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Background: HPV antibodies are a marker of past exposure to the virus. Our objective was to assess HPV serostatus pre- and post-vaccination among HIV-negative women. Methods: Women aged 16â24 years old were randomized in a placebo controlled trial utilizing the 4-valent HPV (4vHPV) vaccine (NCT01489527, clinicaltrials.gov). Participants (n=389) received the 4vHPV vaccine or placebo following a three dose schedule. Sera were collected at Day 1 and Month 7 for assessment of HPV 6, 11, 16, and 18 neutralizing antibody levels using a multiplex competitive Luminex immunoassay (Merck) based on detecting the L1 capsid antigen for each HPV type. Results: Seroprevalence was 73% for HPV6, 47% for HPV11, 33% for HPV16, and 44% for HPV18. Seroprevalence for any HPV type did not significantly differ by age or lifetime number of partners. The majority of participants (64%) had two or more 4vHPV antibodies present at enrollment and 12% had antibodies to all four. Among women in the vaccine arm, those that were seropositive for HPV16 at enrollment had higher titers at month 7 compared to women that were seronegative for HPV16 at enrollment; this trend holds for the other HPV types as well. Seroconversion among baseline seronegative participants in the placebo group ranged from 5% for HPV16 to 23% for HPV6. Conclusion: HPV seroprevalence was high in this population, emphasizing the need to vaccinate prior to sexual debut. Keywords: HPV vaccine, EVRI, Seroprevalence, cLIA

Cervical cancer poses a significant global health challenge, particularly impacting women in economically developing nations. This disparity stems from a combination of factors, including inadequate screening infrastructure and resource limitations. However, the foremost contributor is the widespread lack of awareness and limited accessibility to Human Papillomavirus (HPV) vaccination, which is a key preventative measure against cervical cancer development. Despite advancements in cervical cancer prevention, treatment resistance remains a major hurdle in achieving improved patient outcomes. Cellular senescence, specifically the senescence-associated secretory phenotype (SASP) and its bidirectional relationship with the immune system, has been implicated in resistance to conventional cervical cancer chemotherapy treatments. The exact mechanisms by which this state of growth arrest and the associated changes in immune regulation contribute to cervical cancer progression and the associated drug resistance are not entirely understood. This underscores the necessity for innovative strategies to address the prevalence of treatment-resistant cervical cancer, with one promising avenue being the utilisation of senolytics. Senolytics are agents that have promising efficacy in clearing senescent cells from tumour tissues, however neither the utilisation of senolytics for addressing senescence-induced treatment resistance nor the potential integration of immunotherapy as senolytic agents in cervical cancer treatment has been explored to date. This review provides a concise overview of the mechanisms underlying senescence induction and the pivotal role of the immune system in this process. Additionally, it explores various senolytic approaches that hold significant potential for advancing cervical cancer research., 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 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Background: Many patients with idiopathic normal pressure hydrocephalus (iNPH) have medical comorbidities requiring anticoagulation that could negatively impact outcomes. This study evaluated the safety of ventriculoperitoneal shunt placement in iNPH patients on systemic anticoagulation versus those not on anticoagulation., Methods: Patients >60 years of age with iNPH who underwent shunting between 2018 and 2022 were retrospectively reviewed. Baseline demographics, comorbidities (quantified by modified frailty index and Charlson comorbidity index), anticoagulant/antiplatelet agent use (other than aspirin), operative details, and complications were collected. Outcomes of interest were the occurrence of postoperative hemorrhage and overdrainage., Results: A total of 234 patients were included in the study (mean age 75.22 ± 6.04 years; 66.7% male); 36 were on anticoagulation/antiplatelet therapy (excluding aspirin). This included 6 on Warfarin, 19 on direct Xa inhibitors, 10 on Clopidogrel, and 1 on both Clopidogrel and Warfarin. Notably, 70% of patients (164/234) used aspirin alone or combined with anticoagulation or clopidogrel. Baseline modified frailty index was similar between groups, but those on anticoagulant/antiplatelet therapy had a higher mean Charlson comorbidity index (2.67 ± 1.87 vs. 1.75 ± 