477 results on '"Lowe VJ"'
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2. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimers disease: Implications for sequence of pathological events in Alzheimers disease
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Jack, CR, Lowe, VJ, Weigand, SD, Wiste, HJ, Senjem, ML, Knopman, DS, Shiung, MM, Gunter, JL, Boeve, BF, Kemp, BJ, Weiner, M, and Petersen, RC
- Abstract
The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimers disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial 11C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimers disease. Subjects were drawn from two sourcesongoing longitudinal registries at Mayo Clinic, and the Alzheimers disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm3 by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm3/year) < amnestic mild cognitive impairment (2.5 cm3/year) < Alzheimers disease (7.7 cm3/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r -0.01, P 0.97) but some evidence of a weak correlation with MMSE (r -0.22, P 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r 0.42, P < 0.01) and MMSE (r -0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimers disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimers disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimers disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration. © 2009 The Author(s)2009This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2009 Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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- 2009
3. Indicators of amyloid burden in a population-based study of cognitively normal elderly.
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Mielke MM, Wiste HJ, Weigand SD, Knopman DS, Lowe VJ, Roberts RO, Geda YE, Swenson-Dravis DM, Boeve BF, Senjem ML, Vemuri P, Petersen RC, Jack CR Jr, Mielke, Michelle M, Wiste, Heather J, Weigand, Stephen D, Knopman, David S, Lowe, Val J, Roberts, Rosebud O, and Geda, Yonas E
- Published
- 2012
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4. Similar clinical and neuroimaging features in monozygotic twin pair with mutation in progranulin.
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McDade E, Boeve BF, Burrus TM, Boot BP, Kantarci K, Fields J, Lowe VJ, Peller P, Knopman D, Baker M, Finch N, Rademakers R, Petersen R, McDade, E, Boeve, B F, Burrus, T M, Boot, B P, Kantarci, K, Fields, J, and Lowe, V J
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- 2012
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5. The value of [18F]fluorodeoxyglucose positron emission tomography/computed tomography in extranodal natural killer/T-cell lymphoma.
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Karantanis D, Subramaniam RM, Peller PJ, Lowe VJ, Durski JM, Collins DA, Georgiou E, Ansell SM, and Wiseman GA
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- 2008
6. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment.
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Jack CR Jr, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, Shiung MM, Knopman DS, Boeve BF, Klunk WE, Mathis CA, Petersen RC, Jack, Clifford R Jr, Lowe, Val J, Senjem, Matthew L, Weigand, Stephen D, Kemp, Bradley J, Shiung, Maria M, Knopman, David S, Boeve, Bradley F, and Klunk, William E
- Abstract
To date, most diagnostic imaging comparisons between amyloid labelling ligands and other imaging modalities have been between the use of amyloid labelling ligand (11)C Pittsburgh Compound B (PiB) and FDG-PET. Our objectives were to compare cognitive performance and diagnostic group-wise discrimination between cognitively normal, amnestic mild cognitive impairment (MCI) and Alzheimer's disease subjects with MRI-based measures of hippocampal volume and PiB retention, and secondly to evaluate the topographic distribution of PiB retention and grey matter loss using 3D voxel-wise methods. Twenty cognitively normal, 17 amnestic MCI and 8 probable Alzheimer's disease subjects were imaged with both MRI and PiB. PiB retention was quantified as the ratio of uptake in cortical to cerebellar regions of interest (ROIs) 40-60 min post-injection. A global cortical PiB retention summary measure was derived from six cortical ROIs. Statistical parametric mapping (SPM) and voxel-based morphometry (VBM) were used to evaluate PiB retention and grey matter loss on a 3D voxel-wise basis. Alzheimer's disease subjects had high global cortical PiB retention and low hippocampal volume; most cognitively normal subjects had low PiB retention and high hippocampal volume; and on average amnestic MCI subjects were intermediate on both PiB and hippocampal volume. A target-to-cerebellar ratio of 1.5 was used to designate subjects with high or low PiB cortical retention. All Alzheimer's disease subjects fell above this ratio, as did 6 out of 20 cognitively normal subjects and 9 out of 17 MCI subjects, indicating bi-modal PiB retention in the latter two groups. Interestingly, we found no consistent differences in learning and memory performance between high versus low PiB cognitively normal or amnestic MCI subjects. The SPM/VBM voxel-wise comparisons of Alzheimer's disease versus cognitively normal subjects provided complementary information in that clear and meaningful similarities and differences in topographical distribution of amyloid deposition and grey matter loss were shown. The frontal lobes had high PiB retention with little grey matter loss, anteromedial temporal areas had low PiB retention with significant grey matter loss, whereas lateral temporoparietal association cortex displayed both significant PiB retention and grey matter loss. A voxel-wise SPM conjunction analysis revealed that subjects with high PiB retention shared a common PiB retention topographical pattern regardless of clinical category, and this matched that of amyloid plaque distribution from autopsy studies of Alzheimer's disease. Both global cortical PiB retention and hippocampal volumes demonstrated significant correlation in the expected direction with cognitive testing performance; however, correlations were stronger with MRI than PiB. Pair-wise inter-group diagnostic separation was significant for all group-wise pairs for both PiB and hippocampal volume with the exception of the comparison of cognitively normal versus amnestic MCI, which was not significant for PiB. PiB and MRI provided complementary information such that clinical diagnostic classification using both methods was superior to using either in isolation. [ABSTRACT FROM AUTHOR]
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- 2008
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7. Normal variants and pitfalls in whole-body PET imaging with 18F FDG.
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Bogsrud TV and Lowe VJ
- Abstract
Positron-emission tomography (PET) is an important oncologic imaging tool for primary tumor staging, evaluation of treatment response, recurrence detection, and restaging. Combined with computed tomography (CT), PET/CT has increased the diagnostic accuracy and dramatically reduced the acquisition time. This article describes the normal uptake, distribution, and excretion of Fluorine-18-labeled deoxyglucose (18F FDG) as well as normal variations, response to treatment regimes, artifacts, and potential pitfalls that are important for correct image interpretation of whole-body PET/CT in oncology. [ABSTRACT FROM AUTHOR]
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- 2006
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8. Etanercept therapy for immune-mediated cochleovestibular disorders: a multi-center, open-label, pilot study.
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Matteson EL, Choi HK, Poe DS, Wise C, Lowe VJ, McDonald TJ, and Rahman MU
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- 2005
9. Fluorodeoxyglucose positron emission tomography in the evaluation of tumors of the nasopharynx, paranasal sinuses, and nasal cavity.
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Stack BC Jr., Lowe VJ, and Lane RV
- Abstract
Introduction: The purpose of this study was to review the clinical utility of 2- [18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the diagnostic evaluation of a series of patients with tumors of the nasopharynx, paranasal sinuses, and nasal cavity. Methods: The study group included 16 patients from a single institution who underwent a total of 31 FDG-PET scans for the evaluation of various histologic types of masses of the nasopharynx, nasal cavity, and paranasal sinuses for diagnosis and or surveillance. A review of the patients' medical records was performed in order to obtain all data including tumor type and location, PET scan results, CT and MRI results, treatments performed, tumor recurrence, and clinical outcome. This data was analyzed to determine the utility of FDGPET in the identification of primary tumors and/or recurrent disease. Results: FDG-PET identified 100% of all primary tumors examined with initial diagnostic intent (n=8). In addition, 1 case of lymphoid hyperplasia was correctly identified as nonmalignant. Of 22 PET scans performed for tumor surveillance, 16 scans identified recurrent disease and 5 scans were correctly interpreted as negative. One scan showed an area of increased metabolism at the base of tongue suspicious for malignancy that later proved to be an inflammatory process (1 false positive). Conclusion: FDG-PET was an effective imaging modality in the evaluation of primary and recurrent tumors of the nasopharynx, paranasal sinuses, and nasal cavities in our series. As a functional scanning modality, FDG-PET is particularly useful in tumor surveillance where normal anatomy has been disrupted by prior surgery or radiation. Our series reaffirms the results of similar series with respect to the use of PET in these particular sub sites of the head and neck. [ABSTRACT FROM AUTHOR]
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- 2004
10. Clinical 18F-FDG oncology patient preparation techniques.
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Hamblen SM and Lowe VJ
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- 2003
11. 9:15—9:30: A Clinical Evaluation of Segmented Attenuation Correction
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Kemp, BJ, Hamblen, SM, and Lowe, VJ
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- 2000
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12. 9:15—9:30
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Kemp, BJ, Hamblen, SM, and Lowe, VJ
- Abstract
Segmented attenuation correction (SAC) has been introduced as a method of reducing transmission scan times without degrading the quality of PET images. Presented are the results of a clinical evaluation of a SAC algorithm implemented on the GE Advance PET system. FDG whole body patient emission scans of eight minute duration were acquired. Dynamic transmission (Tx) scans of 5 frames and 6 minute total duration were acquired and rebinned into Tx scans of 2, 3, 4, 5 and 6 minute duration. Images (I) were generated using iterative reconstruction with measured attenuation correction (MAC) or SAC for all Tx scans—denoted as I(Tx6MAC), I(Tx6SAC), etc. Anthropomorphic phantom data was also acquired and reconstructed using the same methodology. Images were evaluated quantitatively using the normalized mean square error (NMSE) of different regions and the variance and bias of liver activity. I(Tx6MAC) served as the reference. A blinded observer ranked image quality. The NMSE increased as the Tx duration decreased; for patient images the NMSE was typically 20% and 40% greater for I(Tx3SAC) and I(Tx2SAC) than I(Tx6SAC) respectively. The NMSE of the MAC images increased much more rapidly as the Tx duration decreased. Similar trends were found for the variance in the liver. Bias in liver activity of the SAC images was approximately −8% for large patients. The observer consistently preferred SAC images over MAC images. SAC images demonstrated improved boundary delineation and reduced noise in areas of homogeneous high activity background. Areas of discordance were projected into areas of large difference between Tx and segmented Tx sinograms. This study has validated the use of SAC with short Tx scans. Images reconstructed with Tx scans of 3 minutes were not compromised with noise or severe artifacts.
