Publications by authors named "Scott A Przybelski"

92 Publications

FDG PET metabolic signatures distinguishing prodromal DLB and prodromal AD.

Neuroimage Clin 2021 Jul 4;31:102754. Epub 2021 Jul 4.

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Background And Purpose: Patients with dementia with Lewy bodies (DLB) are characterized by hypometabolism in the parieto-occipital cortex and the cingulate island sign (CIS) on 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.
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http://dx.doi.org/10.1016/j.nicl.2021.102754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278422PMC
July 2021

Diffusion models reveal white matter microstructural changes with ageing, pathology and cognition.

Brain Commun 2021 19;3(2):fcab106. Epub 2021 May 19.

Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA.

White matter microstructure undergoes progressive changes during the lifespan, but the neurobiological underpinnings related to ageing and disease remains unclear. We used an advanced diffusion MRI, Neurite Orientation Dispersion and Density Imaging, to investigate the microstructural alterations due to demographics, common age-related pathological processes (amyloid, tau and white matter hyperintensities) and cognition. We also compared Neurite Orientation Dispersion and Density Imaging findings to the older Diffusion Tensor Imaging model-based findings. Three hundred and twenty-eight participants (264 cognitively unimpaired, 57 mild cognitive impairment and 7 dementia with a mean age of 68.3 ± 13.1 years) from the Mayo Clinic Study of Aging with multi-shell diffusion imaging, fluid attenuated inversion recovery MRI as well as amyloid and tau PET scans were included in this study. White matter tract level diffusion measures were calculated from Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging. Pearson correlation and multiple linear regression analyses were performed with diffusion measures as the outcome and age, sex, education/occupation, white matter hyperintensities, amyloid and tau as predictors. Analyses were also performed with each diffusion MRI measure as a predictor of cognitive outcomes. Age and white matter hyperintensities were the strongest predictors of all white matter diffusion measures with low associations with amyloid and tau. However, neurite density decrease from Neurite Orientation Dispersion and Density Imaging was observed with amyloidosis specifically in the temporal lobes. White matter integrity (mean diffusivity and free water) in the corpus callosum showed the greatest associations with cognitive measures. All diffusion measures provided information about white matter ageing and white matter changes due to age-related pathological processes and were associated with cognition. Neurite orientation dispersion and density imaging and diffusion tensor imaging are two different diffusion models that provide distinct information about variation in white matter microstructural integrity. Neurite Orientation Dispersion and Density Imaging provides additional information about synaptic density, organization and free water content which may aid in providing mechanistic insights into disease progression.
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http://dx.doi.org/10.1093/braincomms/fcab106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202149PMC
May 2021

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies.

Neurobiol Aging 2021 May 14;105:252-261. Epub 2021 May 14.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.029DOI Listing
May 2021

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

Neuroimage 2021 Jun 9;238:118259. Epub 2021 Jun 9.

Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester 55905, MN, USA.

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.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118259DOI Listing
June 2021

Dementia with Lewy bodies: association of Alzheimer pathology with functional connectivity networks.

Brain 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer's disease (AD) pathology in the form of β-amyloid plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of AD co-pathology on functional network changes within the default mode network (DMN) in DLB. Secondly, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 AD, and 99 cognitively unimpaired (CU) participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), β-amyloid-PET with Pittsburgh compound-B (PiB), and resting state (rs)-fMRI scans. The rs-fMRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir-PET and PiB-PET standardized uptake value ratio (SUVr). The strength of inter-regional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and coldspot) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot- and coldspots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r=-0.39, p = 0.04) and amyloid-PET uptake (r=-0.41, p = 0.03) in the DLB group, i.e. DLB patients with more concurrent AD pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in CU, AD, and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVRs in the target region whereas higher functional connectivity to the tau coldspot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of AD co-pathology in DLB patients is associated with more AD-like changes in functional connectivity. Furthermore, we found an association between the brain's functional network architecture and the distribution of tau pathology which has recently been described in AD. We show that this relationship also exists in DLB patients, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.
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http://dx.doi.org/10.1093/brain/awab218DOI Listing
June 2021

MRI quantitative susceptibility mapping of the substantia nigra as an early biomarker for Lewy body disease.

J Neuroimaging 2021 May 25. Epub 2021 May 25.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Background And Purpose: Neurodegeneration of the substantia nigra in Lewy body disease is associated with iron deposition, which increases the magnetic susceptibility of the substantia nigra on MRI. Our objective was to measure iron deposition in the substantia nigra in patients with probable dementia with Lewy bodies (pDLB) and patients who are at risk for pDLB by quantitative susceptibility mapping (QSM).

Methods: Participants included pDLB (n = 36), mild cognitive impairment with at least one core feature of DLB (MCI-LB; n = 15), idiopathic rapid eye movement sleep behavior disorder (iRBD; n = 11), and an age-and gender-matched clinically unimpaired control group (n = 102). QSM was derived from multi-echo 3D gradient recalled echo MRI at 3T, and groups were compared on mean susceptibility values of the substantia nigra and its relation to parkinsonism severity.

Results: Patients with pDLB had higher susceptibility in the substantia nigra compared to controls (p< 0.001) and MCI-LB (p = 0.043). The susceptibility of substantia nigra showed an increasing trend from controls to iRBD and MCI-LB, and to pDLB (p< 0.001). Parkinsonism severity was not associated with the mean susceptibility in the substantia nigra in the patient groups.

Conclusions: Our data suggested that QSM is sensitive to the increased magnetic susceptibility due to higher iron content in the substantia nigra in pDLB. The trend of increasing susceptibility from controls to iRBD and MCI-LB, and to pDLB suggests that iron deposition in the substantia nigra starts to increase as early as the prodromal stage in DLB and continues to increase as the disease progresses, independent of parkinsonism severity.
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http://dx.doi.org/10.1111/jon.12878DOI Listing
May 2021

White matter abnormalities are key components of cerebrovascular disease impacting cognitive decline.

Brain Commun 2021 12;3(2):fcab076. Epub 2021 Apr 12.

Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA.