1.84; P = 0.001). Patients on anticoagulants were more likely to experience tract hemorrhage (11.1 vs. 2.5%; P = 0.03), with no significant difference in the rates of intraventricular hemorrhage or overdrainage-related subdural fluid collection., Conclusions: Anticoagulant and antiplatelet agents are common in the iNPH population, and patients on these agents experienced higher rates of tract hemorrhage following ventriculoperitoneal shunt placement; however, overall hemorrhagic complication rates were similar., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We assessed white matter (WM) integrity in MAPT mutation carriers (16 asymptomatic, 5 symptomatic) compared to 31 non-carrier family controls using diffusion tensor imaging (DTI) (fractional anisotropy; FA, mean diffusivity; MD) and neurite orientation dispersion and density imaging (NODDI) (neurite density index; NDI, orientation and dispersion index; ODI). Linear mixed-effects models accounting for age and family relatedness revealed alterations across DTI and NODDI metrics in all mutation carriers and in symptomatic carriers, with the most significant differences involving fronto-temporal WM tracts. Asymptomatic carriers showed higher entorhinal MD and lower cingulum FA and patterns of higher ODI mostly involving temporal areas and long association and projections fibers. Regression models between estimated time to or time from disease and DTI and NODDI metrics in key regions (amygdala, cingulum, entorhinal, inferior temporal, uncinate fasciculus) in all carriers showed increasing abnormalities with estimated time to or time from disease onset, with FA and NDI showing the strongest relationships. Neurite-based metrics, particularly ODI, appear to be particularly sensitive to early WM involvement in asymptomatic carriers., Competing Interests: Declaration of Competing Interest CRJ receives no personal compensation from any commercial entity. He receives research support from National Institute of Health (NIH), the GHR Foundation, and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. RCP consults for Roche, Inc., Merck, Inc., Biogen, Inc., Genentech, Inc., Eisai, Inc., and Nestle, Inc. but does not receive significant fees due to NIH limitations from the U24 AG057437 Co-PI role. BB receives honoraria for SAB activities for the Tau Consortium, and has received research grant support but no personal compensation for clinical trials from Alector, Biogen, Transposon, Cognition Therapeutics, GE Healthcare. VKR receives research funding from the NIH and the Mangurian Foundation for Lewy Body disease research, has provided educational content for Medscape, is co-PI for a clinical trial supported by the Alzheimer’s Association, and is a site clinician for clinical trials supported by Eisai, the Alzheimer's Treatment and Research Institute at USC, and Transposon Therapeutics, Inc. EMR has no disclosure and receives funding from the NIH. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157–206) and Vigil Neuroscience, Inc. (VGL101–01.002, VGL101–01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. KK consults Biogen, Inc.; receives research support from Avid Radiopharmaceuticals and Eli Lilly and receives funding from NIH and Alzheimer’s Drug Discovery Foundation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary progressive aphasia (PPA) variants present with distinct disruptions in speech-language functions with little known about the interplay between affected and spared regions within the speech-language network and their interaction with other functional networks. The Neurodegenerative Research Group, Mayo Clinic, recruited 123 patients with PPA (55 logopenic (lvPPA), 44 non-fluent (nfvPPA) and 24 semantic (svPPA)) who were matched to 60 healthy controls. We investigated functional connectivity disruptions between regions within the left-speech-language network (Broca, Wernicke, anterior middle temporal gyrus (aMTG), supplementary motor area (SMA), planum temporale (PT) and parietal operculum (PO)), and disruptions to other networks (visual association, dorsal-attention, frontoparietal and default mode networks (DMN)). Within the speech-language network, multivariate linear regression models showed reduced aMTG-Broca connectivity in all variants, with lvPPA and nfvPPA findings remaining significant after Bonferroni correction. Additional loss in Wernicke-Broca connectivity in nfvPPA, Wernicke-PT connectivity in lvPPA and greater aMTG-PT connectivity in svPPA were also noted. Between-network connectivity findings in all variants showed reduced aMTG-DMN and increased aMTG-dorsal-attention connectivity, with additional disruptions between aMTG-visual association in both lvPPA and svPPA, aMTG-frontoparietal in lvPPA, and Wernicke-DMN breakdown in svPPA. These findings suggest that aMTG connectivity breakdown is a shared feature in all PPA variants, with lvPPA showing more extensive connectivity disruptions with other networks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Singh has no disclosures to report. Drs. Whitwell, Botha, Utianski, Clark, Duffy, Machulda, Schwarz, Lowe and Josephs reported receiving research funding from the NIH. Dr. Graff-Radford reported receiving research support from the NIH and DSMB for StrokeNET. He is an investigator in a trial sponsored by USC and EISAI. 