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- 2000
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13. 18F-FDG PET and PET/CT in Burkitt's lymphoma.
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Karantanis D, Durski JM, Lowe VJ, Nathan MA, Mullan BP, Georgiou E, Johnston PB, and Wiseman GA
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- 2010
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14. Amyloid-β deposition and regional grey matter atrophy rates in dementia with Lewy bodies
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Matthew L. Senjem, Lidia Sarro, David S. Knopman, Bradley F. Boeve, Massimo Filippi, Giancarlo Comi, Clifford R. Jack, Ronald C. Petersen, Jonathan Graff-Radford, Scott A. Przybelski, Timothy G. Lesnick, Kejal Kantarci, Emily S. Lundt, Val J. Lowe, Tanis J. Ferman, Sarro, L, Senjem, Ml, Lundt, E, Przybelski, Sa, Lesnick, Tg, Graff-Radford, J, Boeve, Bf, Lowe, Vj, Ferman, Tj, Knopman, D, Comi, G, Filippi, M, Petersen, Rc, Jack CR, Jr, and Kantarci, K
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Lewy Body Disease ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Clinical Dementia Rating ,Grey matter ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Positron Emission Tomography Computed Tomography ,mental disorders ,medicine ,Humans ,Gray Matter ,Aged ,Amyloid beta-Peptides ,medicine.diagnostic_test ,Dementia with Lewy bodies ,Neurodegeneration ,Magnetic resonance imaging ,Original Articles ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,medicine.anatomical_structure ,Positron emission tomography ,Female ,Neurology (clinical) ,Occipital lobe ,Psychology ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
Alzheimer's disease pathology frequently coexists with Lewy body disease at autopsy in patients with probable dementia with Lewy bodies. More than half of patients with probable dementia with Lewy bodies have high amyloid-β deposition as measured with 11C-Pittsburgh compound B binding on positron emission tomography. Biomarkers of amyloid-β deposition precede neurodegeneration on magnetic resonance imaging during the progression of Alzheimer's disease, but little is known about how amyloid-β deposition relates to longitudinal progression of atrophy in patients with probable dementia with Lewy bodies. We investigated the associations between baseline 11C-Pittsburgh compound B binding on positron emission tomography and the longitudinal rates of grey matter atrophy in a cohort of clinically diagnosed patients with dementia with Lewy bodies (n = 20), who were consecutively recruited to the Mayo Clinic Alzheimer's Disease Research Centre. All patients underwent 11C-Pittsburgh compound B positron emission tomography and magnetic resonance imaging examinations at baseline. Follow-up magnetic resonance imaging was performed after a mean (standard deviation) interval of 2.5 (1.1) years. Regional grey matter loss was determined on three-dimensional T1-weighted magnetic resonance imaging with the tensor-based morphometry-symmetric normalization technique. Linear regression was performed between baseline 11C-Pittsburgh compound B standard unit value ratio and longitudinal change in regional grey matter volumes from an in-house modified atlas. We identified significant associations between greater baseline 11C-Pittsburgh compound B standard unit value ratio and greater grey matter loss over time in the posterior cingulate gyrus, lateral and medial temporal lobe, and occipital lobe as well as caudate and putamen nuclei, after adjusting for age (P < 0.05). Greater baseline 11C-Pittsburgh compound B standard unit value ratio was also associated with greater ventricular expansion rates (P < 0.01) and greater worsening over time in Clinical Dementia Rating Scale, sum of boxes (P = 0.02). In conclusion, in patients with probable dementia with Lewy bodies, higher amyloid-β deposition at baseline is predictive of faster neurodegeneration in the cortex and also in the striatum. This distribution is suggestive of possible interactions among amyloid-β, tau and α-synuclein aggregates, which needs further investigation. Furthermore, higher amyloid-β deposition at baseline predicts a faster clinical decline over time in patients with probable dementia with Lewy bodies.
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- 2016
15. Advancing Tau PET Quantification in Alzheimer Disease with Machine Learning: Introducing THETA, a Novel Tau Summary Measure.
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Gebre RK, Rial AM, Raghavan S, Wiste HJ, Heeman F, Costoya-Sánchez A, Schwarz CG, Spychalla AJ, Lowe VJ, Graff-Radford J, Knopman DS, Petersen RC, Schöll M, Murray ME, Jack CR Jr, and Vemuri P
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- Humans, Female, Male, Aged, Image Processing, Computer-Assisted, Aged, 80 and over, Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Positron-Emission Tomography, Machine Learning, tau Proteins metabolism
- Abstract
Alzheimer disease (AD) exhibits spatially heterogeneous 3- or 4-repeat tau deposition across participants. Our overall goal was to develop an automated method to quantify the heterogeneous burden of tau deposition into a single number that would be clinically useful. Methods: We used tau PET scans from 3 independent cohorts: the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center (Mayo, n = 1,290), the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 831), and the Open Access Series of Imaging Studies (OASIS-3, n = 430). A machine learning binary classification model was trained on Mayo data and validated on ADNI and OASIS-3 with the goal of predicting visual tau positivity (as determined by 3 raters following Food and Drug Administration criteria for
18 F-flortaucipir). The machine learning model used region-specific SUV ratios scaled to cerebellar crus uptake. We estimated feature contributions based on an artificial intelligence-explainable method (Shapley additive explanations) and formulated a global tau summary measure, Tau Heterogeneity Evaluation in Alzheimer's Disease (THETA) score, using SUV ratios and Shapley additive explanations for each participant. We compared the performance of THETA with that of commonly used meta-regions of interest (ROIs) using the Mini-Mental State Examination, the Clinical Dementia Rating-Sum of Boxes, clinical diagnosis, and histopathologic staging. Results: The model achieved a balanced accuracy of 95% on the Mayo test set and at least 87% on the validation sets. It classified tau-positive and -negative participants with an AUC of 1.00, 0.96, and 0.94 on the Mayo, ADNI, and OASIS-3 cohorts, respectively. Across all cohorts, THETA showed a better correlation with the Mini-Mental State Examination and the Clinical Dementia Rating-Sum of Boxes (ρ ≥ 0.45, P < 0.05) than did meta-ROIs (ρ < 0.44, P < 0.05) and discriminated between participants who were cognitively unimpaired and those who had mild cognitive impairment with an effect size of 10.09, compared with an effect size of 3.08 for meta-ROIs. Conclusion: Our proposed approach identifies positive tau PET scans and provides a quantitative summary measure, THETA, that effectively captures heterogeneous tau deposition observed in AD. The application of THETA for quantifying tau PET in AD exhibits great potential., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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16. Patterns of glucose hypometabolism can help differentiate FTLD-FET from other types of FTLD.
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Garcia-Guaqueta DP, Ghayal NB, Lowe VJ, Dickson DW, Whitwell JL, and Josephs KA
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- Humans, Female, Male, Middle Aged, Retrospective Studies, Aged, Glucose metabolism, Diagnosis, Differential, Adult, Positron-Emission Tomography, Frontotemporal Lobar Degeneration diagnostic imaging, Frontotemporal Lobar Degeneration metabolism, Fluorodeoxyglucose F18
- Abstract
Introduction: FTLD-FET is a newly described subtype of frontotemporal lobar degeneration (FTLD characterized by pathologic inclusions of FET proteins: fused in sarcoma (FUS), Ewing sarcoma, and TATA-binding protein-associated factor 2N (TAF15)). Severe caudate volume loss on MRI has been linked to FTLD-FUS, yet glucose hypometabolism in FTLD-FET has not been studied. We assessed [
18 F] fluorodeoxyglucose PET (FDG-PET) hypometabolism in FTLD-FET subtypes and compared metabolism to FTLD-tau and FTLD-TDP., Methods: We retrospectively reviewed medical records of 26 autopsied FTLD patients (six FTLD-FET, ten FTLD-Tau, and ten FTLD-TDP) who had completed antemortem FDG-PET. We evaluated five regions, caudate nucleus, medial frontal cortex, lateral frontal cortex, and medial temporal using a 0-3 visual rating scale and validated our findings quantitatively using CORTEX-ID suite Z scores., Results: Of the six FTLD-FET cases (three females) with median age at onset = 36, three were atypical FTLD-U (aFTLD-U) and three were neuronal intermediate filament inclusion disease (NIFID). bvFTD was the most common presentation. Four of the six FTLD cases (3 aFTLD-U + 1 NIFID) showed prominent caudate hypometabolism relatively early in the disease course. FTLD-tau and FTLD-TDP did not show early prominent caudate hypometabolism. Hypometabolism in medial and lateral temporal cortex was associated with FTLD-TDP, while FTLD-tau had normal-minimal regional metabolism., Discussion: Prominent caudate hypometabolism, especially early in the disease course, appears to be a hallmark feature of the aFTLD-U subtype of FTLD-FET. Assessing caudate and temporal hypometabolism on FDG-PET will help to differentiate FTLD-FET from FTLD-tau and FTLD-TDP., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2024
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17. Cancer in Patients With Incidental Asymmetric Oropharynx Positron Emission Tomography Uptake.