While cerebrovascular disease can be observed using MRI, the multiplicity and heterogeneity in the mechanisms of cerebrovascular damage impede accounting for these measures in ageing and dementia studies. Our primary goal was to investigate the key sources of variability across MRI markers of cerebrovascular disease and evaluate their impact in comparison to amyloidosis on cognitive decline in a population-based sample. Our secondary goal was to evaluate the prognostic utility of a cerebrovascular summary measure from all markers. We included both visible lesions seen on MRI (white matter hyperintensities, cortical and subcortical infarctions, lobar and deep microbleeds) and early white matter damage due to systemic vascular health using diffusion changes in the genu of the corpus callosum. We identified 1089 individuals aged ≥60 years with concurrent amyloid-PET and MRI scans from the population-based Mayo Clinic Study of Aging. We divided these into discovery and validation datasets. Using the discovery dataset, we conducted principal component analyses and ascertained the main sources of variability in cerebrovascular disease markers. Using linear regression and mixed effect models, we evaluated the utility of these principal components and combinations of these components for the prediction of cognitive performance along with amyloidosis. Our main findings were (i) there were three primary sources of variability among the CVD measures-white matter changes are driven by white matter hyperintensities and diffusion changes; number of microbleeds (lobar and deep); and number of infarctions (cortical and subcortical); (ii) Components of white matter changes and microbleeds but not infarctions significantly predicted cognition trajectories in all domains with greater contributions from white matter; and (iii) The summary vascular score explained 3-5% of variability in baseline global cognition in comparison to 3-6% variability explained by amyloidosis. Across all cognitive domains, the vascular summary score had the least impact on memory performance (∼1%). Though there is mechanistic heterogeneity in the cerebrovascular disease markers measured on MRI, these changes can be grouped into three components and together explain variability in cognitive performance equivalent to the impact of amyloidosis on cognition. White matter changes represent dynamic ongoing damage, predicts future cognitive decline across all domains and diffusion measurements help capture white matter damage due to systemic vascular changes. Therefore, measuring and accounting for white matter changes using diffusion MRI and white matter hyperintensities along with microbleeds will allow us to capture vascular contributions to cognitive impairment and dementia.
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http://dx.doi.org/10.1093/braincomms/fcab076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072521PMC
April 2021

Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology.

Acta Neuropathol Commun 2021 03 23;9(1):48. Epub 2021 Mar 23.

Department of Radiology, Mayo Clinic-Minnesota, 200 First Street SW, Rochester, MN, 55905, USA.

Although abnormal accumulation of amyloid in the brain is an early biomarker of Alzheimer's disease (AD), wide variation in cognitive trajectories during life can be seen in the setting of brain amyloidosis, ranging from maintenance of normal function to progression to dementia. It is widely presumed that cognitive resilience (i.e., coping) to amyloidosis may be influenced by environmental, lifestyle, and inherited factors, but relatively little in specifics is known about this architecture. Here, we leveraged multimodal longitudinal data from a large, population-based sample of older adults to discover genetic factors associated with differential cognitive resilience to brain amyloidosis determined by positron emission tomography (PET). Among amyloid-PET positive older adults, the AD risk allele APOE ɛ4 was associated with worse longitudinal memory trajectories as expected, and was thus covaried in the main analyses. Through a genome-wide association study (GWAS), we uncovered a novel association with cognitive resilience on chromosome 8 at the MTMR7/CNOT7/ZDHHC2/VPS37A locus (p = 4.66 × 10, β = 0.23), and demonstrated replication in an independent cohort. Post-hoc analyses confirmed this association as specific to the setting of elevated amyloid burden and not explained by differences in tau deposition or cerebrovascular disease. Complementary gene-based analyses and publically available functional data suggested that the causative variant at this locus may tag CNOT7 (CCR4-NOT Transcription Complex Subunit 7), a gene linked to synaptic plasticity and hippocampal-dependent learning and memory. Pathways related to cell adhesion and immune system activation displayed enrichment of association in the GWAS. Our findings, resulting from a unique study design, support the hypothesis that genetic heterogeneity is one of the factors that explains differential cognitive resilience to brain amyloidosis. Further characterization of the underlying biological mechanisms influencing cognitive resilience may facilitate improved prognostic counseling, therapeutic application, and trial enrollment in AD.
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http://dx.doi.org/10.1186/s40478-021-01154-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986461PMC
March 2021

Cerebral Amyloid Angiopathy Burden and Cerebral Microbleeds: Pathological Evidence for Distinct Phenotypes.

J Alzheimers Dis 2021 ;81(1):113-122

Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.

Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia.

Objective: To determine whether CMBs on antemortem MRI correlate with CAA.

Methods: We reviewed 54 consecutive participants with antemortem T2*GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By a clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs.

Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal/cortical components correlated with number of lobar CMBs.

Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOEɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.
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http://dx.doi.org/10.3233/JAD-201536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113155PMC
January 2021

Study of Symptomatic vs. Silent Brain Infarctions on MRI in Elderly Subjects.

Front Neurol 2021 17;12:615024. Epub 2021 Feb 17.

Departments of Radiology, Mayo Clinic, Rochester, MN, United States.

Brain infarctions are closely associated with future risk of stroke and dementia. Our goal was to report (i) frequency and characteristics that differentiate symptomatic vs. silent brain infarctions (SBI) on MRI and (ii) frequency and location by vascular distribution (location of stroke by major vascular territories) in a population based sample. From Mayo Clinic Study of Aging, 347 participants (≥50 years) with infarcts detected on their first MRI were included. Infarct information was identified visually on a FLAIR MRI image and a vascular territory atlas was registered to the FLAIR image data in order to identify the arterial territory of infarction. We identified the subset with a clinical history of stroke based on medical chart review and used a logistic regression to evaluate the risk factors associated with greater probability of a symptomatic stroke vs. SBI. We found that 14% of all individuals with infarctions had a history of symptomatic stroke (Silent: = 300, symptomatic: = 47). Factors associated with a symptomatic vs. SBI were size which had an odds ratio of 3.07 ( < 0.001), greater frequency of hypertension (odds ratio of 4.12, = 0.025) and alcohol history (odds ratio of 4.58, = 0.012). The frequency of infarcts was greater in right hemisphere compared to the left for SBI. This was primarily driven by middle cerebral artery (MCA) infarcts (right = 60%, left = 40%, = 0.005). While left hemisphere strokes are more common for symptomatic carotid disease and in clinical trials, right hemispheric infarcts may be more frequent in the SBI group.
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http://dx.doi.org/10.3389/fneur.2021.615024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925615PMC
February 2021

Comparison of CSF neurofilament light chain, neurogranin, and tau to MRI markers.