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., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Genetic mutations causative of frontotemporal lobar degeneration (FTLD) are highly predictive of a specific proteinopathy, but there exists substantial inter-individual variability in their patterns of network degeneration and clinical manifestations. We collected clinical and 18 Fluorodeoxyglucose-positron emission tomography (FDG-PET) data from 39 patients with genetic FTLD, including 11 carrying the C9orf72 hexanucleotide expansion, 16 carrying a MAPT mutation and 12 carrying a GRN mutation. We performed a spectral covariance decomposition analysis between FDG-PET images to yield unbiased latent patterns reflective of whole brain patterns of metabolism ("eigenbrains" or EBs). We then conducted linear discriminant analyses (LDAs) to perform EB-based predictions of genetic mutation and predominant clinical phenotype (i.e., behavior/personality, language, asymptomatic). Five EBs were significant and explained 58.52 % of the covariance between FDG-PET images. EBs indicative of hypometabolism in left frontotemporal and temporo-parietal areas distinguished GRN mutation carriers from other genetic mutations and were associated with predominant language phenotypes. EBs indicative of hypometabolism in prefrontal and temporopolar areas with a right hemispheric predominance were mostly associated with predominant behavioral phenotypes and distinguished MAPT mutation carriers from other genetic mutations. The LDAs yielded accuracies of 79.5 % and 76.9 % in predicting genetic status and predominant clinical phenotype, respectively. A small number of EBs explained a high proportion of covariance in patterns of network degeneration across FTLD-related genetic mutations. These EBs contained biological information relevant to the variability in the pathophysiological and clinical aspects of genetic FTLD, and for offering valuable guidance in complex clinical decision-making, such as decisions related to genetic testing., 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 © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Most recent studies of progressive apraxia of speech (PAOS) have focused on patients with phonetic or prosodic predominant PAOS to understand the implications of the presenting clinical phenotype. Patients without a clearly predominating speech quality, or mixed AOS, have been excluded. Given the implications for disease progression, it is important to understand these patients early in the disease course to inform appropriate education and prognostication. The aim of this study was to describe a cohort of ten patients with initially mixed PAOS and how their clinical course evolves. Four patients were rated prosodic predominant later on (mild AOS at first visit); five were later designated phonetic (four with more than mild AOS at first visit); one was judged mixed at all visits. The study suggests patients without a clear predominance of speech featuresshould still be included in PAOS studies and thought of on the continuum of the disease spectrum., 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 © 2023 Elsevier Inc. All rights reserved.)

Speech rate can be judged clinically using diadochokinetic (DDK) tasks, such as alternating motion rates (AMR) and sequential motion rates (SMR). We evaluated whether acoustic AMR/SMR speech rates would differentiate primary progressive apraxia of speech (PPAOS) from healthy controls, and determined how DDK rates relate to phonetic and prosodic speech characteristics and brain metabolism on FDG-PET. Rate was calculated for each of three AMRs (repetitions of 'puh', 'tuh', and 'kuh') and for SMRs (repetitions of 'puhtuhkuh') for 27 PPAOS patients and 52 controls who underwent FDG-PET. PPAOS patients were slower than controls on all DDK tasks. All DDK rates correlated with apraxia of speech severity, with strongest associations with prosodic speech features. Slower DDK rates were associated with hypometabolism in the right cerebellar dentate and left supplementary motor area. Performance on AMR rate, not just SMR rate, may be impaired in mild PPAOS, but sensitivity and specificity require further study.