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Armstrong MF, Burkett BJ, O'Byrne TJ, Gottlich HC, Yin LX, Tasche KK, Price DL, Moore EJ, Routman DM, Gamez M, Lester SC, Neben-Wittich MA, Ma DJ, Price KA, Lowe VJ, and Van Abel KM
- Abstract
Importance: Asymmetric oropharynx uptake on positron emission tomography (PET)/computed tomography (CT) is a common incidental finding and often prompts otolaryngology referral to rule out malignancy; however, the true risk of malignancy based on this finding is unknown., Objective: To identify the incidence of oropharynx cancer in patients with incidental asymmetric oropharynx PET uptake., Design, Setting, and Participants: In this retrospective cohort study, patients 18 years and older undergoing PET/CT scans at Mayo Clinic between January 2001 and December 2018 were included. Patients with a history or pretest suspicion of oropharynx cancer were excluded. Data were analyzed from March 2021 to December 2023., Exposure: Blinded radiologic review of imaging studies, including measurement of maximum standardized uptake values (SUVmax) of the ipsilateral side of concern and contralateral side. Retrospective medical record review for associated clinical data., Main Outcomes and Measures: The primary study outcome was the incidence of oropharynx cancer diagnosis in patients with asymmetric oropharynx PET uptake. The primary outcome was formulated before data collection., Results: Of the 1854 patients identified with asymmetric oropharynx PET uptake, 327 (17.6%) met inclusion criteria. Of these, 173 (52.9%) were male, and the median (range) age was 65.0 (24.8-90.7) years. The mean (SD) follow-up interval was 52.1 (43.4) months. A total of 18 of 327 patients (5.5%) were newly diagnosed with oropharynx cancer. The most common diagnosis was squamous cell carcinoma (n = 9), followed by lymphoma (n = 8), and sarcoma (n = 1). Patients with an incidental diagnosis of oropharynx cancer had higher mean (SD) ipsilateral SUVmax (8.7 [3.7] vs 5.3 [1.9]) and SUVmax ratio (3.0 [1.6] vs 1.6 [0.6]) compared with patients with normal examination findings. SUVmax ratio and difference were found to be good discriminators of oropharynx cancer, with areas under the receiver operating characteristic curve of 86.3% (95% CI, 76.4-94.6) and 85.8% (95% CI, 74.8-94.6), respectively. Patients with a new diagnosis of oropharynx cancer were more likely to have a corresponding CT abnormality than those with normal examination findings (6 of 18 [33%] vs 24 of 295 [8.1%]). Patients with concerning lesions on oropharynx palpation by an otolaryngology health care professional were significantly more likely to be diagnosed with oropharynx cancer compared with patients with normal examination findings (odds ratio, 28.4; 95% CI, 6.6-145.8)., Conclusions and Relevance: In this cohort study, while incidental asymmetric oropharynx PET uptake was common, a new diagnosis of oropharynx cancer was not and potentially results in a large volume of unnecessary referrals and work-up. Using SUVmax ratio, SUVmax difference, and CT correlation may increase the benefit of referral. Patients with a palpable oropharynx lesion and asymmetric oropharynx PET uptake should undergo confirmatory biopsy.
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- 2024
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18. Quality of life following surgery for head and neck cancer: Evidence from ACRIN 6685.
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Hollenbeak CS, Duan F, Subramaniam RM, Taurone A, Sicks J, Lowe VJ, and Stack BC Jr
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- Humans, Male, Female, Middle Aged, Aged, Prospective Studies, Adult, Squamous Cell Carcinoma of Head and Neck surgery, Squamous Cell Carcinoma of Head and Neck psychology, Neoplasm Staging, Quality of Life, Neck Dissection, Head and Neck Neoplasms surgery, Head and Neck Neoplasms psychology
- Abstract
Background: This study examined the trajectory of health-related quality of life (HRQoL) for patients with clinical stage N0 HNSCC enrolled in ACRIN 6685 who underwent elective neck dissection(s)., Methods: HRQoL of 230 patients in the ACRIN 6685 trial was measured prospectively up to 2 years following surgery using the University of Washington Quality of Life instrument., Results: General Health Within the Last 7 Days did not differ significantly from baseline at any follow-up. General Health Relative to Before Cancer fell significantly by 5.8 points following surgery (p = 0.048), and then returned to 3.0 points above baseline at 1 year (p = 0.65). For Overall Quality of Life, HRQoL fell significantly by 4.3 points following surgery (p = 0.031) and then returned to levels not significantly different from baseline., Conclusions: Patients with stage N0 HNSCC experience significant declines in HRQoL immediately following surgery, including neck dissection, which recovers to near or better than baseline within 1-2 years., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)
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- 2024
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19. Comparing classic-onset corticobasal syndrome to speech/language-onset corticobasal syndrome.
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Garcia-Guaqueta DP, Stephens YC, Ali F, Utianski RL, Duffy JR, Clark HM, Thu Pham NT, Machulda MM, Lowe VJ, Dickson DW, Whitwell JL, and Josephs KA
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- Humans, Male, Female, Aged, Middle Aged, Retrospective Studies, Aged, 80 and over, Speech Disorders etiology, Speech Disorders pathology, Language Disorders etiology, Language Disorders pathology, Parkinsonian Disorders pathology, Parkinsonian Disorders diagnostic imaging, Parkinsonian Disorders complications, Corticobasal Degeneration pathology
- Abstract
Introduction: Patients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS., Methods: We conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy., Results: Median age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS., Conclusion: Classic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Keith A. Josephs reports financial support was provided by National Institute on Deafness and Other Communication Disorders. Jennifer L. Whitwell reports financial support was provided by National Institute on Deafness and Other Communication Disorders. If there are other authors, they 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 Elsevier Ltd. All rights reserved.)
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- 2024
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20. NODDI in gray matter is a sensitive marker of aging and early AD changes.
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Yu X, Przybelski SA, Reid RI, Lesnick TG, Raghavan S, Graff-Radford J, Lowe VJ, Kantarci K, Knopman DS, Petersen RC, Jack CR Jr, and Vemuri P
- Abstract
Introduction: Age-related and Alzheimer's disease (AD) dementia-related neurodegeneration impact brain health. While morphometric measures from T1-weighted scans are established biomarkers, they may be less sensitive to earlier changes. Neurite orientation dispersion and density imaging (NODDI), offering biologically meaningful interpretation of tissue microstructure, may be an advanced brain health biomarker., Methods: We contrasted regional gray matter NODDI and morphometric evaluations concerning their correlation with (1) age, (2) clinical diagnosis stage, and (3) tau pathology as assessed by AV1451 positron emission tomography., Results: Our study hypothesizes that NODDI measures are more sensitive to aging and early AD changes than morphometric measures. One NODDI output, free water fraction (FWF), showed higher sensitivity to age-related changes, generally better effect sizes in separating mild cognitively impaired from cognitively unimpaired participants, and stronger associations with regional tau deposition than morphometric measures., Discussion: These findings underscore NODDI's utility in capturing early neurodegenerative changes and enhancing our understanding of aging and AD., Highlights: Neurite orientation dispersion and density imaging can serve as an effective brain health biomarker for aging and early Alzheimer's disease (AD).Free water fraction has higher sensitivity to normal brain aging.Free water fraction has stronger associations with early AD and regional tau deposition., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2024
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21. Flortaucipir PET uncovers relationships between tau and amyloid-β in primary age-related tauopathy and Alzheimer's disease.
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Josephs KA, Tosakulwong N, Weigand SD, Graff-Radford J, Schwarz CG, Senjem ML, Machulda MM, Kantarci K, Knopman DS, Nguyen A, Reichard RR, Dickson DW, Petersen RC, Lowe VJ, Jack CR Jr, and Whitwell JL
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- Humans, Aged, Female, Male, Aged, 80 and over, Middle Aged, Brain metabolism, Brain diagnostic imaging, Brain pathology, Positron-Emission Tomography methods, Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Alzheimer Disease pathology, tau Proteins metabolism, Carbolines metabolism, Amyloid beta-Peptides metabolism, Tauopathies diagnostic imaging, Tauopathies metabolism, Tauopathies pathology
- Abstract
[
18 F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer's disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-β. It is also unclear whether flortaucipir can detect tau in definite primary age-related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [18 F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-β PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-β phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-β phase. Flortaucipir uptake linearly increased with the amyloid-β phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer's disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-β phase, and were useful for distinguishing different ADNC scores and PART.- Published
- 2024
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22. Optimizing cutpoints for clinical interpretation of brain amyloid status using plasma p-tau217 immunoassays.
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Figdore DJ, Griswold M, Bornhorst JA, Graff-Radford J, Ramanan VK, Vemuri P, Lowe VJ, Knopman DS, Jack CR Jr, Petersen RC, and Algeciras-Schimnich A
- Abstract
Introduction: We aimed to evaluate clinical interpretation cutpoints for two plasma phosphorylated tau (p-tau)217 assays (ALZpath and Lumipulse) as predictors of amyloid status for implementation in clinical practice., Methods: Clinical performance of plasma p-tau217 against amyloid positron emission tomography status was evaluated in participants with mild cognitive impairment or mild dementia (n = 427)., Results: Using a one-cutpoint approach (negative/positive), neither assay achieved ≥ 90% in both sensitivity and specificity. A two-cutpoint approach yielding 92% sensitivity and 96% specificity provided the desired balance of false positives and false negatives, while categorizing 20% and 39% of results as indeterminate for the Lumipulse and ALZpath assays, respectively., Discussion: This study provides a systematic framework for selection of assay-specific cutpoints for clinical use of plasma p-tau217 for determination of amyloid status. Our findings suggest that a two-cutpoint approach may have advantages in optimizing diagnostic accuracy while minimizing potential harm from false positive results., Highlights: Phosphorylated tau (p-tau)217 cutpoints for detection of amyloid pathology were established. A two-cutpoint approach exhibited the best performance for clinical laboratory use. p-tau217 assays differed in the percentage of results categorized as intermediate., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2024
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23. Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome.
