Kantarci
Bradley F. Boeve
Scott A. Przybelski
Timothy G. Lesnick
Qin Chen
Julie Fields
Christopher G. Schwarz
Matthew L. Senjem

BACKGROUND AND PURPOSE: F-fluorodeoxyglucose (FDG) PET. Whether this pattern of hypometabolism is present as early as the prodromal stage of DLB is unknown. We investigated the pattern of hypometabolism in patients with mild cognitive impairment (MCI) who progressed to probable DLB compared to MCI patients who progressed to Alzheimer's disease (AD) dementia and clinically unimpaired (CU) controls. METHODS: Patients with MCI from the Mayo Clinic Alzheimer's Disease Research Center who underwent FDG PET at baseline and progressed to either probable DLB (MCI-DLB; n = 17) or AD dementia (MCI-AD; n = 41) during follow-up, and a comparison cohort of CU controls (n = 100) were included. RESULTS: Patients with MCI-DLB had hypometabolism in the parieto-occipital cortex extending into temporal lobes, substantia nigra and thalamus. When compared to MCI-AD, medial temporal and posterior cingulate metabolism were preserved in patients with MCI-DLB, accompanied by greater hypometabolism in the substantia nigra in MCI-DLB compared to MCI-AD. In distinguishing MCI-DLB from MCI-AD at the maximum value of Youden's index, CIS ratio was highly specific (90%) but not sensitive (59%), but a higher medial temporal to substantia nigra ratio was both sensitive (94%) and specific (83%). CONCLUSION: FDG PET is a potential biomarker for the prodromal stage of DLB. A higher medial temporal metabolism and CIS ratio, and lower substantia nigra metabolism have additive value in distinguishing prodromal DLB and AD.

YNICL Journal 2021 Journal Article

Neuroimaging correlates of gait abnormalities in progressive supranuclear palsy

Irene Sintini
Kenton Kaufman
Hugo Botha
Peter R. Martin
Stacy R. Loushin
Matthew L. Senjem
Robert I. Reid
Christopher G. Schwarz

Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET uptake in the left paracentral lobule and supplementary motor area and white matter disruption in the superior cerebellar peduncle, putamen, pontine crossing tract and corticospinal tract. A partial least square model identified flortaucipir-PET uptake in midbrain, basal ganglia and thalamus as the main correlate of speed and dynamic component of gait in progressive supranuclear palsy. Although causality cannot be established in this analysis, our study sheds light on neurodegeneration of brain regions and white matter tracts that underlies gait and balance impairment in progressive supranuclear palsy.

YNIMG Journal 2021 Journal Article

Relationships between β-amyloid and tau in an elderly population: An accelerated failure time model

Terry M. Therneau
David S. Knopman
Val J. Lowe
Hugo Botha
Jonathan Graff-Radford
David T. Jones
Prashanthi Vemuri
Michelle M. Mielke

Using positron emission tomography (PET)-derived amyloid and tau measurements from 1,495 participants, we explore the evolution of these values over time via an accelerated failure time (AFT) model. The AFT model assumes a shared pattern of progression, but one which is shifted earlier or later in time for each individual; an individual's time shift for amyloid and for tau are assumed to be linked. The resulting pattern for each outcome consists of an earlier indolent phase followed by sharp progression of the accumulation rate. APOE ε4 shifts the amyloid curve leftward (earlier) by 6.1 years, and the tau curve leftward by 2.6 years. Female sex shifts the amyloid curve leftward by 2.4 years and the tau curve leftward by 2.6 years. Per-person shifts (i.e., the individual's deviation from the population mean) for the onset of amyloid accumulation ranged from 13 years earlier to 13 years later (10th to 90th percentile) than average and 11 years earlier to 14 years later for tau, with an estimated correlation of 0.49. The average delay between amyloid increase and tau increase was 13.3 years.

