Hope Center Member Publications

Tau accumulation in autosomal dominant Alzheimer’s disease: a longitudinal [18F]flortaucipir study
(2023) Alzheimer’s Research and Therapy, 15 (1), art. no. 99, . 

O’Connor, A.^a b , Cash, D.M.^a , Poole, T.^a c , Markiewicz, P.J.^d , Fraser, M.R.^a , Malone, I.B.^a , Jiao, J.^d , Weston, P.S.J.^a , Flores, S.^e , Hornbeck, R.^e , McDade, E.^f , Schöll, M.^a g , Gordon, B.A.^e , Bateman, R.J.^f , Benzinger, T.L.S.^e , Fox, N.C.^a b

^a Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
^b UK Dementia Research Institute at UCL, London, United Kingdom
^c Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, United Kingdom
^d Centre for Medical Image Computing, Medical Physics and Biomedical Engineering, UCL, London, United Kingdom
^e Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^g Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden

Abstract
Cortical tau accumulation is a key pathological event that partly defines Alzheimer’s disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation. All had baseline flortaucipir (FTP) PET, MRI and clinical assessments; 26 individuals had more than one FTP PET scan. Standardised uptake value ratios (SUVRs) in prespecified regions of interest (ROIs) were obtained using inferior cerebellar grey matter as the reference region. We compared the changes in FTP SUVRs between presymptomatic carriers, symptomatic carriers and non-carriers, adjusting for age, sex and study site. We also investigated the relationship between regional FTP SUVRs and estimated years to/from symptom onset (EYO). Compared to both non-carriers and presymptomatic carriers, FTP SUVRs were significantly higher in symptomatic carriers in all ROIs tested (p < 0.001). There were no significant regional differences between presymptomatic carriers and non-carriers in FTP SUVRs, or their rates of change (p > 0.05), although increased FTP signal uptake was seen posteriorly in some individuals around the time of expected symptom onset. When we examined the relationship of FTP SUVR with respect to EYO, the earliest significant regional difference between mutation carriers and non-carriers was detected within the precuneus prior to estimated symptom onset in some cases. This study supports preliminary studies suggesting that presymptomatic tau tracer uptake is rare in ADAD. In cases where early uptake was seen, there was often a predilection for posterior regions (the precuneus and post-cingulate) as opposed to the medial temporal lobe, highlighting the importance of examining in vivo tau uptake beyond the confines of traditional Braak staging. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHK01AG053474
National Institute on AgingNIAUFAG032438
Alzheimer’s AssociationAASG-20-690363-DIAN
Office of Extramural Research, National Institutes of HealthOER
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMED
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP
Memphis Research ConsortiumMRC
Canadian Institutes of Health ResearchIRSC
Fonds de Recherche du Québec – SantéFRQS
Medical Research CouncilMRC
Alzheimer’s SocietyAS-CTF-18001
University College LondonUCL
Rosetrees Trust
Alzheimer’s Research UKARUKARUK-PG2017-1946
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
UCLH Biomedical Research CentreNIHR BRC
Fleni
UK Dementia Research InstituteUK DRI

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations between age, sex, APOE genotype, and regional vascular physiology in typically aging adults
(2023) NeuroImage, 275, art. no. 120167, . 

Damestani, N.L.^a b , Jacoby, J.^a , Yadav, S.M.^a , Lovely, A.E.^a , Michael, A.^a , Terpstra, M.^c , Eshghi, M.^d , Rashid, B.^a e , Cruchaga, C.^f g h , Salat, D.H.^a b i , Juttukonda, M.R.^a b

^a Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, United States
^b Department of Radiology, Harvard Medical School, Boston, MA, United States
^c Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
^d MGH Institute of Health Professions, Boston, MA, United States
^e Department of Neurology, Harvard Medical School, Boston, MA, United States
^f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^g NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^h Hope Center for Neurologic Diseases, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, United States