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Corriveau-Lecavalier N, Botha H, Graff-Radford J, Switzer AR, Przybelski SA, Wiste HJ, Murray ME, Reichard RR, Dickson DW, Nguyen AT, Ramanan VK, McCarter SJ, Boeve BF, Machulda MM, Fields JA, Stricker NH, Nelson PT, Grothe MJ, Knopman DS, Lowe VJ, Petersen RC, Jack CR Jr, and Jones DT
- Abstract
Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials., Competing Interests: 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 and the NIH (NIA, NCI). D.S.K. serves on a Data Safety Monitoring Board for the DIAN study and for a tau therapeutic for Biogen but receives no personal compensation; is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California; has served as a consultant for Roche, Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation; and receives funding from the NIH. B.F.B. receives honorarium for SAB activities for the Tau Consortium, is an investigator in clinical trials sponsored by Alector, Biogen, Cognition Therapeutics, EIP Pharma and Transposon and receives funding from the NIH. C.R.J. has no commercial conflicts and receives research support from the NIH, the GHR Foundation and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. R.C.P. 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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24. Patterns of brain volume and metabolism predict clinical features in the progressive supranuclear palsy spectrum.
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Ali F, Clark H, Machulda M, Senjem ML, Lowe VJ, Jack CR Jr, Josephs KA, Whitwell J, and Botha H
- Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that presents with highly heterogenous clinical syndromes. We perform cross-sectional data-driven discovery of independent patterns of brain atrophy and hypometabolism across the entire PSP spectrum. We then use these patterns to predict specific clinical features and to assess their relationship to phenotypic heterogeneity. We included 111 patients with PSP (60 with Richardson syndrome and 51 with cortical and subcortical variant subtypes). Ninety-one were used as the training set and 20 as a test set. The presence and severity of granular clinical variables such as postural instability, parkinsonism, apraxia and supranuclear gaze palsy were noted. Domains of akinesia, ocular motor impairment, postural instability and cognitive dysfunction as defined by the Movement Disorders Society criteria for PSP were also recorded. Non-negative matrix factorization was used on cross-sectional MRI and fluorodeoxyglucose-positron emission tomography (FDG-PET) scans. Independent models for each as well as a combined model for MRI and FDG-PET were developed and used to predict the granular clinical variables. Both MRI and FDG-PET were better at predicting presence of a symptom than severity, suggesting identification of disease state may be more robust than disease stage. FDG-PET predicted predominantly cortical abnormalities better than MRI such as ideomotor apraxia, apraxia of speech and frontal dysexecutive syndrome. MRI demonstrated prediction of cortical and more so sub-cortical abnormalities, such as parkinsonism. Distinct neuroanatomical foci were predictive in MRI- and FDG-PET-based models. For example, vertical gaze palsy was predicted by midbrain atrophy on MRI, but frontal eye field hypometabolism on FDG-PET. Findings also differed by scale or instrument used. For example, prediction of ocular motor abnormalities using the PSP Saccadic Impairment Scale was stronger than with the Movement Disorders Society Diagnostic criteria for PSP oculomotor impairment designation. Combination of MRI and FDG-PET demonstrated enhanced detection of parkinsonism and frontal syndrome presence and apraxia, cognitive impairment and bradykinesia severity. Both MRI and FDG-PET patterns were able to predict some measures in the test set; however, prediction of global cognition measured by Montreal Cognitive Assessment was the strongest. MRI predictions generalized more robustly to the test set. PSP leads to neurodegeneration in motor, cognitive and ocular motor networks at cortical and subcortical foci, leading to diverse yet overlapping clinical syndromes. To advance understanding of phenotypic heterogeneity in PSP, it is essential to consider data-driven approaches to clinical neuroimaging analyses., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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25. Synthesis and preliminary evaluation of novel PET probes for GSK-3 imaging.
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Gundam SR, Bansal A, Kethamreddy M, Ghatamaneni S, Lowe VJ, Murray ME, and Pandey MK
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- Animals, Humans, Mice, Radiopharmaceuticals chemistry, Radiopharmaceuticals chemical synthesis, Blood-Brain Barrier metabolism, Blood-Brain Barrier diagnostic imaging, Tissue Distribution, Positron-Emission Tomography methods, Fluorine Radioisotopes chemistry, Brain diagnostic imaging, Brain metabolism, Glycogen Synthase Kinase 3 metabolism
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Non-invasive imaging of GSK-3 expression in the brain will help to understand the role of GSK-3 in disease pathology and progression. Herein, we report the radiosynthesis and evaluation of two novel isonicotinamide based
18 F labeled PET probes, [18 F]2 and [18 F]6 for noninvasive imaging of GSK3. Among the developed PET probes, the in vitro blood-brain permeability coefficient of 2 (38 ± 20 × 10-6 cm/s, n = 3) was found to be better than 6 (8.75 ± 3.90 × 10-6 cm/s, n = 5). The reference compounds 2 and 6 showed nanomolar affinity towards GSK-3α and GSK-3β. PET probe [18 F]2 showed higher stability (100%) in mouse and human serums compared to [18 F]6 (67.01 ± 4.93%, n = 3) in mouse serum and 66.20 ± 6.38%, n = 3) in human serum at 120 min post incubation. The in vivo imaging and blocking studies were performed in wild-type mice only with [18 F]2 due to its observed stability. [18 F]2 showed a SUV of 0.92 ± 0.28 (n = 6) in mice brain as early as 5 min post-injection followed by gradual clearance over time., (© 2024. The Author(s).)- Published
- 2024
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26. Can white matter hyperintensities based Fazekas visual assessment scales inform about Alzheimer's disease pathology in the population?
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Pradeep A, Raghavan S, Przybelski SA, Preboske GM, Schwarz CG, Lowe VJ, Knopman DS, Petersen RC, Jack CR Jr, Graff-Radford J, Cogswell PM, and Vemuri P
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- Humans, Female, Male, Aged, Aged, 80 and over, Reproducibility of Results, Middle Aged, tau Proteins metabolism, Brain diagnostic imaging, Brain pathology, Alzheimer Disease diagnostic imaging, Alzheimer Disease pathology, White Matter diagnostic imaging, White Matter pathology, Magnetic Resonance Imaging methods, Positron-Emission Tomography
- Abstract
Background: White matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer's disease (AD) pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, AD imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging., Methods: We identified 1144 participants from the Mayo Clinic Study of Aging consisting of a population-based sample from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET, and tau-PET standardized uptake value ratio, automated WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC)., Results: Periventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p < 0.001). Both periventricular WMH and deep WMH showed weak associations with amyloidosis (R = 0.07, p = < 0.001), and none with tau burden. We found substantial agreement between data from the two scanners for Fazekas measurements (ICC = 0.82 and 0.74). The automated WMH volume had high discriminating power for identifying participants with Fazekas ≥ 2 (area under curve = 0.97) and showed poor correlation with amyloid and tau PET markers similar to the visual grading., Conclusion: Our study investigated risk factors underlying WMH spatial patterns and their impact on global cognition, with no discernible differences between periventricular and deep WMH. We observed minimal impact of amyloidosis on WMH severity. These findings, coupled with enhanced inter-scanner reproducibility of WMH data, suggest the combinability of inter-scanner data assessed by harmonized protocols in the context of vascular contributions to cognitive impairment and dementia biomarker research., (© 2024. The Author(s).)
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- 2024
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27. Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.
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Song C, Jung D, Kendi AT, Rho JK, Kim EJ, Horn I, Curran GL, Ghattamaneni S, Shim JY, Kang PS, Kang D, Thakkar JB, Dewan S, Lowe VJ, and Lee SB
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- Humans, Female, Gene Expression Regulation, Neoplastic drug effects, Cell Line, Tumor, Receptors, Estrogen metabolism, Receptors, Estrogen genetics, Neoplasm Invasiveness, MCF-7 Cells, Receptors, Progesterone metabolism, Receptors, Progesterone genetics, Hepatocyte Nuclear Factor 3-alpha metabolism, Hepatocyte Nuclear Factor 3-alpha genetics, Metformin pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Breast Neoplasms genetics, Cell Proliferation drug effects
- Abstract
Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 ( FOXA1 ), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1 , MTA3 , PAK4 , FGFR3 , and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.
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- 2024
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28. Speech-language within and between network disruptions in primary progressive aphasia variants.
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Singh-Reilly N, Botha H, Duffy JR, Clark HM, Utianski RL, Machulda MM, Graff-Radford J, Schwarz CG, Petersen RC, Lowe VJ, Jack CR Jr, Josephs KA, and Whitwell JL
- Abstract
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.)
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- 2024
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29. Frontal hypometabolism in the diagnosis of progressive supranuclear palsy clinical variants.
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Black JA, Pham NTT, Ali F, Machulda MM, Lowe VJ, Josephs KA, and Whitwell JL
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- Humans, Female, Male, Aged, Middle Aged, Fluorodeoxyglucose F18, Severity of Illness Index, Aged, 80 and over, Supranuclear Palsy, Progressive diagnostic imaging, Supranuclear Palsy, Progressive metabolism, Frontal Lobe diagnostic imaging, Frontal Lobe metabolism, Positron-Emission Tomography
- Abstract
Objective: Frontal hypometabolism on FDG-PET is observed in progressive supranuclear palsy (PSP), although it is unclear whether it is a feature of all PSP clinical variants and hence whether it is a useful diagnostic feature. We aimed to compare the frequency, severity, and pattern of frontal hypometabolism across PSP variants and determine whether frontal hypometabolism is related to clinical dysfunction., Methods: Frontal hypometabolism in prefrontal, premotor, and sensorimotor cortices was visually graded on a 0-3 scale using CortexID Z-score images in 137 PSP patients. Frontal asymmetry was recorded. Severity scores were used to categorize patients as premotor-predominant, prefrontal-predominant, sensorimotor-predominant, mixed-predominance, or no regional predominance. Frontal ratings were compared across PSP clinical variants, and Spearman correlations were used to assess relationships with the Frontal Assessment Battery (FAB)., Results: 97% showed evidence of frontal hypometabolism which was most common (100%) in the speech-language (PSP-SL), corticobasal (PSP-CBS), and frontal (PSP-F) variants and least common in the progressive gait freezing (PSP-PGF) variant (73%). PSP-SL and PSP-CBS showed more severe hypometabolism than Richardson's syndrome (PSP-RS), Parkinsonism (PSP-P), and PSP-PGF. A premotor-predominant pattern was most common in PSP-SL and PSP-CBS, with more mixed patterns in the other variants. Hypometabolism was most commonly asymmetric in PSP-SL, PSP-P, PSP-F and PSP-CBS. Worse hypometabolism in nearly all frontal regions correlated with worse scores on the FAB., Conclusions: Frontal hypometabolism is a common finding in PSP, although it varies in severity and pattern across PSP variants and will likely be the most diagnostically useful in PSP-SL and PSP-CBS., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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30. Relationships between PET and blood plasma biomarkers in corticobasal syndrome.