Alzheimers Dement 2021 05 4;17(5):801-812. Epub 2021 Mar 4.

Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: We determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total-tau (t-tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH).

Methods: Analyses included 536 non-demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t-tau, amyloid beta (Aβ)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes.

Results: Higher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t-tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF Aβ42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA.

Discussion: CSF NfL predicts changes in white matter integrity, t-tau reflects non-specific changes in cortical thickness, and Ng reflects AD-specific synaptic and neuronal degeneration.
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http://dx.doi.org/10.1002/alz.12239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119371PMC
May 2021

Longitudinal deterioration of white-matter integrity: heterogeneity in the ageing population.

Brain Commun 2021 22;3(1):fcaa238. Epub 2021 Jan 22.

Department of Radiology, Mayo Clinic, Rochester, MN 559 05, USA.

Deterioration in white-matter health plays a role in cognitive ageing. Our goal was to discern heterogeneity of white-matter tract vulnerability in ageing using longitudinal imaging data (two to five imaging and cognitive assessments per participant) from a population-based sample of 553 elderly participants (age ≥60 years). We found that different clusters (healthy white matter, fast white-matter decliners and intermediate white-matter group) were heterogeneous in the spatial distribution of white-matter integrity, systemic health and cognitive trajectories. White-matter health of specific tracts (genu of corpus callosum, posterior corona radiata and anterior internal capsule) informed about cluster assignments. Not surprisingly, brain amyloidosis was not significantly different between clusters. Clusters had differential white-matter tract vulnerability to ageing (commissural fibres > association/brainstem fibres). Identification of vulnerable white-matter tracts is a valuable approach to assessing risk for cognitive decline.
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http://dx.doi.org/10.1093/braincomms/fcaa238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884606PMC
January 2021

Variants in and are associated with higher tau deposition.

Brain Commun 2020 26;2(2):fcaa159. Epub 2020 Sep 26.

Department of Radiology, Mayo Clinic-Minnesota, Rochester, MN 55905, USA.

Tau deposition is a key biological feature of Alzheimer's disease that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau deposition while others are more resistant. The recent availability of assessment of tau burden through positron emission tomography provides an opportunity to test the hypothesis that common genetic variants may influence tau deposition. We performed a genome-wide association study of tau-positron emission tomography on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.6% cognitively unimpaired) from the population-based Mayo Clinic Study of Aging. Linear regression was performed to test nucleotide polymorphism associations with AV-1451 (F-flortaucipir) tau-positron emission tomography burden in an Alzheimer's-signature composite region of interest, using an additive genetic model and covarying for age, sex and genetic principal components. Genome-wide significant associations with higher tau were identified for rs76752255 (=9.91 × 10,  = 0.20) in the tau phosphorylation regulatory gene (protein phosphatase 2 regulatory subunit B) and for rs117402302 (=4.00 × 10,  = 0.19) near (insulin-like growth factor 2 mRNA-binding protein 3). The association remained genome-wide significant after additionally covarying for global amyloid burden and cerebrovascular disease risk, while the association was partially attenuated after accounting for amyloid load. In addition to these discoveries, three single nucleotide polymorphisms within (microtubule-associated protein tau) displayed nominal associations with tau-positron emission tomography burden, and the association of the (apolipoprotein E) ɛ4 allele with tau-positron emission tomography was marginally nonsignificant (=0.06,  = 0.07). No associations with tau-positron emission tomography burden were identified for other single nucleotide polymorphisms associated with Alzheimer's disease clinical diagnosis in prior large case-control studies. Our findings nominate and as novel potential influences on tau pathology which warrant further functional characterization. Our data are also supportive of previous literature on the associations of genetic variation with tau, and more broadly supports the inference that tau accumulation may have a genetic architecture distinct from known Alzheimer's susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting.
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http://dx.doi.org/10.1093/braincomms/fcaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780444PMC
September 2020

The value of multimodal imaging with I-FP-CIT SPECT in differential diagnosis of dementia with Lewy bodies and Alzheimer's disease dementia.

Neurobiol Aging 2021 03 15;99:11-18. Epub 2020 Dec 15.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Reduced nigrostriatal uptake on N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-[I]iodophenyl) nortropane (I-FP-CIT) SPECT reflects dopamine dysfunction, while other imaging markers could be complementary when used together. We assessed how well I-FP-CIT SPECT differentiates dementia with Lewy bodies (DLBs) from Alzheimer's disease dementia (ADem) and whether multimodal imaging provides additional value. I-FP-CIT SPECT, magnetic resonance imaging, [F]2-fluoro-deoxy-D-glucose-positron emission tomography (PET), and C-Pittsburgh compound B (PiB)-PET were assessed in 35 participants with DLBs and 14 participants with ADem (autopsy confirmation in 9 DLBs and 4 ADem). Nigrostriatal dopamine transporter uptake was evaluated with I-FP-CIT SPECT using DaTQUANT software. Hippocampal volume was calculated with magnetic resonance imaging, cingulate island sign ratio with FDG-PET, and global cortical PiB retention with PiB-PET. The DaTQUANT z-scores of the putamen showed the highest c-statistic of 0.916 in differentiating DLBs from ADem among the analyzed imaging biomarkers. Adding another imaging modality to I-FP-CIT SPECT had c-statistics ranging from 0.968 to 0.975, and I-FP-CIT SPECT in combination with 2 other imaging modalities presented c-statistics ranging from 0.987 to 0.996. These findings suggest that multimodal imaging with I-FP-CIT SPECT aids in differentiating DLBs and ADem and in detecting comorbid Lewy-related and Alzheimer's disease pathology in patients with DLBs and ADem.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902470PMC
March 2021

β-Amyloid PET and I-FP-CIT SPECT in Mild Cognitive Impairment at Risk for Lewy Body Dementia.

Neurology 2021 Jan 6. Epub 2021 Jan 6.

Department of Radiology, Mayo Clinic, Rochester, Minnesota

Objective: To determine the clinical phenotypes associated with the amyloid-β PET and dopamine transporter imaging (I-FP-CIT SPECT) findings in mild cognitive impairment (MCI) with the core clinical features of dementia with Lewy bodies (DLB; MCI-LB).