Purpose: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder affecting the planning or programming of speech. Little is known about its magnetic susceptibility profiles indicative of biological processes such as iron deposition and demyelination. This study aims to clarify (1) the pattern of susceptibility in PAOS patients, (2) the susceptibility differences between the phonetic (characterized by predominance of distorted sound substitutions and additions) and prosodic (characterized by predominance of slow speech rate and segmentation) subtypes of PAOS, and (3) the relationships between susceptibility and symptom severity., Methods: Twenty patients with PAOS (nine phonetic and eleven prosodic subtypes) were prospectively recruited and underwent a 3 Tesla MRI scan. They also underwent detailed speech, language, and neurological evaluations. Quantitative susceptibility maps (QSM) were reconstructed from multi-echo gradient echo MRI images. Region of interest analysis was conducted to estimate susceptibility coefficients in several subcortical and frontal regions. We compared susceptibility values between PAOS and an age-matched control group and performed a correlation analysis between susceptibilities and an apraxia of speech rating scale (ASRS) phonetic and prosodic feature ratings., Results: The magnetic susceptibility of PAOS was statistically greater than that of controls in subcortical regions (left putamen, left red nucleus, and right dentate nucleus) (p < 0.01, also survived FDR correction) and in the left white-matter precentral gyrus (p < 0.05, but not survived FDR correction). The prosodic patients showed greater susceptibilities than controls in these subcortical and precentral regions. The susceptibility in the left red nucleus and in the left precentral gyrus correlated with the prosodic sub-score of the ASRS., Conclusion: Magnetic susceptibility in PAOS patients was greater than controls mainly in the subcortical regions. While larger samples are needed before QSM is considered ready for clinical differential diagnosis, the present study contributes to our understanding of magnetic susceptibility changes and the pathophysiology of PAOS., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Progressive apraxia of speech (AOS) is a motor speech disorder affecting the ability to produce phonetically or prosodically normal speech. Progressive AOS can present in isolation or co-occur with agrammatic aphasia and is associated with degeneration of the supplementary motor area. We aimed to assess breakdowns in structural connectivity from the supplementary motor area in patients with any combination of progressive AOS and/or agrammatic aphasia to determine which supplementary motor area tracts are specifically related to these clinical symptoms. Eighty-four patients with progressive AOS or progressive agrammatic aphasia were recruited by the Neurodegenerative Research Group and underwent neurological, speech/language, and neuropsychological testing, as well as 3 T diffusion magnetic resonance imaging. Of the 84 patients, 36 had apraxia of speech in isolation (primary progressive apraxia of speech, PPAOS), 40 had apraxia of speech and agrammatic aphasia (AOS-PAA), and eight had agrammatic aphasia in isolation (progressive agrammatic aphasia, PAA). Tractography was performed to identify 5 distinct tracts connecting to the supplementary motor area. Fractional anisotropy and mean diffusivity were assessed at 10 positions along the length of the tracts to construct tract profiles, and median profiles were calculated for each tract. In a case-control comparison, decreased fractional anisotropy and increased mean diffusivity were observed along the supplementary motor area commissural fibers in all three groups compared to controls. PPAOS also had abnormal diffusion in tracts from the supplementary motor area to the putamen, prefrontal cortex, Broca's area (frontal aslant tract) and motor cortex, with greatest abnormalities observed closest to the supplementary motor area. The AOS-PAA group showed abnormalities in the same set of tracts, but with greater involvement of the supplementary motor area to prefrontal tract compared to PPAOS. PAA showed abnormalities in the left prefrontal and frontal aslant tracts compared to both other groups, with PAA showing greatest abnormalities furthest from the supplementary motor area. Severity of AOS correlated with tract metrics in the supplementary motor area commissural and motor cortex tracts. Severity of aphasia