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Singh NA, Alnobani A, Graff-Radford J, Machulda MM, Mielke MM, Schwarz CG, Senjem ML, Jack CR Jr, Lowe VJ, Kanekiyo T, Josephs KA, and Whitwell JL
- Subjects
- Humans, Female, Male, Aged, Middle Aged, Alzheimer Disease blood, Alzheimer Disease diagnostic imaging, Corticobasal Degeneration diagnostic imaging, Corticobasal Degeneration blood, Cohort Studies, Positron-Emission Tomography, Biomarkers blood, tau Proteins blood, Amyloid beta-Peptides blood, Neurofilament Proteins blood, Glial Fibrillary Acidic Protein blood
- Abstract
Introduction: Corticobasal syndrome (CBS) can result from underlying Alzheimer's disease (AD) pathologies. Little is known about the utility of blood plasma metrics to predict positron emission tomography (PET) biomarker-confirmed AD in CBS., Methods: A cohort of eighteen CBS patients (8 amyloid beta [Aβ]+; 10 Aβ-) and 8 cognitively unimpaired (CU) individuals underwent PET imaging and plasma analysis. Plasma concentrations were compared using a Kruskal-Wallis test. Spearman correlations assessed relationships between plasma concentrations and PET uptake., Results: CBS Aβ+ group showed a reduced Aβ42/40 ratio, with elevated phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentrations, while CBS Aβ- group only showed elevated NfL concentration compared to CU. Both p-tau181 and GFAP were able to differentiate CBS Aβ- from CBS Aβ+ and showed positive associations with Aβ and tau PET uptake., Discussion: This study supports use of plasma p-tau181 and GFAP to detect AD in CBS. NfL shows potential as a non-specific disease biomarker of CBS regardless of underlying pathology., Highlights: Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) concentrations differentiate corticobasal syndrome (CBS) amyloid beta (Aβ)- from CBS Aβ+. Plasma neurofilament light concentrations are elevated in CBS Aβ- and Aβ+ compared to controls. Plasma p-tau181 and GFAP concentrations were associated with Aβ and tau positron emission tomography (PET) uptake. Aβ42/40 ratio showed a negative correlation with Aβ PET uptake., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2024
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31. A multimodal clinical diagnostic approach using MRI and 18 F-FDG-PET for antemortem diagnosis of TDP-43 in cases with low-intermediate Alzheimer's disease neuropathologic changes and primary age-related tauopathy.
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Lavrova A, Pham NTT, Vernon CJ, Carlos AF, Petersen RC, Dickson DW, Lowe VJ, Jack CR Jr, Whitwell JL, and Josephs KA
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- Humans, Female, Male, Aged, Cross-Sectional Studies, Aged, 80 and over, Multimodal Imaging, Brain diagnostic imaging, Brain pathology, Brain metabolism, Middle Aged, TDP-43 Proteinopathies diagnostic imaging, TDP-43 Proteinopathies pathology, Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Alzheimer Disease pathology, Positron-Emission Tomography methods, Fluorodeoxyglucose F18, Tauopathies diagnostic imaging, Tauopathies metabolism, Tauopathies pathology, Magnetic Resonance Imaging, DNA-Binding Proteins metabolism
- Abstract
Objective: To evaluate the utility of clinical assessment scales for MRI and
18 F-FDG-PET as potential in vivo predictive diagnostic tools for TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy in cases with low-intermediate Alzheimer's disease neuropathologic changes (ADNC) and primary age-related tauopathy (PART)., Methods: We conducted a cross-sectional analysis on patients with antemortem MRI and18 F-FDG-PET scans and postmortem diagnosis of low-intermediate ADNC or PART (Braak stage ≤ III; Thal β-amyloid phase 0-5). We employed visual imaging scales to grade structural changes on MRI and metabolic changes on18 F-FDG-PET and statistically compared demographic and clinicopathological characteristics between TDP-43 positive and negative cases. Independent regression analyses were performed to assess further influences of pathological characteristics on imaging outcomes. Within-reader repeatability and inter-reader reliability were calculated (CI = 0.95). Additional quantitative region-of-interest analyses of MRI gray matter volumes and PET ligand uptake were performed., Results: Of the 64 cases in the study, 20 (31%) were TDP-43 ( +), of which 12 (60%) were female. TDP-43 ( +) cases were more likely to have hippocampal sclerosis (HS) (p = 0.014) and moderate-severe medial temporal lobe atrophy on MRI (p = 0.048). TDP-43( +) cases also showed a trend for less parietal atrophy on MRI (p = 0.086) and more medial temporal lobe hypometabolism on18 F-FDG-PET (p = 0.087) than TDP-43( - ) cases. Regression analysis showed an association between medial temporal hypometabolism and HS (p = 0.0113). ICC values for MRI and PET within one reader were 0.75 and 0.91; across two readers were 0.79 and 0.82. The region-of-interest-based analysis confirmed a significant difference between TDP-43( +) and TDP-43( - ) cases for medial temporal lobe gray matter volume on MRI (p = 0.014) and medial temporal metabolism on PET (p = 0.011)., Conclusion: Visual inspection of the medial temporal lobe on MRI and FDG-PET may help to predict TDP-43 status in the context of low-intermediate ADNC and PART., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)- Published
- 2024
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32. Patterns of Early Neocortical Amyloid-β Accumulation: A PET Population-Based Study.
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Lecy EE, Min HK, Apgar CJ, Maltais DD, Lundt ES, Albertson SM, Senjem ML, Schwarz CG, Botha H, Graff-Radford J, Jones DT, Vemuri P, Kantarci K, Knopman DS, Petersen RC, Jack CR Jr, Lee J, and Lowe VJ
- Subjects
- Humans, Male, Female, Aged, Aniline Compounds, Middle Aged, Aged, 80 and over, Cross-Sectional Studies, Longitudinal Studies, Radiopharmaceuticals, Positron-Emission Tomography, Neocortex diagnostic imaging, Neocortex metabolism, Amyloid beta-Peptides metabolism, Alzheimer Disease diagnostic imaging, Alzheimer Disease metabolism, Thiazoles
- Abstract
The widespread deposition of amyloid-β (Aβ) plaques in late-stage Alzheimer disease is well defined and confirmed by in vivo PET. However, there are discrepancies between which regions contribute to the earliest topographic Aβ deposition within the neocortex. Methods: This study investigated Aβ signals in the perithreshold SUV ratio range using Pittsburgh compound B (PiB) PET in a population-based study cross-sectionally and longitudinally. PiB PET scans from 1,088 participants determined the early patterns of PiB loading in the neocortex. Results: Early-stage Aβ loading is seen first in the temporal, cingulate, and occipital regions. Regional early deposition patterns are similar in both apolipoprotein ε4 carriers and noncarriers. Clustering analysis shows groups with different patterns of early amyloid deposition. Conclusion: These findings of initial Aβ deposition patterns may be of significance for diagnostics and understanding the development of Alzheimer disease phenotypes., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)
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- 2024
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33. Complex relationships of socioeconomic status with vascular and Alzheimer's pathways on cognition.
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Shir D, Graff-Radford J, Fought AJ, Lesnick TG, Przybelski SA, Vassilaki M, Lowe VJ, Knopman DS, Machulda MM, Petersen RC, Jack CR Jr, Mielke MM, and Vemuri P
- Abstract
Introduction: AD and CVD, which frequently co-occur, are leading causes of age-related cognitive decline. We assessed how demographic factors, socioeconomic status (SES) as indicated by education and occupation, vascular risk factors, and a range of biomarkers associated with both CVD (including white matter hyperintensities [WMH], diffusion MRI abnormalities, infarctions, and microbleeds) and AD (comprising amyloid-PET and tau-PET) collectively influence cognitive function., Methods: In this cross-sectional population study, structural equation models were utilized to understand these associations in 449 participants (mean age (SD) = 74.5 (8.4) years; 56% male; 7.5% cognitively impaired)., Results: (1) Higher SES had a protective effect on cognition with mediation through the vascular pathway. (2) The effect of amyloid directly on cognition and through tau was 11-fold larger than the indirect effect of amyloid on cognition through WMH. (3) There is a significant effect of vascular risk on tau deposition., Discussion: The utilized biomarkers captured the impact of CVD and AD on cognition. The overall effect of vascular risk and SES on these biomarkers are complex and need further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.M. Mielke served as a consultant to Brain Protection Company, Biogen, and LabCorp and receives research support from the National Institutes of Health and the Department of Defense. She is a Senior Associate Editor forAlzheimer's and Dementia: The Journal of the Alzheimer's Association. Dr. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study. He served on a Data Safety monitoring Board for a tau therapeutic for Biogen (until 2021) but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie and Alzeca Biosciences but receives no personal compensation. He attended an Eisai advisory board meeting for Lecanemab on December 2, 2022 but received no compensation directly or indirectly. He receives funding from the NIH. Maria Vassilaki has received research funding from F. Hoffmann-La Roche Ltd and Biogen in the past and consulted for F. Hoffmann-La Roche Ltd; she currently receives research funding from NIH and have equity ownership in Johnson and Johnson, Merck, Medtronic, and Amgen. P. Vemuri received speaking fees from Miller Medical Communications, LLC, and receives research support from the National Institutes of Health. J. Graff-Radford receives NIH funding and serves on the data and safety monitoring board board for Neurology. He has received payment for speaking at the American Academy of Neurology Annual meeting. C.R. Jack serves on an independent data monitoring board for Roche, but he receives no personal compensation from any commercial entity. He receives research support from the National Institutes of Health, the GHR Foundation and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. R.C. Petersen is a consultant for Roche, Inc., Eli Lilly and Co. Nestle, Inc. and Eisai, Inc. He receives royalties from Oxford University Press and UpToDate and receives research support from the National Institutes of Health. V. J. Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, Life Molecular Imaging, Eisai Inc., AVID Radiopharmaceuticals, Elly Lilly and Company and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals and the NIH (NIA, NCI). D. Shir, T.G. Lesnick, S. Przybelski, A.J. Fought, and M.M. Machulda have no conflicts to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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34. Evaluation of Neurodegenerative Disorders with Amyloid-β, Tau, and Dopaminergic PET Imaging: Interpretation Pitfalls.
