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Progressive supranuclear palsy (PSP) can present with different clinical variants which show distinct, but partially overlapping, patterns of neurodegeneration and tau deposition in a network of regions including cerebellar dentate, superior cerebellar peduncle, midbrain, thalamus, basal ganglia, and frontal lobe. We sought to determine whether disruptions in functional connectivity within this PSP network measured using resting-state functional MRI (rs-fMRI) differed between PSP-Richardson's syndrome (PSP-RS) and the cortical and subcortical clinical variants of PSP. Structural MRI and rs-fMRI scans were collected for 36 PSP-RS, 25 PSP-cortical and 34 PSP-subcortical participants who met the Movement Disorder Society PSP clinical criteria. Ninety participants underwent flortaucipir-PET scans. MRIs were processed using CONN Toolbox. Functional connectivity between regions of the PSP network was compared between each PSP group and 83 healthy controls, and between the PSP groups, covarying for age. The effect of flortaucipir uptake and clinical scores on connectivity was assessed. Connectivity was reduced in PSP-RS compared to controls throughout the network, involving cerebellar dentate, midbrain, basal ganglia, thalamus, and frontal regions. Frontal regions showed reduced connectivity to other regions in the network in PSP-cortical, particularly the thalamus, caudate and substantia nigra. Disruptions in connectivity in PSP-subcortical were less pronounced, with the strongest disruption between the pallidum and striatum. There was moderate evidence that elevated subcortical flortaucipir uptake correlated with both increased and reduced connectivity between regions of the PSP network. Lower connectivity within the PSP network correlated with worse performance on clinical tests, including PSP rating scale. Patterns of disrupted functional connectivity revealed both variant-specific and shared disease pathways within the PSP network among PSP clinical variants, providing insight into disease heterogeneity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Glial fibrillary acidic protein (GFAP) in plasma is a proxy for astrocytic activity and is elevated in amyloid-β (Aβ)-positive individuals, making GFAP a potential blood-based biomarker for Alzheimer's disease (AD)., Methods: We assessed plasma GFAP in 72 Aβ-positive participants diagnosed with the visual or language variant of AD who underwent Aβ- and tau-PET. Fifty-nine participants had follow-up imaging. Linear regression was applied on GFAP and imaging quantities., Results: GFAP did not correlate with Aβ- or tau-PET cross-sectionally. There was a limited positive correlation between GFAP and rates of tau accumulation, particularly in the language variant of AD, although associations were weaker after removing one outlier patient with the highest GFAP level., Discussion: Among Aβ-positive AD participants with atypical presentations, plasma GFAP did not correlate with levels of AD pathology on PET, suggesting that the associations between GFAP and AD pathology might plateau during the advanced phase of the disease., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) show distinct atrophy and overlapping hypometabolism profiles, but it is unknown how disruptions in structural and functional connectivity compare between these disorders and whether breakdowns in connectivity relate to either atrophy or hypometabolism. Thirty amyloid-positive PCA patients, 24 amyloid-negative DLB patients and 30 amyloid-negative cognitively unimpaired (CU) healthy individuals were recruited at Mayo Clinic, Rochester, MN, and underwent a 3T head MRI, including structural MRI, resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) sequences, as well as [ 18 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., Competing Interests: Declaration of competing interest Dr. Singh, Dr. Carlos, Dr. Sintini, Dr. Reid, Carling Robinson and Austin Goodrich have no disclosures to report. Dr. Whitwell, Dr. Machulda and Dr. Josephs reported receiving research funding from the NIH. Dr. Graff-Radford reported receiving research support from the NIH and he also serves as an editorial board member for Neurology. Dr. Jack receives no personal compensation from any commercial entity and has no conflicts. He receives research support from NIH, the GHR foundation and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Dr. Lowe reported consulting for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research and receiving research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, Elli Lilly and Company and the NIH (NIA, NCI). Dr. Peterson reported serving on scientific advisory boards for Elan Pharmaceuticals and GE Healthcare, he receives royalties from publishing mild cognitive impairment (Oxford University Press, 2003) and receives research support from NIH. Dr. Kantarci receives research support from the NIH (K23 AG030935 [PI], P50 AG16574/P1 [PI], and R01 AG11378 [Co-]). Dr. Boeve has served as a consultant to GE Healthcare; receives royalties from the publication of Behavioral Neurology of Dementia (Cambridge Medicine, 2009); and receives research support from Myriad Genetics Inc., Cephalon, Inc., the NIH (P50 AG16574 [Co-I], UO1 AG06786 [Co-I, and RO1 AG15866 [Co-I]), the Alzheimer's Association, and the Center for Inherited Disease Research (U24 AG026395 [Co-I])., (Copyright © 2024. Published by Elsevier Inc.)