Abstract
Altered blood flow in the human brain is characteristic of typical aging. However, numerous factors contribute to inter-individual variation in patterns of blood flow throughout the lifespan. To better understand the mechanisms behind such variation, we studied how sex and APOE genotype, a primary genetic risk factor for Alzheimer’s disease (AD), influence associations between age and brain perfusion measures. We conducted a cross-sectional study of 562 participants from the Human Connectome Project – Aging (36 to >90 years of age). We found widespread associations between age and vascular parameters, where increasing age was associated with regional decreases in cerebral blood flow (CBF) and increases in arterial transit time (ATT). When grouped by sex and APOE genotype, interactions between group and age demonstrated that females had relatively greater CBF and lower ATT compared to males. Females carrying the APOE ε4 allele showed the strongest association between CBF decline and ATT incline with age. This demonstrates that sex and genetic risk for AD modulate age-associated patterns of cerebral perfusion measures. © 2023

Author Keywords
Aging;  APOE;  Arterial spin labeling;  Arterial transit time;  Cerebral blood flow;  Healthy aging;  Perfusion MRI;  Sex differences

Funding details
National Institutes of HealthNIH
National Institute on AgingNIA1K01AG070318, R21AG072068, U01AG052564-S1
American Heart AssociationAHA19CDA34790002
Massachusetts Life Sciences CenterMLSC

Document Type: Article
Publication Stage: Final
Source: Scopus

Progenitor-derived glia are required for spinal cord regeneration in zebrafish
(2023) Development (Cambridge, England), 150 (10), . 

Zhou, L.^a b , McAdow, A.R.^a b , Yamada, H.^a b , Burris, B.^a b , Klatt Shaw, D.^a b , Oonk, K.^c , Poss, K.D.^c , Mokalled, M.H.^a b

^a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Duke Regeneration Center, Department of Cell Biology, Duke University Medical Center, Durham, United States

Abstract
Unlike mammals, adult zebrafish undergo spontaneous recovery after major spinal cord injury. Whereas reactive gliosis presents a roadblock for mammalian spinal cord repair, glial cells in zebrafish elicit pro-regenerative bridging functions after injury. Here, we perform genetic lineage tracing, assessment of regulatory sequences and inducible cell ablation to define mechanisms that direct the molecular and cellular responses of glial cells after spinal cord injury in adult zebrafish. Using a newly generated CreERT2 transgenic line, we show that the cells directing expression of the bridging glial marker ctgfa give rise to regenerating glia after injury, with negligible contribution to either neuronal or oligodendrocyte lineages. A 1 kb sequence upstream of the ctgfa gene was sufficient to direct expression in early bridging glia after injury. Finally, ablation of ctgfa-expressing cells using a transgenic nitroreductase strategy impaired glial bridging and recovery of swim behavior after injury. This study identifies key regulatory features, cellular progeny, and requirements of glial cells during innate spinal cord regeneration. © 2023. Published by The Company of Biologists Ltd.

Author Keywords
Glia;  Neural repair;  Regeneration;  Spinal cord injury;  Zebrafish

Document Type: Article
Publication Stage: Final
Source: Scopus

KATP channels are necessary for glucose-dependent increases in amyloid-β and Alzheimer’s disease-related pathology
(2023) JCI Insight, 8 (10), . 

Grizzanti, J.^a b , Moritz, W.R.^c , Pait, M.C.^a b , Stanley, M.^c d , Kaye, S.D.^a b , Carroll, C.M.^a b , Constantino, N.J.^a b , Deitelzweig, L.J.^a b , Snipes, J.A.^a b , Kellar, D.^b , Caesar, E.E.^c , Pettit-Mee, R.J.^a , Day, S.M.^a , Sens, J.P.^a , Nicol, N.I.^a b , Dhillon, J.^a b , Remedi, M.S.^a e , Kiraly, D.D.^a , Karch, C.M.^f g h , Nichols, C.G.ⁱ , Holtzman, D.M.^c g h , Macauley, S.L.^{a b j k l m}