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Burkett BJ, Johnson DR, and Lowe VJ
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- Humans, Image Interpretation, Computer-Assisted methods, Brain diagnostic imaging, Brain metabolism, Positron-Emission Tomography methods, tau Proteins metabolism, Amyloid beta-Peptides metabolism, Neurodegenerative Diseases diagnostic imaging, Neurodegenerative Diseases metabolism, Dopamine metabolism
- Abstract
Antiamyloid therapies for Alzheimer disease recently entered clinical practice, making imaging biomarkers for Alzheimer disease even more relevant to guiding patient management. Amyloid and tau PET are valuable tools that can provide objective evidence of Alzheimer pathophysiology in living patients and will increasingly be used to complement
18 F-FDG PET in the diagnostic evaluation of cognitive impairment and dementia. Parkinsonian syndromes, also common causes of dementia, can likewise be evaluated with a PET imaging biomarker,18 F-DOPA, allowing in vivo assessment of the presynaptic dopaminergic neurons. Understanding the role of these PET biomarkers will help the nuclear medicine physician contribute to the appropriate diagnosis and management of patients with cognitive impairment and dementia. To successfully evaluate brain PET examinations for neurodegenerative diseases, knowledge of the necessary protocol details for obtaining a reliable imaging study, inherent limitations for each PET radiopharmaceutical, and pitfalls in image interpretation is critical. This review will focus on underlying concepts for interpreting PET examinations, important procedural details, and guidance for avoiding potential interpretive pitfalls for amyloid, tau, and dopaminergic PET examinations., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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35. Multimodal cross-examination of progressive apraxia of speech by diffusion tensor imaging-based tractography and Tau-PET scans.
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Gatto RG, Pham NTT, Duffy JR, Clark HM, Utianski RL, Botha H, Machulda MM, Lowe VJ, Schwarz CG, Jack CR Jr, Josephs KA, and Whitwell JL
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- Humans, Male, Female, Aged, Middle Aged, Apraxias diagnostic imaging, Apraxias pathology, White Matter diagnostic imaging, White Matter pathology, tau Proteins metabolism, Aphasia, Primary Progressive diagnostic imaging, Aphasia, Primary Progressive pathology, Brain diagnostic imaging, Brain pathology, Diffusion Tensor Imaging methods, Positron-Emission Tomography methods, Carbolines pharmacokinetics, Multimodal Imaging methods
- Abstract
Progressive apraxia of speech (PAOS) is a 4R tauopathy characterized by difficulties with motor speech planning. Neurodegeneration in PAOS targets the premotor cortex, particularly the supplementary motor area (SMA), with degeneration of white matter (WM) tracts connecting premotor and motor cortices and Broca's area observed on diffusion tensor imaging (DTI). We aimed to assess flortaucipir uptake across speech-language-related WM tracts identified using DTI tractography in PAOS. Twenty-two patients with PAOS and 26 matched healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent MRI and flortaucipir-PET. The patient population included patients with primary progressive apraxia of speech (PPAOS) and non-fluent variant/agrammatic primary progressive aphasia (agPPA). Flortaucipir PET scans and DTI were coregistered using rigid registration with a mutual information cost function in subject space. Alignments between DTI and flortaucipir PET were inspected in all cases. Whole-brain tractography was calculated using deterministic algorithms by a tractography reconstruction tool (DSI-studio) and specific tracts were identified using an automatic fiber tracking atlas-based method. Fractional anisotropy (FA) and flortaucipir standardized uptake value ratios (SUVRs) were averaged across the frontal aslant tract, arcuate fasciculi, inferior frontal-occipital fasciculus, inferior and middle longitudinal fasciculi, as well as the SMA commissural fibers. Reduced FA (p < .0001) and elevated flortaucipir SUVR (p = .0012) were observed in PAOS cases compared to controls across all combined WM tracts. For flortaucipir SUVR, the greatest differentiation of PAOS from controls was achieved with the SMA commissural fibers (area under the receiver operator characteristic curve [AUROC] = 0.83), followed by the left arcuate fasciculus (AUROC = 0.75) and left frontal aslant tract (AUROC = 0.71). Our findings demonstrate that flortaucipir uptake is increased across WM tracts related to speech/language difficulties in PAOS., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)
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- 2024
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36. Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.
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Kouri N, Frankenhauser I, Peng Z, Labuzan SA, Boon BDC, Moloney CM, Pottier C, Wickland DP, Caetano-Anolles K, Corriveau-Lecavalier N, Tranovich JF, Wood AC, Hinkle KM, Lincoln SJ, Spychalla AJ, Senjem ML, Przybelski SA, Engelberg-Cook E, Schwarz CG, Kwan RS, Lesser ER, Crook JE, Carter RE, Ross OA, Lachner C, Ertekin-Taner N, Ferman TJ, Fields JA, Machulda MM, Ramanan VK, Nguyen AT, Reichard RR, Jones DT, Graff-Radford J, Boeve BF, Knopman DS, Petersen RC, Jack CR Jr, Kantarci K, Day GS, Duara R, Graff-Radford NR, Dickson DW, Lowe VJ, Vemuri P, and Murray ME
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- Humans, Male, Female, Aged, Aged, 80 and over, Cross-Sectional Studies, Retrospective Studies, Neurofibrillary Tangles pathology, tau Proteins metabolism, Middle Aged, Neuroimaging, Cohort Studies, Brain diagnostic imaging, Brain pathology, Brain metabolism, Autopsy, Alzheimer Disease diagnostic imaging, Alzheimer Disease pathology, Alzheimer Disease metabolism, Neuroglia pathology, Neuroglia metabolism, Magnetic Resonance Imaging, Positron-Emission Tomography
- Abstract
Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement., Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy., Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses., Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET)., Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02)., Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.
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- 2024
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37. Atypical Alzheimer's disease: new insights into an overlapping spectrum between the language and visual variants.
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Singh NA, Graff-Radford J, Machulda MM, Carlos AF, Schwarz CG, Senjem ML, Jack CR Jr, Lowe VJ, Josephs KA, and Whitwell JL
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- Humans, Male, Female, Aged, Middle Aged, Vision Disorders etiology, Vision Disorders physiopathology, Aged, 80 and over, Brain diagnostic imaging, Brain pathology, tau Proteins, Alzheimer Disease diagnostic imaging, Alzheimer Disease diagnosis, Positron-Emission Tomography, Language Disorders etiology, Language Disorders physiopathology, Magnetic Resonance Imaging
- Abstract
Overlap between language and visual variants of atypical Alzheimer's disease (AD) has been reported. However, the extent, frequency of overlap, and its neuroanatomical underpinnings remain unclear. Eighty-two biomarker-confirmed AD patients who presented with either predominant language (n = 34) or visuospatial/perceptual (n = 48) deficits underwent detailed clinical examinations, MRI, and [
18 F]flortaucipir-PET. Subgroups were defined based on language/visual testing and patterns of volume loss and tau uptake were assessed. 28% of the language group had visual dysfunction (marked in 8%), and 47% of the visual group had language impairment (marked in 26%). Progressive involvement of the parieto-occipital and frontal lobes was noted with greater visual impairment in the language group, and greater left parieto-temporal and frontal involvement with worsening language impairment in the visual group. Only 25% of our cohort showed a pure language or visual presentation, highlighting the high frequency of syndromic overlap in atypical AD and the diagnostic challenge of categorical phenotyping., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)- Published
- 2024
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38. Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.
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Arnaldi D, Mattioli P, Raffa S, Pardini M, Massa F, Iranzo A, Perissinotti A, Niñerola-Baizán A, Gaig C, Serradell M, Muñoz-Lopetegi A, Mayà G, Liguori C, Fernandes M, Placidi F, Chiaravalloti A, Šonka K, Dušek P, Zogala D, Trnka J, Boeve BF, Miyagawa T, Lowe VJ, Miyamoto T, Miyamoto M, Puligheddu M, Figorilli M, Serra A, Hu MT, Klein JC, Bes F, Kunz D, Cochen De Cock V, de Verbizier D, Plazzi G, Antelmi E, Terzaghi M, Bossert I, Kulcsárová K, Martino A, Giuliani A, Pagani M, Nobili F, and Morbelli S
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- Humans, Male, Female, Aged, Middle Aged, Tomography, Emission-Computed, Single-Photon, Presynaptic Terminals metabolism, Dopaminergic Imaging, REM Sleep Behavior Disorder diagnostic imaging, Synucleinopathies diagnostic imaging, Lewy Body Disease diagnostic imaging, Parkinson Disease diagnostic imaging, Parkinson Disease complications, Machine Learning, Dopamine metabolism
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Objective: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB)., Methods: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion., Results: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters., Interpretation: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2024
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39. Author Response: Eligibility for Anti-Amyloid Treatment in a Population-Based Study of Cognitive Aging.