Methods: Patients with MCI who had at least one core clinical feature of DLB (n=34) were grouped into β-amyloid A+ or A- and I-FP-CIT SPECT D+ or D- groups based on previously established abnormality cut points for A+ with Pittsburgh compound-B PET standardized uptake value ratio (PiB SUVR) ≥1.48 and D+ with putamen z-score with DATQUANT < -0.82 on I-FP-CIT SPECT. Individual MCI-LB patients fell into one of four groups: A+D+, A+D-, A-D+, or A-D-. Log transformed PiB SUVR and putamen z-score were tested for associations with patient characteristics.

Results: The A-D+ biomarker profile was most common (38.2%) followed by A+D+ (26.5%) and A-D- (26.5%). Least common was A+D- biomarker profile (8.8 %). The A+ group was older, had a higher frequency of ε4 carriers, and a lower MMSE score than the A- group. The D+ group was more likely to have probable rapid eye movement sleep behavior disorder. Lower putamen DATQUANT z-scores and lower PiB SUVRs were independently associated with higher Unified Parkinson Disease Rating Scale (UPDRS)-III scores.

Conclusions: A majority of MCI-LB patients are characterized by low amyloid-β deposition and reduced dopaminergic activity. Amyloid-β PET and I-FP-CIT SPECT are complementary in characterizing clinical phenotypes of patients with MCI-LB.
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http://dx.doi.org/10.1212/WNL.0000000000011454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055344PMC
January 2021

Brain MRI after critical care admission: A longitudinal imaging study.

J Crit Care 2021 Apr 5;62:117-123. Epub 2020 Dec 5.

Department of Radiology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. Electronic address:

Purpose: To investigate the association between episodes of critical care hospitalizations and delirium with structural brain changes in older adults.

Materials And Methods: We included Mayo Clinic Study of Aging participants ≥60 years old at the time of study enrollment (October 29, 2004, through September 11, 2017) with available brain MRI and 'amyloid' positron emission tomography (PET) scans. We tested the hypothesis that a) intensive care unit (ICU) admission is associated with greater cortical thinning and atrophy in entorhinal cortex, inferior temporal cortex, middle temporal cortex, and fusiform cortex (Alzheimer''s disease-signature regions); b) atrophy in hippocampus and corpus callosum; c) delirium accelerates these changes; and d) ICU admission is not associated with increased deposition of cortical amyloid.

Results: ICU admission was associated with cortical thinning in temporal, frontal, and parietal cortices, and decreases in hippocampal/corpus callosum volumes, but not Alzheimer''s disease-signature regions. For hippocampal volume, and 10 of 14 cortical thickness measurements, the change following ICU admission was significantly more pronounced for those who experienced delirium. ICU admission was not associated with an increased amyloid burden.

Conclusions: Critical care hospitalization is associated with accelerated brain atrophy in selected brain regions, without increases in amyloid deposition, suggesting a pathogenesis based on neurodegeneration unrelated to Alzheimer''s pathway.
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http://dx.doi.org/10.1016/j.jcrc.2020.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946765PMC
April 2021

Reduced fractional anisotropy of the genu of the corpus callosum as a cerebrovascular disease marker and predictor of longitudinal cognition in MCI.

Neurobiol Aging 2020 12 8;96:176-183. Epub 2020 Sep 8.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Our goal was to evaluate the utility of diffusion tensor imaging (DTI) for predicting future cognitive decline in mild cognitive impairment (MCI) in conjunction with Alzheimer's disease (AD) biomarkers (amyloid positron emission tomography and AD signature neurodegeneration) in 132 MCI individuals ≥60 year old with structural magnetic resonance imaging, DTI, amyloid positron emission tomography, and at least one clinical follow-up. We used mixed-effect models to evaluate the prognostic ability of fractional anisotropy of the genu of the corpus callosum (FA-Genu), as a cerebrovascular disease marker, for predicting cognitive decline along with AD biomarkers. We contrasted the value of white matter hyperintensities, a traditional cerebrovascular disease marker as well as FA in the hippocampal cingulum bundle with the FA-Genu models. FA-Genu significantly predicted cognitive decline even after accounting for AD biomarkers. WMH was not associated with cognitive decline in the model with both WMH and FA-Genu. DTI specifically FA-Genu provides unique complementary information to AD biomarkers and has significant utility for prediction of cognitive decline in MCI.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722208PMC
December 2020

β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies.

Neurology 2020 12 28;95(24):e3257-e3268. Epub 2020 Sep 28.

From the Division of Clinical Geriatrics (D.F., S.G.-P., E.W.), Center for Alzheimer's Research, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden; Departments of Radiology (D.F., Z.N., C.G.S., M.L.S., V.J.L., C.R.J., K.K.), Health Sciences (S.A.P., T.G.L.), Neurology (J.G.-R., D.S.K., R.S., R.C.P., B.F.B.), Information Technology (M.L.S.), and Psychiatry and Psychology (J.A.F.), Mayo Clinic, Rochester, MN; Department of Neurology and Alzheimer Center (A.W.L.), VU University Medical Center, Amsterdam, the Netherlands; Clinical Memory Research Unit (E.L.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Day Hospital of Geriatrics (F.B.), Memory Resource and Research Centre (CM2R) of Strasbourg; Department of Geriatrics (F.B.), Hopitaux Universitaires de Strasbourg; University of Strasbourg and French National Centre for Scientific Research (CNRS) (F.B.), ICube Laboratory and Federation de Medecine Translationnelle de Strasbourg (FMTS), Team Imagerie Multimodale Integrative en Sante (IMIS)/ICONE, Strasbourg, France; Department of Neurology (Z.N., J.H.), Charles University, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic; Departments of Psychiatry and Psychology (T.J.F.) and Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Paracelsus-Elena-Klinik (B.M.), Kassel; and University Medical Center (B.M.), Department of Neurosurgery and Institute of Neuropathology, Göttingen, Germany; Fundació ACE (C.A.), Alzheimer Research Center and Memory Clinic, Institut Català de Neurociències Aplicades, Barcelona, Spain; International Clinical Research Center (J.H.), St. Anne's University Hospital Brno, Czech Republic; Department of Neuroscience Imaging and Clinical Sciences and CESI (L.B.), University G d'Annunzio of Chieti-Pescara, Chieti, Italy; Centre for Age-Related Medicine (K.O., D.A.), Stavanger University Hospital; Stavanger Medical Imaging Laboratory (SMIL) (K.O.), Department of Radiology, Stavanger University Hospital; Department of Electrical Engineering and Computer Science (K.O.), University of Stavanger, Norway; Department of Neurology (M.G.K.), University Medical Centre Ljubljana, Medical Faculty, University of Ljubljana, Slovenia; Institute of Psychiatry, Psychology and Neuroscience (D.A.) and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Objective: In a multicenter cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that β-amyloid and tau biomarker positivity increases with age, which is modified by genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype.