YNIMG Journal 2021 Journal Article

Selecting software pipelines for change in flortaucipir SUVR: Balancing repeatability and group separation

Christopher G. Schwarz
Terry M. Therneau
Stephen D. Weigand
Jeffrey L. Gunter
Val J. Lowe
Scott A. Przybelski
Matthew L. Senjem
Hugo Botha

Since tau PET tracers were introduced, investigators have quantified them using a wide variety of automated methods. As longitudinal cohort studies acquire second and third time points of serial within-person tau PET data, determining the best pipeline to measure change has become crucial. We compared a total of 415 different quantification methods (each a combination of multiple options) according to their effects on a) differences in annual SUVR change between clinical groups, and b) longitudinal measurement repeatability as measured by the error term from a linear mixed-effects model. Our comparisons used MRI and Flortaucipir scans of 97 Mayo Clinic study participants who clinically either: a) were cognitively unimpaired, or b) had cognitive impairments that were consistent with Alzheimer's disease pathology. Tested methods included cross-sectional and longitudinal variants of two overarching pipelines (FreeSurfer 6.0, and an in-house pipeline based on SPM12), three choices of target region (entorhinal, inferior temporal, and a temporal lobe meta-ROI), five types of partial volume correction (PVC) (none, two-compartment, three-compartment, geometric transfer matrix (GTM), and a tau-specific GTM variant), seven choices of reference region (cerebellar crus, cerebellar gray matter, whole cerebellum, pons, supratentorial white matter, eroded supratentorial WM, and a composite of eroded supratentorial WM, pons, and whole cerebellum), two choices of region masking (GM or GM and WM), and two choices of statistic (voxel-wise mean vs. median). Our strongest findings were: 1) larger temporal-lobe target regions greatly outperformed entorhinal cortex (median sample size estimates based on a hypothetical clinical trial were 520-526 vs. 1740); 2) longitudinal processing pipelines outperformed cross-sectional pipelines (median sample size estimates were 483 vs. 572); and 3) reference regions including supratentorial WM outperformed traditional cerebellar and pontine options (median sample size estimates were 370 vs. 559). Altogether, our results favored longitudinally SUVR methods and a temporal-lobe meta-ROI that includes adjacent (juxtacortical) WM, a composite reference region (eroded supratentorial WM + pons + whole cerebellum), 2-class voxel-based PVC, and median statistics.

YNICL Journal 2020 Journal Article

Brain volume and flortaucipir analysis of progressive supranuclear palsy clinical variants

Jennifer L. Whitwell
Nirubol Tosakulwong
Hugo Botha
Farwa Ali
Heather M. Clark
Joseph R. Duffy
Rene L. Utianski
Chase A. Stevens

BACKGROUND AND PURPOSE: F]flortaucipir uptake on PET across PSP variants. MATERIALS AND METHODS: 105 PSP patients (53 PSP-RS, 23 PSP-SL, 12 PSP-P, 8 PSP-CBS, 5 PSP-F and 4 PSP-PGF) underwent volumetric MRI, with 59 of these also undergoing flortaucipir PET. Voxel-level and region-level analyses were performed comparing PSP variants to 30 controls and to each other. Semi-quantitative tau burden measurements were also performed in 21 patients with autopsy-confirmed PSP. RESULTS: All variants showed evidence for atrophy or increased flortaucipir uptake in striatum, globus pallidus and thalamus. Superior cerebellar peduncle volume loss was only observed in PSP-RS, PSP-CBS and PSP-F. Volume loss in the frontal lobes was observed in PSP-SL, PSP-CBS and PSP-F, with these variants also showing highest cortical tau burden at autopsy. The PSP-P and PSP-PGF variants showed more restricted patterns of neurodegeneration predominantly involving striatum, globus pallidus, subthalamic nucleus and thalamus. The PSP-SL variant showed greater volume loss and flortaucipir uptake in supplementary motor area and motor cortex compared to all other variants, but showed less involvement of subthalamic nucleus and midbrain. Compared to PSP-RS, PSP-P had larger midbrain volume and greater flortaucipir uptake in putamen. CONCLUSION: The PSP variants have different patterns of involvement of subcortical circuitry, perhaps suggesting different patterns of disease spread through the brain. These findings will be important in the development of appropriate neuroimaging biomarkers for the different PSP variants.