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Vassilaki M, Pittock RR, Aakre JA, Castillo AM, Ramanan VK, Kremers WK, Jack CR Jr, Vemuri P, Lowe VJ, Knopman DS, Petersen RC, and Graff-Radford J
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- Humans, Alzheimer Disease drug therapy, Amyloid beta-Peptides, Cognitive Aging
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- 2024
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40. Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood-Brain Barrier.
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Zhou AL, Swaminathan SK, Salian VS, Wang L, Curran GL, Min HK, Lowe VJ, and Kandimalla KK
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- Animals, Male, Mice, Alzheimer Disease metabolism, Brain metabolism, Iodine Radioisotopes, Mice, Inbred C57BL, Peptide Fragments metabolism, Receptor, IGF Type 1 metabolism, Receptor, Insulin metabolism, Single Photon Emission Computed Tomography Computed Tomography methods, Tyrphostins pharmacology, Amyloid beta-Peptides metabolism, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, Insulin metabolism, Signal Transduction
- Abstract
The blood-brain barrier (BBB) is instrumental in clearing toxic metabolites from the brain, such as amyloid-β (Aβ) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer's disease (AD) brain, increased Aβ levels are paralleled by decreased insulin levels, which are accompanied by insulin signaling deficits at the BBB. Thus, we investigated the impact of insulin-like growth factor and insulin receptor (IGF1R and IR) signaling on Aβ and insulin trafficking at the BBB. Following intravenous infusion of an IGF1R/IR kinase inhibitor (AG1024) in wild-type mice, the BBB trafficking of
125 I radiolabeled Aβ peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [125 I]iodo-Aβ42 decreased upon AG1024 treatment. Additionally, the brain influx of [125 I]iodoinsulin, [125 I]iodo-Aβ42, [125 I]iodo-Aβ40, and [125 I]iodo-BSA (BBB integrity marker) was decreased, increased, unchanged, and unchanged, respectively, upon AG1024 treatment. Subsequent mechanistic studies were performed using an in vitro BBB cell model. The cell uptake of [125 I]iodoinsulin, [125 I]iodo-Aβ42, and [125 I]iodo-Aβ40 was decreased, increased, and unchanged, respectively, upon AG1024 treatment. Further, AG1024 reduced the phosphorylation of insulin signaling kinases (Akt and Erk) and the membrane expression of Aβ and insulin trafficking receptors (LRP-1 and IR-β). These findings reveal that insulin signaling differentially regulates the BBB trafficking of Aβ peptides and insulin. Moreover, deficits in IGF1R and IR signaling, as observed in the brains of type II diabetes and AD patients, are expected to increase Aβ accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.- Published
- 2024
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41. Longitudinal flortaucipir, metabolism and volume differ between phonetic and prosodic speech apraxia.
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Tetzloff KA, Martin PR, Duffy JR, Utianski RL, Clark HM, Botha H, Machulda MM, Thu Pham NT, Schwarz CG, Senjem ML, Jack CR Jr, Lowe VJ, Josephs KA, and Whitwell JL
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- Humans, Male, Female, Aged, Middle Aged, Longitudinal Studies, Magnetic Resonance Imaging, Brain metabolism, Brain diagnostic imaging, Brain pathology, Atrophy pathology, Fluorodeoxyglucose F18, Phonetics, Aged, 80 and over, tau Proteins metabolism, Carbolines, Apraxias diagnostic imaging, Apraxias metabolism, Positron-Emission Tomography methods
- Abstract
Progressive apraxia of speech (PAOS) is a neurodegenerative motor-speech disorder that most commonly arises from a four-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech and the mixed subtype by a combination of both but lack of predominance of either. There is some evidence that cross-sectional patterns of neurodegeneration differ across subtypes, although it is unknown whether longitudinal patterns of neurodegeneration differ. We examined longitudinal patterns of atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose-PET and tau uptake on flortaucipir-PET in a large cohort of subjects with PAOS that had been followed for many years. Ninety-one subjects with PAOS (51 phonetic, 40 prosodic) were recruited by the Neurodegenerative Research Group. Of these, 54 (27 phonetic, 27 prosodic) returned for annual follow-up, with up to seven longitudinal visits (total visits analysed = 217). Volumes, metabolism and flortaucipir uptake were measured for subcortical and cortical regions, for all scans. Bayesian hierarchical models were used to model longitudinal change across imaging modalities with PAOS subtypes being compared at baseline, 4 years from baseline, and in terms of rates of change. The phonetic group showed smaller volumes and worse metabolism in Broca's area and the striatum at baseline and after 4 years, and faster rates of change in these regions, compared with the prosodic group. There was also evidence of faster spread of hypometabolism and flortaucipir uptake into the temporal and parietal lobes in the phonetic group. In contrast, the prosodic group showed smaller cerebellar dentate, midbrain, substantia nigra and thalamus volumes at baseline and after 4 years, as well as faster rates of atrophy, than the phonetic group. Greater hypometabolism and flortaucipir uptake were also observed in the cerebellar dentate and substantia nigra in the prosodic group. Mixed findings were observed in the supplementary motor area and precentral cortex, with no clear differences observed across phonetic and prosodic groups. These findings support different patterns of disease spread in PAOS subtypes, with corticostriatal patterns in the phonetic subtype and brainstem and thalamic patterns in the prosodic subtype, providing insight into the pathophysiology and heterogeneity of PAOS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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42. Plasma glial fibrillary acidic protein in the visual and language variants of Alzheimer's disease.
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Sintini I, Singh NA, Li D, Mielke MM, Machulda MM, Schwarz CG, Senjem ML, Jack CR Jr, Lowe VJ, Graff-Radford J, Josephs KA, and Whitwell JL
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- Humans, Female, Male, Aged, Cross-Sectional Studies, Aged, 80 and over, Language, Brain diagnostic imaging, Brain pathology, Alzheimer Disease blood, Glial Fibrillary Acidic Protein blood, Positron-Emission Tomography, Biomarkers blood, tau Proteins blood, Amyloid beta-Peptides blood
- Abstract
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.)
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- 2024
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43. Altered structural and functional connectivity in Posterior Cortical Atrophy and Dementia with Lewy bodies.
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Singh NA, Goodrich AW, Graff-Radford J, Machulda MM, Sintini I, Carlos AF, Robinson CG, Reid RI, Lowe VJ, Jack CR Jr, Petersen RC, Boeve BF, Josephs KA, Kantarci K, and Whitwell JL
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- Humans, Diffusion Tensor Imaging, Fluorodeoxyglucose F18, Magnetic Resonance Imaging, Atrophy, Lewy Body Disease diagnostic imaging, Alzheimer Disease metabolism
- Abstract
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.)- Published
- 2024
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44. Grey matter networks in women and men with dementia with Lewy bodies.
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Habich A, Oltra J, Schwarz CG, Przybelski SA, Oppedal K, Inguanzo A, Blanc F, Lemstra AW, Hort J, Westman E, Segura B, Junque C, Lowe VJ, Boeve BF, Aarsland D, Dierks T, Kantarci K, and Ferreira D
- Abstract
Sex differences permeate many aspects of dementia with Lewy bodies (DLB), yet sex differences in patterns of neurodegeneration in DLB remain largely unexplored. Here, we test whether grey matter networks differ between sexes in DLB and compare these findings to sex differences in healthy controls. In this cross-sectional study, we analysed clinical and neuroimaging data of patients with DLB and cognitively healthy controls matched for age and sex. Grey matter networks were constructed by pairwise correlations between 58 regional volumes after correction for age, intracranial volume, and centre. Network properties were compared between sexes and diagnostic groups. Additional analyses were conducted on w-scored data to identify DLB-specific sex differences. Data from 119 (68.7 ± 8.4 years) men and 45 women (69.9 ± 9.1 years) with DLB, and 164 healthy controls were included in this study. Networks of men had a lower nodal strength compared to women. In comparison to healthy women, the grey matter networks of healthy men showed a higher global efficiency, modularity, and fewer modules. None of the network measures showed significant sex differences in DLB. Comparing DLB patients with healthy controls revealed global differences in women and more local differences in men. Modular analyses showed a more distinct demarcation between cortical and subcortical regions in men compared with women. While topologies of grey matter networks differed between sexes in healthy controls, those sex differences were diluted in DLB patients. These findings suggest a disease-driven convergence of neurodegenerative patterns in women and men with DLB, which may inform precision medicine in DLB., (© 2024. The Author(s).)
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- 2024
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45. Uncovering the distinct macro-scale anatomy of dysexecutive and behavioural degenerative diseases.