Disruption of the default mode network is a hallmark of Alzheimer's disease, which has not been extensively examined in atypical phenotypes. We investigated cross-sectional and 1-year longitudinal changes in default mode network sub-systems in the visual and language variants of Alzheimer's disease, in relation to age and tau. Sixty-one amyloid-positive Alzheimer's disease participants diagnosed with posterior cortical atrophy ( n = 33) or logopenic progressive aphasia ( n = 28) underwent structural MRI, resting-state functional MRI and [ 18 F]flortaucipir PET. One-hundred and twenty-two amyloid-negative cognitively unimpaired individuals and 60 amyloid-positive individuals diagnosed with amnestic Alzheimer's disease were included as controls and as a comparison group, respectively, and had structural and resting-state functional MRI. Forty-one atypical Alzheimer's disease participants, 26 amnestic Alzheimer's disease participants and 40 cognitively unimpaired individuals had one follow-up functional MRI ∼1-2 years after the baseline scan. Default mode network connectivity was calculated using the dual regression method for posterior, ventral, anterior ventral and anterior dorsal sub-systems derived from independent component analysis. A global measure of default mode network connectivity, the network failure quotient, was also calculated. Linear mixed-effects models and voxel-based analyses were computed for each connectivity measure. Both atypical and amnestic Alzheimer's disease participants had lower cross-sectional posterior and ventral and higher anterior dorsal connectivity and network failure quotient relative to cognitively unimpaired individuals. Age had opposite effects on connectivity in Alzheimer's disease participants and cognitively unimpaired individuals. While connectivity declined with age in cognitively unimpaired individuals, younger Alzheimer's disease participants had lower connectivity than the older ones, particularly in the ventral default mode network. Greater baseline tau-PET uptake was associated with lower ventral and anterior ventral default mode network connectivity in atypical Alzheimer's disease. Connectivity in the ventral default mode network declined over time in atypical Alzheimer's disease, particularly in older participants, with lower tau burden. Voxel-based analyses validated the findings of higher anterior dorsal default mode network connectivity, lower posterior and ventral default mode network connectivity and decline in ventral default mode network connectivity over time in atypical Alzheimer's disease. Visuospatial symptoms were associated with default mode network connectivity disruption. In summary, default mode connectivity disruption was similar between atypical and amnestic Alzheimer's disease variants, and discriminated Alzheimer's disease from cognitively unimpaired individuals, with decreased posterior and increased anterior connectivity and with disruption more pronounced in younger participants. The ventral default mode network declined over time in atypical Alzheimer's disease, suggesting a shift in default mode network connectivity likely related to tau pathology., Competing Interests: I.S., N.C.-L., N.A.S. and J.L.G. have no disclosures to report. J.L.W., K.A.J., J.G.-R., C.G.S., M.M.M., D.T.J., H.B. and C.R.J. reported receiving research funding from the NIH. J.G.-R. is DSMB for NINDS STROKENE. V.J.L. reported consulting for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals and Merck Research and receiving research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). R.C.P. has consulted for Roche, Inc., Merck, Inc., Biogen, Inc., Eisai, Inc., Nestle, Inc., and Genentech, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Transactive response DNA-binding protein 43 (TDP-43) pathology is categorized as type A-E in frontotemporal lobar degeneration and as type α-β in Alzheimer disease (AD) based on inclusion type. We screened amygdala slides of 131 cases with varying ages at death, clinical/neuroimaging findings, and AD neuropathologic changes for TDP-43 pathology using anti-phospho-TDP-43 antibodies. Seven cases (5%) only showed atypical TDP-43 inclusions that could not be typed. Immunohistochemistry and immunofluorescence assessed the atypical star-shaped TDP-43 pathology including its distribution, species, cellular localization, and colocalization with tau. All 7 had died at an extremely