Methods: We included 417 patients with DLB (age 45-93 years, 31% women). Positivity on β-amyloid (A+) and tau (T+) biomarkers was determined by CSF β-amyloid and phosphorylated tau in the European cohort and by Pittsburgh compound B and AV-1451 PET in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, and A+T+.

Results: A-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age, and A+ and T+ increased with age in both women and men. A+ increased more in ε4 carriers with age than in noncarriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable REM sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.

Conclusions: Alzheimer disease pathologic changes are common in DLB and are associated with the clinical phenotype. β-Amyloid is associated with cognitive impairment, and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.

Classification Of Evidence: This study provides Class II evidence that in patients with probable DLB, β-amyloid is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.
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http://dx.doi.org/10.1212/WNL.0000000000010943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836666PMC
December 2020

Progressive dysexecutive syndrome due to Alzheimer's disease: a description of 55 cases and comparison to other phenotypes.

Brain Commun 2020 27;2(1):fcaa068. Epub 2020 May 27.

Department of Neurology Mayo Clinic, Rochester, MN 55902, USA.

We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer's pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer's disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with F-fluorodeoxyglucose-positron emission tomography and Alzheimer's disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as 'memory problems' but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one ε allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer's disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic ( = 110), visual ( = 18) and language ( = 7) predominate clinical phenotypes of Alzheimer's disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer's disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation.
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http://dx.doi.org/10.1093/braincomms/fcaa068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325839PMC
May 2020

F-fluorodeoxyglucose positron emission tomography in dementia with Lewy bodies.

Brain Commun 2020 8;2(1):fcaa040. Epub 2020 Apr 8.

Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Among individuals with dementia with Lewy bodies, pathologic correlates of clinical course include the presence and extent of coexisting Alzheimer's pathology and the presence of transitional or diffuse Lewy body disease. The objectives of this study are to determine (i) whether F-fluorodeoxyglucose PET signature patterns of dementia with Lewy bodies are associated with the extent of coexisting Alzheimer's pathology and the presence of transitional or diffuse Lewy body disease and (ii) whether these F-fluorodeoxyglucose pattern(s) are associated with clinical course in dementia with Lewy bodies. Two groups of participants were included: a pathology-confirmed subset with Lewy body disease ( = 34) and a clinically diagnosed group of dementia with Lewy bodies ( = 87). A subset of the clinically diagnosed group was followed longitudinally ( = 51). We evaluated whether F-fluorodeoxyglucose PET features of dementia with Lewy bodies (higher cingulate island sign ratio and greater occipital hypometabolism) varied by Lewy body disease subtype (transitional versus diffuse) and Braak neurofibrillary tangle stage. We investigated whether the PET features were associated with the clinical trajectories by performing regression models predicting Clinical Dementia Rating Scale Sum of Boxes. Among autopsied participants, there was no difference in cingulate island sign or occipital hypometabolism by Lewy body disease type, but those with a lower Braak tangle stage had a higher cingulate island sign ratio compared to those with a higher Braak tangle stage. Among the clinically diagnosed dementia with Lewy bodies participants, a higher cingulate island ratio was associated with better cognitive scores at baseline and longitudinally. A higher F-fluorodeoxyglucose PET cingulate island sign ratio was associated with lower Braak tangle stage at autopsy, predicted a better clinical trajectory in dementia with Lewy body patients and may allow for improved prognostication of the clinical course in this disease.
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http://dx.doi.org/10.1093/braincomms/fcaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293797PMC
April 2020

Witnessed apneas are associated with elevated tau-PET levels in cognitively unimpaired elderly.

Neurology 2020 04 26;94(17):e1793-e1802. Epub 2020 Mar 26.

From the Departments of Neurology (D.Z.C., E.K.S.L., B.F.B., M.M.M., D.S.K., R.C.P.), Radiology (C.G.S., V.J.L., A.R., C.R.J., P.V.), and Health Sciences Research (S.A.P., M.M.M.), Mayo Clinic, Rochester, MN.

Objective: To assess whether informant-reported apneas during sleep (witnessed apneas) in cognitively unimpaired (CU) elderly persons are associated with higher levels of brain tau.

Methods: From the population-based Mayo Clinic Study of Aging, we identified 292 CU elderly ≥65 years of age with both AV-1451 tau-PET and Pittsburgh compound B (PiB)-PET scans and whose bed partners and close relatives had completed a questionnaire that assessed whether participants had witnessed apneas during sleep. For this cross-sectional analysis, we selected the entorhinal and inferior temporal cortices as our regions of interest (ROIs) because they are highly susceptible to tau accumulation. PET signal was scaled to the cerebellum crus to calculate standardized uptake value ratio (SUVR). We fit linear models to assess the association between regional tau and witnessed apneas while controlling for age, sex, years of education, body mass index, hypertension, hyperlipidemia, diabetes, reduced sleep, excessive daytime sleepiness, and global PiB.

Results: Forty-three participants (14.7%) were found to have witnessed apneas during sleep. The report of witnessed apneas was associated with higher tau-PET SUVR elevation in our ROIs: 0.049 SUVR (95% confidence interval [CI] 0.010-0.087, = 0.015) in the entorhinal cortex and 0.037 SUVR (95% CI 0.006-0.067, = 0.019) in the inferior temporal cortex after controlling for confounders.

Conclusion: We identified a significant association between witnessed apneas in CU elderly and elevated tau-PET signal in tau-susceptible brain regions. These results suggest a plausible mechanism that could contribute to cognitive impairment and the development of Alzheimer disease. Longitudinal observations are necessary to determine direction of causality.
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http://dx.doi.org/10.1212/WNL.0000000000009315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274847PMC
April 2020

Confirmation of I-FP-CIT SPECT Quantification Methods in Dementia with Lewy Bodies and Other Neurodegenerative Disorders.

J Nucl Med 2020 11 20;61(11):1628-1635. Epub 2020 Mar 20.