^a Department of Physiology and Pharmacology and
^b Department of Internal Medicine, Wake Forest School of Medicine, Winston-SalemNC, United States
^c Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Department of Biology, College of Arts and Sciences, University of Vermont, Burlington, VT, United States
^e Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research
^f Department of Psychiatry
^g Hope Center for Neurological Disorders
^h Knight Alzheimer’s Disease Research Center, Department of Neurology; and
ⁱ Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^j Alzheimer’s Disease Research Center
^k Center on Diabetes, Obesity and Metabolism
^l Center for Precision Medicine; and
^m Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston-SalemNC, United States

Abstract
Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer’s disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2-/- mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes.

Author Keywords
Aging;  Alzheimer disease;  Glucose metabolism;  Ion channels;  Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound
(2023) Nature Metabolism, 5 (5), pp. 789-803. Cited 1 time.

Yang, Y.^a , Yuan, J.^a , Field, R.L.^b , Ye, D.^a , Hu, Z.^a , Xu, K.^a , Xu, L.^a , Gong, Y.^a , Yue, Y.^a , Kravitz, A.V.^c , Bruchas, M.R.^d , Cui, J.^a , Brestoff, J.R.^b , Chen, H.^a e f g

^a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^d Departments of Anesthesiology and Pain Medicine, Pharmacology, and Bioengineering, Center for Neurobiology of Addiction, Pain, and Emotion, University of Washington, Seattle, WA, United States
^e Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, United States
^f Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^g Division of Neurotechnology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (>24 h) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHDP5 OD028125, R01EB027223, R01EB030102, R01MH116981, UG3MH126861
Burroughs Wellcome FundBWF1019648
University of WashingtonUW

Document Type: Article
Publication Stage: Final
Source: Scopus

Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease
(2023) Brain, 146 (4), pp. 1592-1601. Cited 17 times.

Janelidze, S.^a , Bali, D.^a , Ashton, N.J.^b c d e , Barthelemy, N.R.^f g , Vanbrabant, J.^h , Stoops, E.^h , Vanmechelen, E.^h , He, Y.^f g , Dolado, A.O.^a , Triana-Baltzer, G.ⁱ , Pontecorvo, M.J.^j k , Zetterberg, H.^{b l m n o} , Kolb, H.ⁱ , Vandijck, M.^p , Blennow, K.^b l , Bateman, R.J.^f g , Hansson, O.^a q

^a Clinical Memory Research Unit, Lund University, Lund, Sweden
^b Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
^c Institute of Psychiatry Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, United Kingdom
^d NIHR Biomedical Research Centre for Mental Health, Biomedical Research Unit for Dementia, South London and Maudsley NHS Foundation, London, United Kingdom
^e Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway
^f Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^g Tracy Family SILQ Center, St Louis, MO, United States
^h ADx NeuroSciences, Gent, Belgium
ⁱ Neuroscience Biomarkers, Janssen Research & Development, La JollaCA, United States
^j Avid Radiopharmaceuticals, Philadelphia, PA, United States
^k Eli Lilly and Company, Indianapolis, IN, United States
^l Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^m Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
ⁿ UK Dementia Research Institute at UCL, London, United Kingdom
^o Hong Kong Center for Neurodegenerative Diseases, Hong Kong, Hong Kong
^p Fujirebio Europe N.V., Gent, Belgium
^q Memory Clinic, Skåne University Hospital, Malmö, Sweden