old age (median: 100 years [IQR: 94-101]) from nonneurological causes and none had dementia (4 cognitively unimpaired, 3 with amnestic mild cognitive impairment). Neuroimaging showed mild medial temporal involvement. Pathologically, the star-shaped TDP-43-positive inclusions were found in medial (subpial) amygdala and, occasionally, in basolateral regions. Hippocampus only showed TDP-43-positive neurites in the fimbria and subiculum while the frontal lobe was free of TDP-43 inclusions. The star-shaped inclusions were better detected with antibodies against N-terminal than C-terminal TDP-43. Double-labeling studies confirmed deposition of TDP-43 within astrocytes and colocalization with tau. We have identified a novel TDP-43 pathology with star-shaped morphology associated with superaging, with a homogeneous clinicopathologic picture, possibly representing a novel, true aging-related TDP-43 pathology., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Atypical variants of Alzheimer's disease (AD) include the visual variant, known as posterior cortical atrophy (PCA), and the language variant, known as logopenic progressive aphasia (LPA). Clinically, rates of disease progression differ between them., Methods: We evaluated 34 PCA and 29 LPA participants. Structural magnetic resonance imaging and 18 F-flortaucipir positron emission tomography were performed at baseline and at 1-year follow-up. Rates of change in tau uptake and grey matter volumes were compared between PCA and LPA with linear mixed-effects models and voxel-based analyses., Results: PCA had faster rates of occipital atrophy. LPA had faster rates of left temporal atrophy and faster rates of tau accumulation in the parietal, right temporal, and occipital lobes. Age was negatively associated with rates of atrophy and tau accumulation., Discussion: Longitudinal patterns of neuroimaging abnormalities differed between PCA and LPA, although with divergent results for tau accumulation and atrophy., Highlights: The language variant of Alzheimer's disease accumulates tau faster than the visual variant. Each variant shows faster rates of atrophy than the other in its signature regions. Age negatively influences rates of atrophy and tau accumulation in both variants., (© 2023 the Alzheimer's Association.)

Posterior cortical atrophy and logopenic progressive aphasia are atypical clinical presentations of Alzheimer's disease. Resting-state functional connectivity studies have shown functional network disruptions in both phenotypes, particularly involving the language network in logopenic progressive aphasia and the visual network in posterior cortical atrophy. However, little is known about how connectivity differs both within and between brain networks in these atypical Alzheimer's disease phenotypes. A cohort of 144 patients was recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, USA, and underwent structural and resting-state functional MRI. Spatially preprocessed data were analysed to explore the default mode network and the salience, sensorimotor, language, visual and memory networks. The data were analysed at the voxel and network levels. Bayesian hierarchical linear models adjusted for age and sex were used to analyse within- and between-network connectivity. Reduced within-network connectivity was observed in the language network in both phenotypes, with stronger evidence of reductions in logopenic progressive aphasia compared to controls. Only posterior cortical atrophy showed reduced within-network connectivity in the visual network compared to controls. Both phenotypes showed reduced within-network connectivity in the default mode and sensorimotor networks. No significant change was noted in the memory network, but a slight increase in the salience within-network connectivity was seen in both phenotypes compared to controls. Between-network analysis in posterior cortical atrophy showed evidence of reduced visual-to-language network connectivity, with reduced visual-to-salience network connectivity, compared to controls. An increase in visual-to-default mode network connectivity was noted in posterior cortical atrophy compared to controls. Between-network analysis in logopenic progressive aphasia showed evidence of reduced language-to-visual network connectivity and an increase in language-to-salience network connectivity compared to controls. Findings from the voxel-level and network-level