YNICL Journal 2019 Journal Article

Longitudinal tau-PET uptake and atrophy in atypical Alzheimer's disease

Irene Sintini
Peter R. Martin
Jonathan Graff-Radford
Matthew L. Senjem
Christopher G. Schwarz
Mary M. Machulda
Anthony J. Spychalla
Daniel A. Drubach

F]AV-1451 PET and PiB PET. Region- and voxel-level rates of tau accumulation and grey matter atrophy relative to cognitively unimpaired individuals, and the influence of age on such rates, were assessed. Univariate and multivariate analyses were performed between baseline measurements and rates of change, between baseline tau and atrophy, and between the two rates of change. Regional patterns of change in tau and volume differed, with highest rates of tau accumulation in frontal lobe and highest rates of atrophy in temporoparietal regions. Age had a negative effect on disease progression, predominantly on tau, with younger patients having a more rapid accumulation. Baseline tau uptake and regions of tau accumulation were disconnected, with high baseline tau uptake across the cortex correlated with high rates of tau accumulation in frontal and sensorimotor regions. In contrast, baseline volume and atrophy were locally related in the occipitoparietal regions. Higher tau uptake at baseline was locally related to higher rates of atrophy in frontal and occipital lobes. Tau accumulation rates positively correlated with rates of atrophy. In summary, our study showed that tau accumulation and atrophy presented different regional patterns in atypical AD, with tau spreading into the frontal lobes while atrophy remains in temporoparietal and occipital cortex, suggesting a temporal disconnect between protein deposition and neurodegeneration.

YNICL Journal 2018 Journal Article

Regional cortical perfusion on arterial spin labeling MRI in dementia with Lewy bodies: Associations with clinical severity, glucose metabolism and tau PET

Zuzana Nedelska
Matthew L. Senjem
Scott A. Przybelski
Timothy G. Lesnick
Val J. Lowe
Bradley F. Boeve
Arvin Arani
Prashanthi Vemuri

Visually preserved metabolism in posterior cingulate cortex relative to hypometabolism in precuneus and cuneus, the cingulate island sign, is a feature of dementia with Lewy bodies (DLB) on FDG-PET. Lower cingulate island sign ratio (posterior cingulate cortex/cuneus+precuneus; FDG-CISr) values have been associated with a higher Braak neurofibrillary tangle stage in autopsied DLB. Using voxel-wise analysis, we assessed the patterns of regional cortical perfusion and metabolism, and using an atlas-based approach, we measured perfusion cingulate island sign ratio on arterial spin labeling MRI (ASL-CISr), and its associations with FDG-CISr, uptake on tau-PET and clinical severity in DLB. Our study sample (n = 114) included clinically probable DLB patients (n = 19), age-matched patients with probable Alzheimer's disease dementia (AD; n = 19) and matched controls (n = 76) who underwent MRI with 3-dimensional pseudo-continuous arterial spin labeling, 18F-FDG-PET and 18F-AV-1451 tau PET. Patterns of cortical perfusion and metabolism were derived from quantitative maps using Statistical Parametric Mapping. DLB patients showed hypoperfusion on ASL-MRI in precuneus, cuneus and posterior parieto-occipital cortices, compared to controls, and relatively spared posterior cingulate gyrus, similar to pattern of hypometabolism on FDG-PET. DLB patients had higher ASL-CISr and FDG-CISr than AD patients (p <0. 001). ASL-CISr correlated with FDG-CISr in DLB patients (r = 0. 67; p =0. 002). Accuracy of distinguishing DLB from AD patients was 0. 80 for ASL-CISr and 0. 91 for FDG-CISr. Lower ASL-CISr was moderately associated with a higher composite medial temporal AV-1451 uptake (r = −0. 50; p =0. 03) in DLB. Lower perfusion in precuneus and cuneus was associated with worse global clinical scores. In summary, the pattern of cortical hypoperfusion on ASL-MRI is similar to hypometabolism on FDG-PET, and respective cingulate island sign ratios correlate with each other in DLB. Non-invasive and radiotracer-free ASL-MRI may be further developed as a tool for the screening and diagnostic evaluation of DLB patients in a variety of clinical settings where FDG-PET is not accessible.