correlated with the frontal aslant and prefrontal tracts. These findings provide insight into how AOS and agrammatism are differentially related to disrupted diffusivity, with progressive AOS associated with abnormalities close to the supplementary motor area, and the frontal aslant and prefrontal tracts being particularly associated with agrammatic aphasia., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy with neurodegeneration typically observed in the superior cerebellar peduncle (SCP) and dentatorubrothalamic tracts (DRTT). However, it is unclear how these tracts are differentially affected in different clinical variants of PSP., Objectives: To determine whether diffusion tractography of the SCP and DRTT can differentiate autopsy-confirmed PSP with Richardson's syndrome (PSP-RS) and PSP with predominant speech/language disorder (PSP-SL)., Methods: We studied 22 autopsy-confirmed PSP patients that included 12 with PSP-RS and 10 with PSP-SL. We compared these two groups to 11 patients with autopsy-confirmed Alzheimer's disease with SL problems, i.e., logopenic progressive aphasia (AD-LPA) (disease controls) and 10 healthy controls. Whole brain tractography was performed to identify the SCP and DRTT, as well as the frontal aslant tract and superior longitudinal fasciculus. We assessed fractional anisotropy and mean diffusivity for each tract. Hierarchical linear modeling was used for statistical comparisons, and correlations were assessed with clinical disease severity, ocular motor impairment, and parkinsonism. DRTT connectomics matrix analysis was also performed across groups., Results: The SCP showed decreased fractional anisotropy for PSP-RS and PSP-SL and increased mean diffusivity in PSP-RS, compared to controls and AD-LPA. Right DRTT fibers showed lower fractional anisotropy in PSP-RS and PSP-SL compared to controls and AD-LPA, with PSP-RS also showing lower values compared to PSP-SL. Reductions in connectivity were observed in infratentorial DRTT regions in PSP-RS vs cortical regions in PSP-SL. PSP-SL showed greater abnormalities in the frontal aslant tract and superior longitudinal fasciculus compared to controls, PSP-RS, and AD-LPA. Significant correlations were observed between ocular motor impairment and SCP in PSP-RS (p = 0.042), and DRTT in PSP-SL (p = 0.022). In PSP-SL, the PSP Rating Scale correlated with the SCP (p = 0.045) and DRTT (p = 0.008), and the Unified Parkinson's Disease Rating Scale correlated with the DRTT (p = 0.014)., Conclusions: Degeneration of the SCP and DRTT are diagnostic features of both PSP-RS and PSP-SL and associations with clinical metrics validate the role of these tracts in PSP-related clinical features, particularly in PSP-SL., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Gait and balance abnormalities are a significant source of morbidity and mortality in progressive supranuclear palsy (PSP). Gait impairment in PSP is primarily assessed clinically on exam or with the use of rating scales. Three dimensional video based gait and balance analysis performed in a laboratory setting is a highly accurate method of motion analysis (Wren et al., 2020), however limited data is available in patients with PSP., Research Question: In this study we assess the objective features of postural control, kinematics, kinetic and temporal-spatial gait metrics in PSP, using three-dimensional video motion analysis in a laboratory setting compared to normal controls., Methods: Three-dimensional motion was captured using a 10-camera motion capture system, 41 body markers and ground embedded force plates in 16 patients with PSP patients and compared to motorically normal controls., Results: Spatiotemporal, kinematic, and kinetic gait measures effectively differentiated patients with PSP from controls. Patients had slower gait velocity, lower cadence, increased double support time and abnormal antero-posterior sway. Joint kinematics and kinetics were reduced and showed less variation among patients with PSP compared to controls which is suggestive of bradykinesia. Objective gait measures of abnormality correlated with clinical disease severity. Postural sway metrics distinguished PSP from controls and captured gait imbalance., Significance: Objective measures of gait and balance abnormalities in patients with PSP provide an outcome measure that can be potentially used for early disease detection, in clinical trials and to validate portable motion capture devices in the future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.)