Department of Radiology, Mayo Clinic, Rochester, Minnesota

Our rationale was to conduct a retrospective study comparing 3 I--ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (I-FP-CIT) SPECT quantitative methods in patients with neurodegenerative syndromes as referenced to neuropathologic findings. I-FP-CIT-SPECT and neuropathologic findings among patients with neurodegenerative syndromes from the Mayo Alzheimer Disease Research Center and Mayo Clinic Study of Aging were examined. Three I-FP-CIT SPECT quantitative assessment methods-MIMneuro, DaTQUANT, and manual region-of-interest creation on a workstation-were compared with neuropathologic findings describing the presence or absence of Lewy body disease (LBD). Striatum-to-background ratios (SBRs) generated by DaTQUANT were compared with the calculated SBRs of the manual method and MIMneuro. The left and right SBRs for caudate, putamen, and striatum were evaluated with the manual method. For DaTQUANT and MIMneuro, the left, right, total, and average SBRs and scores for whole striatum, caudate, putamen, anterior putamen, and posterior putamen were calculated. The cohort included 24 patients (20 [83%] male, mean age for all patients at death, 75.4 ± 10.0 y). The antemortem clinical diagnoses were Alzheimer disease dementia ( = 6), probable dementia with Lewy bodies ( = 12), mixed Alzheimer disease dementia and probable dementia with Lewy bodies ( = 1), Parkinson disease with mild cognitive impairment ( = 2), corticobasal syndrome ( = 1), idiopathic rapid-eye-movement sleep behavior disorder ( = 1), and behavioral-variant frontotemporal dementia ( = 1). Seventeen (71%) had LBD. All 3 I-FP-CIT SPECT quantitative methods had an area under the receiver-operating-characteristics curve ranging from more than 0.93 to up to 1.000 ( < 0.001) and showed excellent discrimination between LBD and non-LBD patients in each region assessed ( < 0.001). There was no significant difference between the accuracy of the regions in discriminating the 2 groups, with good discrimination for both caudate and putamen. All 3 I-FP-CIT SPECT quantitative methods showed excellent discrimination between LBD and non-LBD patients in each region assessed, using both SBRs and scores.
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http://dx.doi.org/10.2967/jnumed.119.239418DOI Listing
November 2020

Exposure to surgery with general anaesthesia during adult life is not associated with increased brain amyloid deposition in older adults.

Br J Anaesth 2020 05 12;124(5):594-602. Epub 2020 Mar 12.

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Background: Exposure to surgery with general anaesthesia (surgery/GA) is associated with cortical atrophy, but the aetiology remains unknown. Amyloid-β (Aβ) deposition is one of the hallmark pathological characteristics of Alzheimer's disease (AD). We examined brain Aβ burden in study participants exposed to surgery/GA.

Methods: We performed a cross-sectional analysis of residents of Olmsted County, MN, USA, in the Mayo Clinic Study of Aging who were aged 70-97 yr and underwent measurement of (i) brain Aβ with Pittsburgh compound B positron emission tomography (PiB PET), (ii) brain glucose metabolism with 18-fluorodeoxyglucose (FDG) PET, and (iii) temporal cortical thickness with MRI. Separate analyses were performed with exposure to surgery/GA, defined as occurring after age 40 yr, and with exposure to surgery/GA, defined as occurring within 20 yr before neuroimaging. Imaging measurements were compared between participants who were exposed to surgery/GA vs not exposed.

Results: Of the 2563 participants, 585 had PET scans. Regardless of the definition used to quantify exposure, no significant associations were detected between exposure and either global PiB PET or FDG PET. In contrast, exposure to surgery/GA was associated with an increased likelihood of abnormal cortical thinning: odds ratio (OR)=1.98 (95% confidence interval [CI]: 1.19-3.31); P=0.010 in those exposed after age 40 yr, and OR=1.64 (95% CI: 1.05-2.55); P=0.029 in those exposed in the prior 20 yr.

Conclusions: Exposure to surgery/GA is not associated with increases in cortical amyloid deposition. This finding suggests that the modest cortical thinning associated with surgery/GA is not related to AD pathology, but rather is caused by other processes.
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http://dx.doi.org/10.1016/j.bja.2020.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222219PMC
May 2020

Relationship Between Risk Factors and Brain Reserve in Late Middle Age: Implications for Cognitive Aging.

Front Aging Neurosci 2019 9;11:355. Epub 2020 Jan 9.

Department of Radiology, Mayo Clinic, Rochester, MN, United States.

Background: Brain reserve can be defined as the individual variation in the brain structural characteristics that later in life are likely to modulate cognitive performance. Late midlife represents a point in aging where some structural brain imaging changes have become manifest but the effects of cognitive aging are minimal, and thus may represent an ideal opportunity to determine the relationship between risk factors and brain imaging biomarkers of reserve.

Objective: We aimed to assess neuroimaging measures from multiple modalities to broaden our understanding of brain reserve, and the late midlife risk factors that may make the brain vulnerable to age related cognitive disorders.

Methods: We examined multimodal [structural and diffusion Magnetic Resonance Imaging (MRI), FDG PET] neuroimaging measures in 50-65 year olds to examine the associations between risk factors (Intellectual/Physical Activity: education-occupation composite, physical, and cognitive-based activity engagement; General Health Factors: presence of cardiovascular and metabolic conditions (CMC), body mass index, hemoglobin A1c, smoking status (ever/never), CAGE Alcohol Questionnaire (>2, yes/no), Beck Depression Inventory score), brain reserve measures [Dynamic: genu corpus callosum fractional anisotropy (FA), posterior cingulate cortex FDG uptake, superior parietal cortex thickness, AD signature cortical thickness; Static: intracranial volume], and cognition (global, memory, attention, language, visuospatial) from a population-based sample. We quantified dynamic proxies of brain reserve (cortical thickness, glucose metabolism, microstructural integrity) and investigated various protective/risk factors.

Results: Education-occupation was associated with cognition and total intracranial volume (static measure of brain reserve), but was not associated with any of the dynamic neuroimaging biomarkers. In contrast, many general health factors were associated with the dynamic neuroimaging proxies of brain reserve, while most were not associated with cognition in this late middle aged group.

Conclusion: Brain reserve, as exemplified by the four dynamic neuroimaging features studied here, is itself at least partly influenced by general health status in midlife, but may be largely independent of education and occupation.
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http://dx.doi.org/10.3389/fnagi.2019.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962238PMC
January 2020

Imaging Biomarkers of Alzheimer Disease in Multiple Sclerosis.

Ann Neurol 2020 04 8;87(4):556-567. Epub 2020 Feb 8.