YNICL Journal 2017 Journal Article

Comparison of [18F]Flutemetamol and [11C]Pittsburgh Compound-B in cognitively normal young, cognitively normal elderly, and Alzheimer's disease dementia individuals

Val J. Lowe
Emily Lundt
David Knopman
Matthew L. Senjem
Jeffrey L. Gunter
Christopher G. Schwarz
Bradley J. Kemp
Clifford R. Jack

BACKGROUND: C]PiB (PiB) PET in the same people. METHODS: -test, respectively. We also compared the ability of the two tracers to discriminate between diagnostic groups using AUROC estimates. The effect of using different normalization regions on SUVr values was also evaluated. RESULTS: Both FMT and PiB showed greater uptake throughout GM structures in AD vs. eCN or yCN. In all dual-modality group comparisons (FMT vs. PiB in yCN, eCN, and AD), greater WM uptake was seen with FMT vs. PiB. In yCN and eCN greater diffuse GM uptake was seen with FMT vs. PiB. When comparing yCN to eCN within each tracer, greater WM uptake was seen in eCN vs yCN. CONCLUSIONS: Flutemetamol and PiB show similar topographical GM uptake in AD and CN participants and the tracers show comparable group discrimination. Greater WM accumulation with FMT suggests that quantitative differences vs. PiB will be apparent when using WM or GM as a reference region. Both imaging tracers demonstrate increased WM uptake in older people. These findings suggest that using different amyloid tracers or different methods of analyses in serial brain imaging in an individual may result in artifactual amyloid change measurements. Clinical use of several amyloid tracers in the same patient will have challenges that need to be carefully considered.

YNIMG Journal 2017 Journal Article

Optimizing PiB-PET SUVR change-over-time measurement by a large-scale analysis of longitudinal reliability, plausibility, separability, and correlation with MMSE

Christopher G. Schwarz
Matthew L. Senjem
Jeffrey L. Gunter
Nirubol Tosakulwong
Stephen D. Weigand
Bradley J. Kemp
Anthony J. Spychalla
Prashanthi Vemuri

Quantitative measurements of change in β-amyloid load from Positron Emission Tomography (PET) images play a critical role in clinical trials and longitudinal observational studies of Alzheimer's disease. These measurements are strongly affected by methodological differences between implementations, including choice of reference region and use of partial volume correction, but there is a lack of consensus for an optimal method. Previous works have examined some relevant variables under varying criteria, but interactions between them prevent choosing a method via combined meta-analysis. In this work, we present a thorough comparison of methods to measure change in β-amyloid over time using Pittsburgh Compound B (PiB) PET imaging. Methods We compare 1, 024 different automated software pipeline implementations with varying methodological choices according to four quality metrics calculated over three-timepoint longitudinal trajectories of 129 subjects: reliability (straightness/variance); plausibility (lack of negative slopes); ability to predict accumulator/non-accumulator status from baseline value; and correlation between change in β-amyloid and change in Mini Mental State Exam (MMSE) scores. Results and conclusion From this analysis, we show that an optimal longitudinal measure of β-amyloid from PiB should use a reference region that includes a combination of voxels in the supratentorial white matter and those in the whole cerebellum, measured using two-class partial volume correction in the voxel space of each subject's corresponding anatomical MR image.

YNICL Journal 2016 Journal Article

Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech

Jennifer L. Whitwell
Stephen D. Weigand
Joseph R. Duffy
Edythe A. Strand
Mary M. Machulda
Matthew L. Senjem
Jeffrey L. Gunter
Val J. Lowe

Beta-amyloid (Aβ) deposition can be observed in primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified) and PAOS (n = 42) subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+) status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+) status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+) status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified PPA subjects.