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

To assess volume loss and flortaucipir uptake in patients with semantic dementia (SD) over time. Eight SD patients (3 female) underwent clinical evaluations, flortaucipir positron emission tomography, and brain magnetic resonance imaging at 2 visits. Voxel-level comparisons of magnetic resonance imaging gray and white matter volume loss and flortaucipir positron emission tomography uptake were performed in SPM12, comparing SD patients to controls at each visit. T-tests on difference images and paired t-tests of flortaucipir uptake were also performed. At the voxel level, SD patients showed asymmetric, bilateral gray volume loss in the temporal lobes, which, via visual inspection, extended posteriorly at follow-up. White matter loss and flortaucipir uptake were noted in SD patients in the left temporal lobe only, which appeared to extend posteriorly, without involvement of the right hemisphere at follow-up. Longitudinal analyses did not support significant changes in flortaucipir uptake between visits. The biological mechanisms of flortaucipir signal in suspected underlying TAR-DNA binding protein 43 pathology are unknown. A 1-year interval is not sufficient time to demonstrate significant longitudinal flortaucipir uptake changes in SD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that is associated with different clinical variants, including PSP-Richardson's syndrome (PSP-RS), PSP-parkinsonism (PSP-P), PSP-corticobasal syndrome (PSP-CBS), PSP-frontal (PSP-F), PSP-progressive gait freezing (PSP-PGF) and PSP-speech/language (PSP-SL). While PSP-RS has been well-characterized on neuroimaging, the characteristics of the other atypical variants are less well defined and it is unknown how they compare to each other or relate to neuropathology. We aimed to assess and compare regional atrophy on MRI and [ 18 F]flortaucipir uptake on PET across PSP variants., Materials and Methods: 105 PSP patients (53 PSP-RS, 23 PSP-SL, 12 PSP-P, 8 PSP-CBS, 5 PSP-F and 4 PSP-PGF) underwent volumetric MRI, with 59 of these also undergoing flortaucipir PET. Voxel-level and region-level analyses were performed comparing PSP variants to 30 controls and to each other. Semi-quantitative tau burden measurements were also performed in 21 patients with autopsy-confirmed PSP., Results: All variants showed evidence for atrophy or increased flortaucipir uptake in striatum, globus pallidus and thalamus. Superior cerebellar peduncle volume loss was only observed in PSP-RS, PSP-CBS and PSP-F. Volume loss in the frontal lobes was observed in PSP-SL, PSP-CBS and PSP-F, with these variants also showing highest cortical tau burden at autopsy. The PSP-P and PSP-PGF variants showed more restricted patterns of neurodegeneration predominantly involving striatum, globus pallidus, subthalamic nucleus and thalamus. The PSP-SL variant showed greater volume loss and flortaucipir uptake in supplementary motor area and motor cortex compared to all other variants, but showed less involvement of subthalamic nucleus and midbrain. Compared to PSP-RS, PSP-P had larger midbrain volume and greater flortaucipir uptake in putamen., Conclusion: The PSP variants have different patterns of involvement of subcortical circuitry, perhaps suggesting different patterns of disease spread through the brain. These findings will be important in the development of appropriate neuroimaging biomarkers for the different PSP variants., Competing Interests: Declaration of Competing Interest The authors do not have any competing interests to declare., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Many patients who meet core/root criteria for Primary Progressive Aphasia (PPA) are not classifiable as a recognized variant and are often excluded from neuroimaging studies. Here, we detail neurological, neuropsychological, speech and language assessments, and anatomic and molecular neuroimaging (MRI, PiB-PET, and FDG-PET) for fifteen (8 female) clinically unclassifiable PPA patients. Median age of onset was 64 years old with median 3 years disease duration at exam. Three patients were amyloid positive on PiB-PET. 14/15 patients had abnormal FDG-PETs with left predominant hypometabolism, affecting frontal, temporal, parietal, and even occipital lobes. Patients had mild to severe clinical presentations. Visualization of the FDG-PETs principal component analysis revealed patterns of hypometabolism similar to those seen in the PPA variants and suggests the brain regions affected in unclassifiable PPA patients are no different from those who are more easily classifiable. These findings may inform future modifications to the diagnostic criteria to improve diagnostic classification., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Primary progressive apraxia of speech (PPAOS) is a clinical syndrome in which apraxia of speech is the initial indication of neurodegenerative disease. Prior studies of PPAOS have identified hypometabolism, grey matter atrophy, and white matter tract degeneration in the frontal gyri, precentral cortex, and supplementary motor area (SMA). Recent clinical observations suggest two distinct subtypes of PPAOS may exist. Phonetic PPAOS is characterized predominantly by distorted sound substitutions. Prosodic PPAOS is characterized predominantly by slow, segmented speech. Demographic, clinical, and neuroimaging data (MRI, DTI, and FDG-PET) were analyzed to validate these subtypes and explore anatomic correlates. The Phonetic subtype demonstrated bilateral involvement of the SMA, precentral gyrus, and cerebellar crus. The Prosodic subtype demonstrated more focal involvement in the SMA and right superior cerebellar peduncle. The findings provide converging evidence that differences in the reliably determined predominant clinical characteristics of AOS are associated with distinct imaging patterns, independent