analysis were in line with the Bayesian hierarchical linear model analysis, showing reduced connectivity in the dominant network based on diagnosis and more crosstalk between networks in general compared to controls. The atypical Alzheimer's disease phenotypes were associated with disruptions in connectivity, both within and between brain networks. Phenotype-specific differences in connectivity patterns were noted in the visual network for posterior cortical atrophy and the language network for logopenic progressive aphasia., Competing Interests: N.A.S., I.S., J.R.D., H.B., D.T.J., J.L.G. and P.R.M. have no disclosures to report. J.L.W., M.M.M. and K.A.J. reported receiving research funding from the NIH. J.G.-R. reported receiving research support from the NIH, and he also serves as an editorial board member for Neurology. C.R.J.J. reported serving on an independent data monitoring board for Roche and has consulted for and served as a speaker for Eisai and consulted for Biogen, but he receives no personal compensation from any commercial entity. He receives research support from the NIH, the GHR Foundation and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. V.J.L. reported consulting for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals and Merck Research and receiving research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Apolipoprotein E (APOE) ε4 is an important genetic risk factor for typical Alzheimer's disease (AD), influencing brain volume and tau burden. Little is known about its influence in atypical presentations of AD., Methods: An atypical AD cohort of 140 patients diagnosed with either posterior cortical atrophy or logopenic progressive aphasia underwent magnetic resonance imaging and positron emission tomography. Linear mixed effects models were fit to assess the influence of APOE ε4 on cross-sectional and longitudinal regional metrics., Results: At baseline, APOE ε4 carriers had smaller hippocampal and amygdala volumes and greater tau standardized uptake volume ratio in the hippocampus and entorhinal cortex compared to non-carriers while longitudinally, APOE ε4 non-carriers showed faster rates of atrophy and tau accumulation in the entorhinal cortex, with faster tau accumulation in the hippocampus., Discussion: APOE ε4 influences patterns of neurodegeneration and tau deposition and was associated with more medial temporal involvement, although there is evidence that non-carriers may be catching up over time., (© 2022 the Alzheimer's Association.)

Primary progressive apraxia of speech (PPAOS) is a neurodegenerative motor speech disorder affecting the ability to produce speech. If agrammatic aphasia is present, it can be referred to as the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA). We investigated whether resting-state functional MRI (rs-fMRI) connectivity from disease "epicenters" correlated with longitudinal gray matter atrophy and hypometabolism in nfvPPA and PPAOS. Eighteen nfvPPA and 23 PPAOS patients underwent clinical assessment, structural MRI, rs-fMRI, and [ 18 F] fluorodeoxyglucose (FDG)-PET at baseline and ∼2 years follow-up. Rates of neurodegeneration in nfvPPA and PPAOS correlated with functional connectivity to the premotor, motor, and frontal cortex. Connectivity to the caudate and thalamus was more strongly associated with rates of hypometabolism than atrophy. Connectivity to the left Broca's area was more strongly associated with rates of atrophy and hypometabolism in nfvPPA. Finally, functional connectivity to a network of regions, and not to a single epicenter, correlated with rates of neurodegeneration in PPAOS and nfvPPA, suggesting similar biological mechanisms driving disease progression, with regional differences related to language., Competing Interests: Declaration of competing interest M.L.S. has owned stocks, within the past 12 months, in Align Technology, Inc., Inovio Pharmaceuticals Inc., LHC Group, Inc., Mesa Laboratories, Inc., and Natus Medical Inc., unrelated to the current study. V.J.L. consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals. C.R.J. serves on a scientific advisory board for Eli Lilly & Company, as a speaker for Eisai and on an independent data safety monitoring board for Roche but he receives no personal compensation from any commercial entity. All other authors report no competing interests for this study., (Copyright © 2022. Published by Elsevier Inc.)