Department of Radiology, Mayo Clinic, Rochester, MN.

Objective: To investigate β-amyloid and tau depositions using Pittsburgh compound B (PiB) positron emission tomography (PET) and AV1451 tau PET imaging in aging multiple sclerosis (MS) patients.

Methods: Patients with MS (n = 16) and controls (n = 80) matched for age, sex, and APOE ε4 status from the population-based Mayo Clinic Study of Aging who underwent PiB PET imaging were studied. Of these individuals, 12 patients with MS and 60 matching controls also underwent AV1451 tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVrs) from the entire cortex and previously determined Alzheimer disease (AD) signature regions in the same population were calculated for group comparisons and testing for associations with age.

Results: AD signature PiB SUVr (odds ratio [OR] [95% confidence interval (CI)] = 0.52 [0.27-0.98], p = 0.044), total cortical PiB SUVr (OR [95% CI] = 0.52 [0.28-0.99], p = 0.048), and the frequency of abnormal PiB SUVrs (OR [95% CI] = 0.10 [0.01-0.90], p = 0.040) were lower in MS than controls. Although AD-signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (OR [95% CI] = 10.65 [1.10-103.35], p = 0.041) in MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = -0.14 [-0.023 to -0.006], p = 0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = -0.13 [-0.021 to -0.005], p = 0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls.

Interpretation: Although both β-amyloid and tau are biomarkers of cognitive aging and AD, cortical β-amyloid deposition was lower in MS than age-matched controls, suggesting that some aspect of MS pathobiology retards the accumulation of β-amyloid but not the accumulation of tau. ANN NEUROL 2020;87:556-567.
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http://dx.doi.org/10.1002/ana.25684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078013PMC
April 2020

Better stress coping associated with lower tau in amyloid-positive cognitively unimpaired older adults.

Neurology 2020 04 21;94(15):e1571-e1579. Epub 2020 Jan 21.

From the Departments of Radiology (E.M.A.-U., V.J.L., A.L.R., C.R.J., P.V.), Health Sciences Research (S.A.P., M.M.M.), Psychiatry and Psychology (M.M. Machulda), and Neurology (D.S.K., M.M. Mielke, R.C.P.), Mayo Clinic, Rochester, MN; and Department of Neurology (Y.E.G.), Mayo Clinic, Scottsdale, AZ.

Objective: Research in animals has shown that chronic stress exacerbates tau pathology. In humans, psychological stress has been associated with higher risk of Alzheimer disease clinical syndrome. The objective of this cross-sectional study was to assess the hypothesis that stress coping ability (assessed via the Brief Resilience Scale [BRS]) is associated with tau burden and to evaluate whether these associations differed by sex and amyloid status (A+/A-) in cognitively unimpaired (CU) older adults.

Methods: We included 225 CU participants (mean age 70.4 ± 10.2 years, 48% female) enrolled in the population-based Mayo Clinic Study of Aging who completed the BRS and underwent amyloid-PET (Pittsburgh compound B-PET) and tau-PET (AV1451-PET). We fitted multiple regression and analysis of covariance models to assess the associations between BRS and tau-PET and the interaction with amyloid status and sex. We focused on entorhinal cortex (ERC) tau burden and also performed voxel-wise analyses. Age, sex, education, depression, and anxiety were considered as covariates.

Results: Higher stress coping ability was associated with lower tau burden in the medial temporal lobe (including ERC) and occipito-temporal and cuneal/precuneal cortices. The association was present in both A+ and A- but weaker in A- CU older adults. There was an interaction between amyloid status and stress coping ability that was restricted to the medial temporal lobe tau such that A+ CU older adults with lower stress coping abilities showed higher tau. There were no significant interactions between stress coping and sex.

Conclusions: A faster termination of the stress response (higher coping ability) may limit the negative effects of stress on tau deposition. Conversely, lower stress coping ability may be an early sign of accumulating tau pathology. Longitudinal studies are warranted to clarify whether stress mechanisms act to exacerbate tau pathology or tau influences stress-related brain mechanisms and lowers the ability to cope with stress.
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http://dx.doi.org/10.1212/WNL.0000000000008979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251516PMC
April 2020

β-Amyloid PET and neuropathology in dementia with Lewy bodies.

Neurology 2020 01 20;94(3):e282-e291. Epub 2019 Dec 20.

From the Departments of Radiology (K.K., V.J.L., Q.C., C.G.S., C.R.J.), Health Sciences Research (S.A.P., T.G.L.), Information Technology (M.L.S., J.L.G.), Neurology (J.G.-R., D.T.J., D.S.K., R.C.P., B.F.B.), and Laboratory Medicine and Pathology (J.E.P.), Mayo Clinic, Rochester, MN; Department of Neurology (Q.C.), West China Hospital, Chengdu, Sichuan; and Departments of Neurology (N.G.-R.), Psychiatry and Psychology (T.J.F.), and Laboratory Medicine and Pathology (D.W.D., M.E.M.), Mayo Clinic, Jacksonville, FL.

Objective: β-Amyloid (Aβ) pathology is common in patients with probable dementia with Lewy bodies (DLB). However, the pathologic basis and the differential diagnostic performance of Aβ PET are not established in DLB. Our objective was to investigate the pathologic correlates of C-Pittsburgh compound B(PiB) uptake on PET in cases with antemortem diagnosis of probable DLB or Lewy body disease (LBD) at autopsy.

Methods: Autopsied cases who underwent antemortem PiB-PET and were assigned a clinical diagnosis of probable DLB or LBD at autopsy were included (n = 39). The primary endpoint was pathologic diagnosis of LBD, Alzheimer disease (AD), or mixed (LBD and AD) pathology; the secondary endpoints included Thal Aβ phase and diffuse and neuritic Aβ plaques.

Results: Lower global cortical PiB standardized uptake value ratio (SUVr) distinguished cases with LBD from cases with AD or mixed pathology with an accuracy of 93%. Greater global cortical PiB SUVr correlated with higher Thal Aβ phase ( = 0.75, ≤ 0.001). Voxel-based analysis demonstrated that Aβ pathology relatively spared the occipital lobes in cases with mixed pathology and LBD compared to cases with AD without LBD, in whom the entire cerebral cortex was involved. Global cortical PiB SUVr was associated primarily with the abundance of diffuse Aβ plaques in cases with LBD in a multivariable regression model.