of severity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In recent years a large and growing body of research has greatly advanced our understanding of primary progressive apraxia of speech. Handedness has emerged as one potential marker of selective vulnerability in degenerative diseases. This study evaluated the clinical and imaging findings in non-right handed compared to right handed participants in a prospective cohort diagnosed with primary progressive apraxia of speech. A total of 30 participants were included. Compared to the expected rate in the population, there was a higher prevalence of non-right handedness among those with primary progressive apraxia of speech (6/30, 20%). Small group numbers meant that these results did not reach statistical significance, although the effect sizes were moderate-to-large. There were no clinical differences between right handed and non-right handed participants. Bilateral hypometabolism was seen in primary progressive apraxia of speech compared to controls, with non-right handed participants showing more right hemispheric involvement. This is the first report of a higher rate of non-right handedness in participants with isolated apraxia of speech, which may point to an increased vulnerability for developing this disorder among non-right handed participants. This challenges prior hypotheses about a relative protective effect of non-right handedness for tau-related neurodegeneration. We discuss potential avenues for future research to investigate the relationship between handedness and motor disorders more generally., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Apraxia of speech is a motor speech disorder thought to result from impaired planning or programming of articulatory movements. It can be the initial or only manifestation of a degenerative disease, termed primary progressive apraxia of speech (PPAOS). The aim of this study was to use task-free functional magnetic resonance imaging (fMRI) to assess large-scale brain network pathophysiology in PPAOS. Twenty-two PPAOS participants were identified from a prospective cohort of degenerative speech and language disorders patients. All participants had a comprehensive, standardized evaluation including an evaluation by a speech-language pathologist, examination by a behavioral neurologist and a multimodal imaging protocol which included a task-free fMRI sequence. PPAOS participants were age and sex matched to amyloid-negative, cognitively normal participants with a 1:2 ratio. We chose a set of hypothesis driven, predefined intrinsic connectivity networks (ICNs) from a large, out of sample independent component analysis and then used them to initialize a spatiotemporal dual regression to estimate participant level connectivity within these ICNs. Specifically, we evaluated connectivity within the speech and language, face and hand sensorimotor, left working memory, salience, superior parietal, supramarginal, insular and deep gray ICNs in a multivariate manner. The spatial maps for each ICN were then compared between PPAOS and control participants. We used clinical measures of apraxia of speech severity to assess for clinical-connectivity correlations for regions found to differ between PPAOS and control participants. Compared to controls, PPAOS participants had reduced connectivity of the right supplementary motor area and left posterior temporal gyrus to the rest of the speech and language ICN. The connectivity of the right supplementary motor area correlated negatively with an articulatory error score. PPAOS participants also had reduced connectivity of the left supplementary motor area to the face sensorimotor ICN, between the left lateral prefrontal cortex and the salience ICN and between the left temporal-occipital junction and the left working memory ICN. The latter connectivity correlated with the apraxia of speech severity rating scale, although the finding did not survive correction for multiple comparisons. Increased connectivity was noted in PPAOS participants between the dorsal posterior cingulate and the left working memory ICN. Our results support the importance of the supplementary motor area in the pathophysiology of PPAOS, which appears to be disconnected from speech and language regions. Supplementary motor area connectivity may serve as a biomarker of degenerative apraxia of speech severity.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is an important and treatable cause of neurologic impairment. Diagnosis is complicated due to symptoms overlapping with other age related disorders. The pathophysiology underlying iNPH is not well understood. We explored FDG-PET abnormalities in iNPH patients in order to determine if FDG-PET may serve as a biomarker to differentiate iNPH from common neurodegenerative disorders., Methods: We retrospectively compared 18 F-FDG PET-CT imaging patterns from seven iNPH patients (mean age 74 ± 6 years) to age and sex matched controls, as well as patients diagnosed with clinical Alzheimer's disease dementia (AD), Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD), and behavioral variant frontotemporal dementia (bvFTD). Partial volume corrected and uncorrected images were reviewed separately., Results: Patients with iNPH, when compared to controls, AD, DLB/PDD, and bvFTD, had significant regional hypometabolism in the dorsal striatum, involving the caudate and putamen bilaterally. These results remained highly significant after partial volume correction., Conclusions: In this study, we report a FDG-PET pattern of hypometabolism in iNPH involving the caudate and putamen with preserved cortical metabolism. This pattern may differentiate iNPH from degenerative diseases and has the potential to serve as a biomarker for iNPH in future studies. These findings also further our understanding of the pathophysiology underlying the iNPH clinical presentation.