Background and Objectives: The aims of this work were to compare rates of longitudinal change in neurologic and neuropsychological test performance between the logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) variants of atypical Alzheimer disease (AD) and to use unbiased principal component analysis to assess heterogeneity in patterns of change and relationships to demographics and concurrent brain atrophy., Methods: Patients with PCA or LPA who were positive for amyloid and tau AD biomarkers and had undergone serial neurologic and neuropsychological assessments and structural MRI were identified. Rates of change in 13 clinical measures were compared between groups in a case-control design, and principal component analysis was used to assess patterns of clinical change unbiased by clinical phenotype. Components were correlated with rates of regional brain atrophy with tensor-based morphometry., Results: Twenty-eight patients with PCA and 27 patients with LPA were identified. Those with LPA showed worse baseline performance and faster rates of decline in naming, repetition, and working memory, as well as faster rates of decline in verbal episodic memory, compared to those with PCA. Conversely, patients with PCA showed worse baseline performance in tests of visuospatial and perceptual function and on the Clinical Dementia Rating Scale and faster rates of decline in visuoperceptual function compared to those with LPA. Principal component analysis showed that patterns of clinical decline were highly heterogeneous across the cohort, with 10 principal components required to explain >90% of the variance. The first principal component reflected overall severity, with higher scores in LPA than PCA reflecting faster decline in LPA, and was related to left temporoparietal atrophy. The second and third principal components were not related to clinical phenotype but showed some relationship to regional atrophy. No relationships were identified between the principal components and age, sex, disease duration, amyloid PET findings, or apolipoprotein genotype., Discussion: Longitudinal patterns of clinical decline differ between LPA and PCA but are heterogeneous and related to different patterns of topographic spread. PCA is associated with a more slowly progressive course than LPA., (© 2022 American Academy of Neurology.)

Background: Clinical variants of progressive supranuclear palsy (PSP) include the classic Richardson's syndrome (PSP-RS), as well as cortical presentations such as PSP-speech/language (PSP-SL) and subcortical presentations such as PSP-parkinsonism (PSP-P). Patterns of white matter tract degeneration underlying these variants, and the degree to which white matter patterns could differentiate these variants, is unclear., Methods: Forty-nine PSP patients (28 PSP-RS, 12 PSP-P, and 9 PSP-SL) were recruited by the Neurodegenerative Research Group and underwent diffusion tensor imaging. Regional diffusion tensor imaging metrics were compared across PSP variants using Bayesian linear mixed-effects models, with inter-variant differentiation assessed using the area under the receiver operator characteristic curve (AUROC)., Results: All three variants showed degeneration of the body of the corpus callosum, posterior thalamic radiation, superior cerebellar peduncle, internal and external capsule, and superior fronto-occipital fasciculus. PSP-RS showed greater degeneration of superior cerebellar peduncle compared to PSP-P and PSP-SL, whereas PSP-SL showed greater degeneration of body and genu of the corpus callosum, internal capsule, external capsule, and superior longitudinal fasciculus compared to the other variants. Fractional anisotropy in body of the corpus callosum provided excellent differentiation of PSP-SL from both PSP-P and PSP-RS (AUROC = 0.91 and 0.92, respectively). Moderate differentiation of PSP-RS and PSP-P was achieved with fractional anisotropy in superior fronto-occipital fasciculus (AUROC = 0.68) and mean diffusivity in the superior cerebellar peduncle (AUROC = 0.65)., Conclusion: In this pilot study, patterns of white matter tract degeneration differed across PSP-RS, PSP-SL, and PSP-P, with the body of the corpus callosum showing some utility in the differentiation of PSP-SL from the other two variants., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose of Review: The purpose of this review was to discuss the contribution of the most recent neuroimaging studies to our understanding of the mechanisms underlying Alzheimer's disease., Recent Findings: Studies have applied cross-sectional and longitudinal positron emission tomography (PET), structural and resting-state functional magnetic resonance imaging to primarily investigate (1) how Alzheimer's disease pathological hallmarks like tau and amyloid-beta build up and spread across the brain at different disease stage and in different disease phenotypes and (2) how the spreading of these proteins is related to atrophy, to neuronal network disruption and to neuroinflammation., Summary: The findings of these studies offer insight on the mechanisms that drive the pathological and clinical progression of Alzheimer's disease, highlighting their multifactorial nature, which is a crucial aspect for the development of disease-modifying therapeutics and can be captured with multimodal imaging approaches., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The mechanisms through which tau and amyloid-beta (Aβ) accumulate in the brain of Alzheimer's disease patients may differ but both are related to neuronal networks. We examined such mechanisms on neuroimaging in 58 participants with atypical Alzheimer's disease (posterior cortical atrophy or logopenic progressive aphasia). Participants underwent Aβ-PET, longitudinal tau-PET, structural MRI and resting-state functional MRI, which was analyzed with graph theory. Regions with high levels of Aβ were more likely to be functional hubs, with a high number of functional connections important for resilience to cascading network failures. Regions with high levels of tau were more likely to have low clustering coefficients and degrees, suggesting a lack of trophic support or vulnerability to local network failures. Regions strongly functionally connected to the disease epicenters were more likely to have higher levels of tau and, less strongly, of Aβ. The regional rate of tau accumulation was associated with tau levels in functionally connected regions, in support of tau accumulation in a functional network. This study elucidates the relations of tau and Aβ to functional connectivity metrics in atypical Alzheimer's disease, strengthening the hypothesis that the spread of the 2 proteins is driven by different biological mechanisms related to functional networks., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease can present clinically with either the typical amnestic phenotype or with atypical phenotypes, such as logopenic progressive aphasia and posterior cortical atrophy. We have recently described longitudinal patterns of flortaucipir PET uptake and grey matter atrophy in the atypical phenotypes, demonstrating a longitudinal regional disconnect between flortaucipir accumulation and brain atrophy. However, it is unclear how these longitudinal patterns differ from typical Alzheimer's disease, to what degree flortaucipir and atrophy mirror clinical phenotype in Alzheimer's disease, and whether optimal longitudinal neuroimaging biomarkers would also differ across phenotypes. We aimed to address these unknowns using a cohort of 57 participants diagnosed with Alzheimer's disease (18 with typical amnestic Alzheimer's disease, 17 with posterior cortical atrophy and 22 with logopenic progressive aphasia) that had undergone baseline and 1-year follow-up MRI and flortaucipir PET. Typical Alzheimer's disease participants were selected to be over 65 years old at baseline scan, while no age criterion was used for atypical Alzheimer's disease participants. Region and voxel-level rates of tau accumulation and atrophy were assessed relative to 49 cognitively unimpaired individuals and among phenotypes. Principal component analysis was implemented to describe variability in baseline tau uptake and rates of accumulation and baseline grey matter volumes and rates of atrophy across phenotypes. The capability of the principal components to discriminate between phenotypes was assessed with logistic regression. The topography of longitudinal tau accumulation and atrophy differed across phenotypes, with key regions of tau accumulation in the frontal and temporal lobes for all phenotypes and key regions of atrophy in the occipitotemporal regions for posterior cortical atrophy, left temporal lobe for logopenic progressive aphasia and medial and lateral temporal lobe for typical Alzheimer's disease. Principal component analysis identified patterns of variation in baseline and longitudinal measures of tau uptake and volume that were significantly different across phenotypes. Baseline tau uptake mapped better onto clinical phenotype than longitudinal tau and MRI measures. Our study suggests that optimal longitudinal neuroimaging biomarkers for future clinical treatment trials in Alzheimer's disease are different for MRI and tau-PET and may