YNIMG Journal 2015 Journal Article

Accelerated vs. unaccelerated serial MRI based TBM-SyN measurements for clinical trials in Alzheimer's disease

Prashanthi Vemuri
Matthew L. Senjem
Jeffrey L. Gunter
Emily S. Lundt
Nirubol Tosakulwong
Stephen D. Weigand
Bret J. Borowski
Matt A. Bernstein

Objective Our primary objective was to compare the performance of unaccelerated vs. accelerated structural MRI for measuring disease progression using serial scans in Alzheimer's disease (AD). Methods We identified cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD subjects from all available Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with usable pairs of accelerated and unaccelerated scans. There were a total of 696 subjects with baseline and 3month scans, 628 subjects with baseline and 6month scans and 464 subjects with baseline and 12month scans available. We employed the Symmetric Diffeomorphic Image Normalization method (SyN) for normalization of the serial scans to obtain tensor based morphometry (TBM) maps which indicate the structural changes between pairs of scans. We computed a TBM-SyN summary score of annualized structural changes over 31 regions of interest (ROIs) that are characteristically affected in AD. TBM-SyN scores were computed using accelerated and unaccelerated scan pairs and compared in terms of agreement, group-wise discrimination, and sample size estimates for a hypothetical therapeutic trial. Results We observed a number of systematic differences between TBM-SyN scores computed from accelerated and unaccelerated pairs of scans. TBM-SyN scores computed from accelerated scans tended to have overall higher estimated values than those from unaccelerated scans. However, the performance of accelerated scans was comparable to unaccelerated scans in terms of discrimination between clinical groups and sample sizes required in each clinical group for a therapeutic trial. We also found that the quality of both accelerated vs. unaccelerated scans were similar. Conclusions Accelerated scanning protocols reduce scan time considerably. Their group-wise discrimination and sample size estimates were comparable to those obtained with unaccelerated scans. The two protocols did not produce interchangeable TBM-SyN estimates, so it is arguably important to use either accelerated pairs of scans or unaccelerated pairs of scans throughout the study duration.

YNICL Journal 2013 Journal Article

Does amyloid deposition produce a specific atrophic signature in cognitively normal subjects?

Jennifer L. Whitwell
Nirubol Tosakulwong
Stephen D. Weigand
Matthew L. Senjem
Val J. Lowe
Jeffrey L. Gunter
Bradley F. Boeve
David S. Knopman

The objective of our study was to evaluate whether cognitively normal (CN) elderly participants showing elevated cortical beta-amyloid (Aβ) deposition have a consistent neuroanatomical signature of brain atrophy that may characterize preclinical Alzheimer's disease (AD). 115 CN participants who were Aβ-positive (CN +) by amyloid PET imaging; 115 CN participants who were Aβ-negative (CN -); and 88 Aβ-positive mild cognitive impairment or AD participants (MCI/AD +) were identified. Cortical thickness (FreeSurfer) and gray matter volume (SPM5) were measured for 28 regions-of-interest (ROIs) across the brain and compared across groups. ROIs that best discriminated CN - from CN + differed for FreeSurfer cortical thickness and SPM5 gray matter volume. Group-wise discrimination was poor with a high degree of uncertainty in terms of the rank ordering of ROIs. In contrast, both techniques showed strong and consistent findings comparing MCI/AD + to both CN - and CN + groups, with entorhinal cortex, middle and inferior temporal lobe, inferior parietal lobe, and hippocampus providing the best discrimination for both techniques. Concordance across techniques was higher for the CN - and CN + versus MCI/AD + comparisons, compared to the CN - versus CN + comparison. The weak and inconsistent nature of the findings across technique in this study cast doubt on the existence of a reliable neuroanatomical signature of preclinical AD in elderly PiB-positive CN participants.