Conclusion: Lower PiB uptake accurately distinguishes cases with LBD from cases with AD or mixed pathology, correlating with the Thal Aβ phase. The severity of diffuse Aβ pathology is the primary contributor to elevated PiB uptake in LBD.

Classification Of Evidence: This study provides Class III evidence that lower PiB uptake accurately distinguishes patients with LBD from those with AD or mixed pathology.
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http://dx.doi.org/10.1212/WNL.0000000000008818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108811PMC
January 2020

Cerebral microbleed incidence, relationship to amyloid burden: The Mayo Clinic Study of Aging.

Neurology 2020 01 4;94(2):e190-e199. Epub 2019 Dec 4.

From the Departments of Neurology (J.G.-R., A.A.R., R.D.B., M.M.M., D.S.K., R.C.P.), Health Sciences Research (T.L., J.G., J.A., S.A.P., M.M.M., W.K.), and Radiology (A.J.S., J.H., V.J.L., C.R.J., P.V., K.K.), Mayo Clinic, Rochester, MN.

Objective: To determine the incidence of cerebral microbleeds (CMBs) and the association of amyloid PET burden with incident CMBs.

Methods: A total of 651 participants, age ≥50 years (55% male), underwent 3T MRI scans with ≥2 separate T2*-weighted gradient recalled echo sequences from October 2011 to August 2017. Eighty-seven percent underwent C Pittsburgh compound B (PiB) PET scans. Age-specific CMB incidence rates were calculated by using the piecewise exponential model. Using structural equation models (SEMs), we assessed the effect of amyloid load and baseline CMBs on future CMBs after considering the direct and indirect age, sex, vascular risk factors, and effects.

Results: Participants' mean age (SD) was 69.8 (10.0) years at baseline MRI, and 111 participants (17%) had ≥1 baseline CMB. The mean (SD) of the time interval between scans was 2.7 (1.0) years. The overall population incidence rate for CMBs was 3.6/100 person-years and increased with age: from 1.5/100 new CMBs at age 50 to 11.6/100 person-years at age 90. Using the piecewise exponential model regression, the incidence rates increased with age and the presence of baseline CMBs. The SEMs showed that (1) increasing age at MRI or carrying an 4 allele was associated with more amyloid at baseline, and higher amyloid, particularly occipital amyloid load, in turn increased the risk of a new lobar CMB; and (2) the presence of CMBs at baseline increased the risk of a lobar CMB and had a larger effect size than amyloid load.

Conclusions: Age and 4 carrier status act through amyloid load to increase the risk of subsequent lobar CMBs, but the presence of baseline CMBs is the most important risk factor for future CMBs.
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http://dx.doi.org/10.1212/WNL.0000000000008735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988987PMC
January 2020

Association of Longitudinal β-Amyloid Accumulation Determined by Positron Emission Tomography With Clinical and Cognitive Decline in Adults With Probable Lewy Body Dementia.

JAMA Netw Open 2019 12 2;2(12):e1916439. Epub 2019 Dec 2.

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Importance: In patients with probable dementia with Lewy bodies (DLB), overlapping Alzheimer disease pathology is frequent and is associated with faster decline and shorter survival. More than half of patients with DLB have elevated β-amyloid levels on carbon-11 labeled Pittsburgh compound B (PiB) positron emission tomography, but the trajectory of longitudinal β-amyloid accumulation and its associations with clinical and cognitive decline in DLB are not known.

Objectives: To determine the trajectory of β-amyloid accumulation in patients with probable DLB and to investigate the associations of β-amyloid accumulation with measures of clinical and cognitive decline over time in DLB.

Design, Setting, And Participants: This cohort study included 35 consecutive patients with probable DLB from the Mayo Clinic Alzheimer Disease Research Center and matched them by age, sex, and apolipoprotein e4 status with 140 cognitively unimpaired participants from the population-based Mayo Clinic Study of Aging. Participants were observed from April 2010 to September 2017. Data analysis was conducted from January 2018 to January 2019.

Exposure: Baseline and follow-up PiB positron emission tomography and comprehensive clinical evaluations.

Main Outcomes And Measures: Rate of change in PiB standardized uptake value ratios (SUVRs) by PiB SUVR and time in years; the associations between baseline PiB SUVR, change in PiB SUVR, and change in several measures of clinical and cognitive decline.

Results: A total of 175 participants were evaluated (35 [20.0%] with probable DLB; mean [SD] age, 69.6 [7.3] years; 16 [45.7%] apolipoprotein e4 carriers; 31 [88.6%] men; and 140 [80.0%] cognitively unimpaired adults; mean [SD] age, 69.7 [7.2] years; 64 [45.7%] apolipoprotein e4 carriers; 124 [88.6%] men). In both groups, the rates of change in PiB SUVR showed an initial acceleration at lower baseline PiB SUVR followed by a deceleration at higher baseline PiB SUVR, thus forming an inverted-U shape. The trajectories of the rates of change in PiB SUVR did not differ between participants with probable DLB and cognitively unimpaired participants in terms of shape (P = .59) or vertical shift (coefficient [SE] 0.007 [0.006]; P = .22). The integral association of cumulative PiB SUVR with time in years showed a sigmoid-shaped functional form in both groups. In participants with probable DLB, higher baseline PiB SUVR and change in PiB SUVR were associated with more rapid clinical decline, as measured by the Clinical Dementia Rating, sum of boxes (baseline PiB SUVR: regression coefficient [SE], 1.90 [0.63]; P = .005; R2 = 0.215; change in PiB SUVR, regression coefficient [SE], 16.17 [7.47]; P = .04; R2 = 0.124) and the Auditory Verbal Learning Test, delayed recall (baseline PiB SUVR, regression coefficient [SE], -2.09 [0.95]; P = .04; R2 = 0.182; change in PiB SUVR, regression coefficient [SE], -25.05 [10.04]; P = .02; R2 = 0.221).

Conclusions And Relevance: In this study, the rate of change in PiB SUVR among participants with probable DLB increased, peaked, and then decreased, which was similar to the trajectory in cognitively unimpaired participants and the Alzheimer disease dementia continuum. Higher baseline PiB SUVR and change in PiB SUVR were associated with more rapid clinical and cognitive decline over time. Measuring the change in PiB SUVR has implications for designing anti-β-amyloid randomized clinical trials for individuals with probable DLB.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.16439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902746PMC
December 2019