differ across phenotypes, particularly for MRI. Baseline tau tracer retention showed the highest fidelity to clinical phenotype, supporting the important causal role of tau as a driver of clinical dysfunction in Alzheimer's disease., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Progressive supranuclear palsy is characterized primarily by 4R tau inclusions, atrophy in the brainstem and basal ganglia, and neurodegeneration along the dentatorubrothalamic tract, which are measurable in vivo using flortaucipir PET, T1-weighted MRI, and MRI with diffusion tensor imaging (DTI). However, little is known about how these processes relate to each other. The aim of this study was to investigate multimodal associations between flortaucipir PET uptake, tissue volume loss on structural MRI and white matter tract disruption on DTI. Thirty-four patients with progressive supranuclear palsy and 29 normal controls underwent flortaucipir PET, MRI and DTI. Voxel-wise comparison was performed between patients and controls. Sparse canonical correlations analysis was applied on regional measurements of flortaucipir uptake, tissue volume, fractional anisotropy and mean diffusivity of the PSP population. Pearson's correlation coefficients were assessed across modalities on the regions identified by the sparse canonical correlation analyses. Sparse canonical correlation analyses identified associations between elevated flortaucipir uptake in the cerebellar dentate, red nucleus and subthalamic nucleus and decreased volume in the same regions, and decreased fractional anisotropy and increased mean diffusivity in tracts including the superior cerebellar peduncle, sagittal striatum and posterior corona radiata. Furthermore, decreased fractional anisotropy and increased mean diffusivity in the body of the corpus callosum and anterior and superior corona radiata were related to volume loss in the frontal lobe. Tau uptake measured by flortaucipir PET appears to be related to the neurodegenerative process of progressive supranuclear palsy, including reduced tissue volume and white matter tract degeneration., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) can present with atypical clinical forms where the prominent domain of deficit is not memory, that is, atypical AD. Atypical AD patients show cortical atrophy on MRI, hypometabolism on [ 18 F]fluorodeoxyglucose (FDG) PET, tau uptake on [ 18 F]AV-1451 PET, and white matter tract degeneration on diffusion tensor imaging (DTI). How these disease processes relate to each other locally and distantly remains unclear. We aimed to examine multimodal neuroimaging relationships in individuals with atypical AD, using univariate and multivariate techniques at region- and voxel-level. Forty atypical AD patients underwent MRI, FDG-PET, tau-PET, beta-amyloid PET, and DTI. Patients were all beta-amyloid positive. Partial Pearson's correlations were performed between tau and FDG standardized uptake value ratios, gray matter MRI-volumes and white matter tract fractional anisotropy. Sparse canonical correlation analysis was applied to identify multivariate relationships between the same quantities. Voxel-level associations across modalities were also assessed. Tau showed strong local negative correlations with FDG metabolism in the occipital and frontal lobes. Tau in frontal and parietal regions was negatively associated with temporoparietal gray matter MRI-volume. Fractional anisotropy in a set of posterior white matter tracts, including the splenium of the corpus callosum, cingulum, and posterior thalamic radiation, was negatively correlated with parietal and occipital tau, atrophy and, predominantly, with hypometabolism. These results support the view that tau is the driving force behind neurodegeneration in atypical AD, and that a breakdown in structural connectivity is related to cortical neurodegeneration, particularly hypometabolism., (© 2018 Wiley Periodicals, Inc.)

The design of total shoulder arthroplasty implants are guided by anatomy. The objective of this study was to develop statistical models to quantify shape and material property variation in the scapula. Material-mapped models were reconstructed from CT scans for a training set of subjects. Statistical shape (SSM) and intensity (SIM) models were created; SSM modes described scaling, changes in the medial border and acromial process, and elongation of the scapular blade. SIM modes captured bone quality changes in the anterior and inferior glenoid. Bone quality was independent of scapular morphology. Variation described by the statistical representations can inform implant design and sizing.