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Corriveau-Lecavalier N, Barnard LR, Botha H, Graff-Radford J, Ramanan VK, Lee J, Dicks E, Rademakers R, Boeve BF, Machulda MM, Fields JA, Dickson DW, Graff-Radford N, Knopman DS, Lowe VJ, Petersen RC, Jack CR Jr, and Jones DT
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- Humans, Fluorodeoxyglucose F18, Executive Function, Cerebral Cortex pathology, Neuropsychological Tests, Alzheimer Disease pathology, Frontotemporal Dementia pathology
- Abstract
There is a longstanding ambiguity regarding the clinical diagnosis of dementia syndromes predominantly targeting executive functions versus behaviour and personality. This is due to an incomplete understanding of the macro-scale anatomy underlying these symptomatologies, a partial overlap in clinical features and the fact that both phenotypes can emerge from the same pathology and vice versa. We collected data from a patient cohort of which 52 had dysexecutive Alzheimer's disease, 30 had behavioural variant frontotemporal dementia (bvFTD), seven met clinical criteria for bvFTD but had Alzheimer's disease pathology (behavioural Alzheimer's disease) and 28 had amnestic Alzheimer's disease. We first assessed group-wise differences in clinical and cognitive features and patterns of fluorodeoxyglucose (FDG) PET hypometabolism. We then performed a spectral decomposition of covariance between FDG-PET images to yield latent patterns of relative hypometabolism unbiased by diagnostic classification, which are referred to as 'eigenbrains'. These eigenbrains were subsequently linked to clinical and cognitive data and meta-analytic topics from a large external database of neuroimaging studies reflecting a wide range of mental functions. Finally, we performed a data-driven exploratory linear discriminant analysis to perform eigenbrain-based multiclass diagnostic predictions. Dysexecutive Alzheimer's disease and bvFTD patients were the youngest at symptom onset, followed by behavioural Alzheimer's disease, then amnestic Alzheimer's disease. Dysexecutive Alzheimer's disease patients had worse cognitive performance on nearly all cognitive domains compared with other groups, except verbal fluency which was equally impaired in dysexecutive Alzheimer's disease and bvFTD. Hypometabolism was observed in heteromodal cortices in dysexecutive Alzheimer's disease, temporo-parietal areas in amnestic Alzheimer's disease and frontotemporal areas in bvFTD and behavioural Alzheimer's disease. The unbiased spectral decomposition analysis revealed that relative hypometabolism in heteromodal cortices was associated with worse dysexecutive symptomatology and a lower likelihood of presenting with behaviour/personality problems, whereas relative hypometabolism in frontotemporal areas was associated with a higher likelihood of presenting with behaviour/personality problems but did not correlate with most cognitive measures. The linear discriminant analysis yielded an accuracy of 82.1% in predicting diagnostic category and did not misclassify any dysexecutive Alzheimer's disease patient for behavioural Alzheimer's disease and vice versa. Our results strongly suggest a double dissociation in that distinct macro-scale underpinnings underlie predominant dysexecutive versus personality/behavioural symptomatology in dementia syndromes. This has important implications for the implementation of criteria to diagnose and distinguish these diseases and supports the use of data-driven techniques to inform the classification of neurodegenerative diseases., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2024
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46. Influences of amyloid-β and tau on white matter neurite alterations in dementia with Lewy bodies.
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Mak E, Reid RI, Przybelski SA, Lesnick TG, Schwarz CG, Senjem ML, Raghavan S, Vemuri P, Jack CR Jr, Min HK, Jain MK, Miyagawa T, Forsberg LK, Fields JA, Savica R, Graff-Radford J, Jones DT, Botha H, St Louis EK, Knopman DS, Ramanan VK, Dickson DW, Graff-Radford NR, Ferman TJ, Petersen RC, Lowe VJ, Boeve BF, O'Brien JT, and Kantarci K
- Abstract
Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer's disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB., (© 2024. The Author(s).)
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- 2024
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47. Plasma biomarkers of Alzheimer's disease in the continuum of dementia with Lewy bodies.
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Diaz-Galvan P, Przybelski SA, Algeciras-Schimnich A, Figdore DJ, Lesnick TG, Schwarz CG, Senjem ML, Gunter JL, Jack CR Jr, Min PH, Jain MK, Miyagawa T, Forsberg LK, Fields JA, Savica R, Graff-Radford J, Ramanan VK, Jones DT, Botha H, St Louis EK, Knopman DS, Graff-Radford NR, Ferman TJ, Petersen RC, Lowe VJ, Boeve BF, and Kantarci K
- Subjects
- Humans, Amyloid beta-Peptides, tau Proteins, Biomarkers metabolism, Alzheimer Disease diagnosis, Lewy Body Disease diagnosis, Cognitive Dysfunction diagnosis, REM Sleep Behavior Disorder
- Abstract
Introduction: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease., Methods: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans., Results: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB., Discussion: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2024
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48. Volumetric analysis of hippocampal subregions and subfields in left and right semantic dementia.
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Carlos AF, Weigand SD, Duffy JR, Clark HM, Utianski RL, Machulda MM, Botha H, Thu Pham NT, Lowe VJ, Schwarz CG, Whitwell JL, and Josephs KA
- Abstract
Two variants of semantic dementia are recognized based on the laterality of temporal lobe involvement: a left-predominant variant associated with verbal knowledge impairment and a right-predominant variant associated with behavioural changes and non-verbal knowledge loss. This cross-sectional clinicoradiologic study aimed to assess whole hippocampal, subregion, and/or subfield volume loss in semantic dementia versus controls and across its variants. Thirty-five semantic dementia participants and 15 controls from the Neurodegenerative Research Group at Mayo Clinic who had completed 3.0-T volumetric magnetic resonance imaging and
18 F-fluorodeoxyglucose-positron emission tomography were included. Classification as left-predominant ( n = 25) or right-predominant ( n = 10) variant was based on temporal lobe hypometabolism. Volumes of hippocampal subregions (head, body, and tail) and subfields (parasubiculum, presubiculum, subiculum, cornu ammonis 1, cornu ammonis 3, cornu ammonis 4, dentate gyrus, molecular layer, hippocampal-amygdaloid transition area, and fimbria) were obtained using FreeSurfer 7. Subfield volumes were measured separately from head and body subregions. We fit linear mixed-effects models using log-transformed whole hippocampal/subregion/subfield volumes as dependent variables; age, sex, total intracranial volume, hemisphere and a group-by-hemisphere interaction as fixed effects; and subregion/subfield nested within hemisphere as a random effect. Significant results ( P < 0.05) are hereby reported. At the whole hippocampal level, the dominant (predominantly involved) hemisphere of both variants showed 23-27% smaller volumes than controls. The non-dominant (less involved) hemisphere of the right-predominant variant also showed volume loss versus controls and the left-predominant variant. At the subregional level, both variants showed 17-28% smaller dominant hemisphere head, body, and tail than controls, with the right-predominant variant also showing 8-12% smaller non-dominant hemisphere head than controls and left-predominant variant. At the subfield level, the left-predominant variant showed 12-36% smaller volumes across all dominant hemisphere subfields and 14-15% smaller non-dominant hemisphere parasubiculum, presubiculum (head and body), subiculum (head) and hippocampal-amygdaloid transition area than controls. The right-predominant variant showed 16-49% smaller volumes across all dominant hemisphere subfields and 14-22% smaller parasubiculum, presubiculum, subiculum, cornu ammonis 3, hippocampal-amygdaloid transition area (all from the head) and fimbria of non-dominant hemisphere versus controls. Comparison of dominant hemispheres showed 16-29% smaller volumes of the parasubiculum, presubiculum (head) and fimbria in the right-predominant than left-predominant variant; comparison of non-dominant hemispheres showed 12-15% smaller cornu ammonis 3, cornu ammonis 4, dentate gyrus, hippocampal-amygdaloid transition area (all from the head) and cornu ammonis 1, cornu ammonis 3 and cornu ammonis 4 (all from the body) in the right-predominant variant. All hippocampal subregion/subfield volumes are affected in semantic dementia, although some are more affected in both dominant and non-dominant hemispheres of the right-predominant than the left-predominant variant by the time of presentation. Involvement of hippocampal structures is apparently more subregion dependent than subfield dependent, indicating possible superiority of subregion volumes as disease biomarkers., Competing Interests: A.F.C., S.D.W. and N.T.T.P. have nothing to disclose. J.R.D., H.M.C., R.L.U., M.M.M., H.B., V.J.L., C.G.S., J.L.W. and K.A.J. receive research support from the US NIH. K.A.J. is an Associate Editor for the Annals of Clinical and Translational Neurology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)- Published
- 2024
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49. Role of GBA variants in Lewy body disease neuropathology.
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Walton RL, Koga S, Beasley AI, White LJ, Griesacker T, Murray ME, Kasanuki K, Hou X, Fiesel FC, Springer W, Uitti RJ, Fields JA, Botha H, Ramanan VK, Kantarci K, Lowe VJ, Jack CR, Ertekin-Taner N, Savica R, Graff-Radford J, Petersen RC, Parisi JE, Reichard RR, Graff-Radford NR, Ferman TJ, Boeve BF, Wszolek ZK, Dickson DW, Ross OA, and Heckman MG
- Subjects
- Humans, Substantia Nigra pathology, Neurofibrillary Tangles pathology, Lewy Body Disease pathology, Parkinson Disease pathology, Alzheimer Disease pathology
- Abstract
Rare and common GBA variants are risk factors for both Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (β: -0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0-1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease-risk associations of GBA in PD, PD dementia, and DLB., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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50. Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals.
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Jack CR Jr, Wiste HJ, Algeciras-Schimnich A, Weigand SD, Figdore DJ, Lowe VJ, Vemuri P, Graff-Radford J, Ramanan VK, Knopman DS, Mielke MM, Machulda MM, Fields J, Schwarz CG, Cogswell PM, Senjem ML, Therneau TM, and Petersen RC
- Subjects
- Humans, Amyloid beta-Peptides metabolism, tau Proteins metabolism, Positron-Emission Tomography, Biomarkers, Memory Disorders diagnostic imaging, Alzheimer Disease, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction complications
- Abstract
Background: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals., Methods: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aβ)42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p-tau217. The outcome was a change in a memory composite measure., Results: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p-tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person-level prediction intervals were wide., Discussion: Plasma p-tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2024
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