Abstract
Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer’s disease. Here, we performed a head-to-head comparison of p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status and predict future progression to Alzheimer’s dementia. The study included 135 patients with baseline diagnosis of mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average of 4.9 years. Seventy-one participants had abnormal Aβ-status (i.e. abnormal CSF Aβ42/40) at baseline; and 45 of these Aβ-positive participants progressed to Alzheimer’s dementia during follow-up. P-tau concentrations were determined in baseline plasma and CSF. P-tau217 and p-tau181 were both measured using immunoassays developed by Lilly Research Laboratories (Lilly) and mass spectrometry assays developed at Washington University (WashU). P-tau217 was also analysed using Simoa immunoassay developed by Janssen Research and Development (Janss). P-tau181 was measured using Simoa immunoassay from ADxNeurosciences (ADx), Lumipulse immunoassay from Fujirebio (Fuji) and Splex immunoassay from Mesoscale Discovery (Splex). Both p-tau181 and p-tau231 were quantified using Simoa immunoassay developed at the University of Gothenburg (UGOT). We found that the mass spectrometry-based p-tau217 (p-tau217WashU) exhibited significantly better performance than all other plasma p-tau biomarkers when detecting abnormal Aβ status [area under curve (AUC) = 0.947; Pdiff < 0.015] or progression to Alzheimer’s dementia (AUC = 0.932; Pdiff < 0.027). Among immunoassays, p-tau217Lilly had the highest AUCs (0.886-0.889), which was not significantly different from the AUCs of p-tau217Janss, p-tau181ADx and p-tau181WashU (AUCrange 0.835-0.872; Pdiff > 0.09), but higher compared with AUC of p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji and p-tau181Splex (AUCrange 0.642-0.813; Pdiff ≤ 0.029). Correlations between plasma and CSF values were strongest for p-tau217WashU (R = 0.891) followed by p-tau217Lilly (R = 0.755; Pdiff = 0.003 versus p-tau217WashU) and weak to moderate for the rest of the p-tau biomarkers (Rrange 0.320-0.669). In conclusion, our findings suggest that among all tested plasma p-tau assays, mass spectrometry-based measures of p-tau217 perform best when identifying mild cognitive impairment patients with abnormal brain Aβ or those who will subsequently progress to Alzheimer’s dementia. Several other assays (p-tau217Lilly, p-tau217Janss, p-tau181ADx and p-tau181WashU) showed relatively high and consistent accuracy across both outcomes. The results further indicate that the highest performing assays have performance metrics that rival the gold standards of Aβ-PET and CSF. If further validated, our findings will have significant impacts in diagnosis, screening and treatment for Alzheimer’s dementia in the future. © 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
Alzheimer’s disease;  amyloid-β;  blood p-tau;  dementia

Document Type: Article
Publication Stage: Final
Source: Scopus

The Association Between Maternal Cortisol and Infant Amygdala Volume Is Moderated by Socioeconomic Status
(2023) Biological Psychiatry Global Open Science, . 

Herzberg, M.P.^a , Triplett, R.^b , McCarthy, R.^c , Kaplan, S.^b , Alexopoulos, D.^b , Meyer, D.^b , Arora, J.^d , Miller, J.P.^d , Smyser, T.A.^a , Herzog, E.D.^e , England, S.K.^c , Zhao, P.^c , Barch, D.M.^a f g , Rogers, C.E.^a h , Warner, B.B.^h , Smyser, C.D.^b g h , Luby, J.^a

^a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: It has been well established that socioeconomic status is associated with mental and physical health as well as brain development, with emerging data suggesting that these relationships begin in utero. However, less is known about how prenatal socioeconomic environments interact with the gestational environment to affect neonatal brain volume. Methods: Maternal cortisol output measured at each trimester of pregnancy and neonatal brain structure were assessed in 241 mother-infant dyads. We examined associations between the trajectory of maternal cortisol output across pregnancy and volumes of cortisol receptor–rich regions of the brain, including the amygdala, hippocampus, medial prefrontal cortex, and caudate. Given the known effects of poverty on infant brain structure, socioeconomic disadvantage was included as a moderating variable. Results: Neonatal amygdala volume was predicted by an interaction between maternal cortisol output across pregnancy and socioeconomic disadvantage (standardized β = −0.31, p <.001), controlling for postmenstrual age at scan, infant sex, and total gray matter volume. Notably, amygdala volumes were positively associated with maternal cortisol for infants with maternal disadvantage scores 1 standard deviation below the mean (i.e., less disadvantage) (simple slope = 123.36, p <.01), while the association was negative in infants with maternal disadvantage 1 standard deviation above the mean (i.e., more disadvantage) (simple slope = −82.70, p =.02). Individuals with disadvantage scores at the mean showed no association, and there were no significant interactions in the other brain regions examined. Conclusions: These data suggest that fetal development of the amygdala is differentially affected by maternal cortisol production at varying levels of socioeconomic advantage. © 2023 The Authors