Objective: To compare [ 18 F]AV-1451 uptake in the semantic variant of primary progressive aphasia (svPPA) to Alzheimer dementia, and determine whether increased uptake in svPPA is associated with the presence of β-amyloid (Aβ)., Methods: Thirty-one participants with svPPA underwent MRI and Pittsburgh compound B-PET scanning, and 17 of these also underwent [ 18 F]AV-1451 tau-PET. A global Pittsburgh compound B standardized uptake value ratio was calculated for all participants, with a cutoff of 1.42 used to define Aβ(+) participants. We assessed region and voxel-level [ 18 F]AV-1451 uptake in the whole svPPA cohort and separately in Aβ(+) and Aβ(-) svPPA groups, compared to 12 Aβ(+) participants with Alzheimer dementia and 170 cognitively normal, Aβ(-) controls., Results: Of the entire cohort of participants with svPPA, 26% were Aβ(+). The Aβ(+) participants were older at scan compared to the Aβ(-) participants. svPPA showed elevated [ 18 F]AV-1451 uptake in anteromedial temporal regions but the degree of uptake was lower than in Alzheimer dementia. After controlling for age, Aβ(+) status in svPPA was associated with significantly higher uptake in all anteromedial and inferior/middle lateral temporal regions, but uptake was still lower than in Alzheimer dementia., Conclusion: Although [ 18 F]AV-1451 uptake is focally elevated in svPPA, the level of uptake is much less than what occurs in Alzheimer dementia and appears to be at least partially related to Aβ. Therefore, it is possible that some of the increased uptake of [ 18 F]AV-1451 in svPPA is related to binding paired helical filament tau., (© 2019 American Academy of Neurology.)

The aims of this study were: to examine regional rates of change in tau-PET uptake and grey matter volume in atypical Alzheimer's disease (AD); to investigate the role of age in such changes; to describe multimodal regional relationships between tau accumulation and atrophy. Thirty atypical AD patients underwent baseline and one-year follow-up MRI, [ 18 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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Morphological variability in the shoulder influences the joint biomechanics and is an important consideration in arthroplasty and implant design. The objectives of this study were to quantify cortical and cancellous proximal humeral morphology and to assess whether shape variation was influenced by gender and ethnicity, with the overarching goal of informing implant design and treatment. A statistical shape model of the proximal humeral cortical and cancellous regions was developed for a training set of 84 subjects of both genders and different ethnicities. Cortical and cancellous bone geometries were reconstructed from CT scans, meshed with triangular elements, and registered to a template. Principal component analysis was applied to quantify modes of variation. Anatomical measurements were computed on the registered geometries to assess correlation with modes of variation. Parallel analysis identified six significant modes of variation, which accounted for 93% of variation in the training set and described scaling (Mode 1), inclination of the head (Modes 2 and 5), and shape of the greater tuberosity and neck region (Modes 3, 4, and 6). Size differences as described by Mode 1 were statistically significant for gender and ethnicity, where female and Asian subjects were smaller than male and Caucasian subjects, respectively; however, differences in other modes were not significant. Cortical thickness of the shaft after normalization by outer diameter was significantly larger for Asian subjects compared to Caucasian subjects. The statistical shape model quantified cortical and cancellous humeral morphology considering gender and ethnicity, providing descriptive data to support surgical planning, and implant design. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3043-3052, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Pre-clinical assessment of stability in total knee replacement is crucial for developing preferred implant performance. Current total knee replacement patients often experience joint instability that the human body addresses with compensatory strategies. Specifically, an increased quadriceps-hamstrings co-contraction serves to increase joint stability through an increased compressive force across the tibiofemoral joint. The aim of this study is to introduce a novel method to evaluate total knee replacement by determining the compressive loading required to achieve natural knee stability. Four current total knee replacement geometries in both their cruciate-retaining and posterior-stabilized forms are modeled in a finite-element framework. The finite-element model is initially validated experimentally using traditional knee laxity testing with a constant compressive load and anterior-posterior displacement or internal-external rotation. Model predictions of constraint are in reasonable agreement with experimental results (average root mean square errors: 0.46 Nm, 62.5 N). The finite-element model is subsequently interfaced with a feedback controller to vary the compressive force that the implant requires in order to match experimental natural knee internal-external and anterior-posterior stability at different flexion angles. Results show that the lower constraint total knee replacement designs require on average 66.7% more compressive load than the higher constraint designs to achieve natural knee constraint. As expected, total knee replacement stability and compressive load requirements to replicate natural kinematics vary with inclusion of tibiofemoral ligaments. The current study represents a novel approach to evaluate stability in existing total knee replacement geometries and to design implants that better restore natural knee mechanics. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1901-1909, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)