Author Keywords
Amygdala;  Cortisol;  Development;  Infancy;  Neonatal MRI;  Socioeconomic status

Funding details
National Institutes of HealthNIHR01 MH113883, T32 MH100019
Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine in St. LouisIDDRCP50 HD103525

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Large-scale proteome and metabolome analysis of CSF implicates altered glucose and carbon metabolism and succinylcarnitine in Alzheimer’s disease
(2023) Alzheimer’s and Dementia, . 

Panyard, D.J.^a , McKetney, J.^b c , Deming, Y.K.^a d e , Morrow, A.R.^a , Ennis, G.E.^d , Jonaitis, E.M.^d f , Van Hulle, C.A.^d e , Yang, C.^g h i , Sung, Y.J.^g h i , Ali, M.^g h i , Kollmorgen, G.^j , Suridjan, I.^k , Bayfield, A.^j , Bendlin, B.B.^d e f l , Zetterberg, H.^{m n o p q} , Blennow, K.^m n , Cruchaga, C.^g h i , Carlsson, C.M.^d e f l , Johnson, S.C.^d e f l , Asthana, S.^d e l , Coon, J.J.^b c r s , Engelman, C.D.^a

^a Department of Population Health Sciences, University of Wisconsin–Madison, Madison, WI, United States
^b National Center for Quantitative Biology of Complex Systems, University of Wisconsin–Madison, Madison, WI, United States
^c Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, WI, United States
^d Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin–Madison, Madison, WI, United States
^e Department of Medicine, University of Wisconsin–Madison, Madison, WI, United States
^f Wisconsin Alzheimer’s Institute, University of Wisconsin–Madison, Madison, WI, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^h NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^j Roche Diagnostics GmbH, Penzberg, Germany
^k Roche Diagnostics International Ltd, Rotkreuz, Switzerland
^l William S. Middleton Memorial Veterans Hospital, Madison, WI, United States
^m Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
ⁿ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^o Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
^p UK Dementia Research Institute at UCL, London, United Kingdom
^q Hong Kong Center for Neurodegenerative Diseases, Hong Kong
^r Morgridge Institute for Research, Madison, WI, United States
^s Department of Chemistry, University of Wisconsin–Madison, Madison, WI, United States

Abstract
INTRODUCTION: A hallmark of Alzheimer’s disease (AD) is the aggregation of proteins (amyloid beta [A] and hyperphosphorylated tau [T]) in the brain, making cerebrospinal fluid (CSF) proteins of particular interest. METHODS: We conducted a CSF proteome-wide analysis among participants of varying AT pathology (n = 137 participants; 915 proteins) with nine CSF biomarkers of neurodegeneration and neuroinflammation. RESULTS: We identified 61 proteins significantly associated with the AT category (P &lt; 5.46 × 10−5) and 636 significant protein-biomarker associations (P &lt; 6.07 × 10−6). Proteins from glucose and carbon metabolism pathways were enriched among amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, whose associations with tau were replicated in an independent cohort (n = 717). CSF metabolomics identified and replicated an association of succinylcarnitine with phosphorylated tau and other biomarkers. DISCUSSION: These results implicate glucose and carbon metabolic dysregulation and increased CSF succinylcarnitine levels with amyloid and tau pathology in AD. HIGHLIGHTS: Cerebrospinal fluid (CSF) proteome enriched for extracellular, neuronal, immune, and protein processing. Glucose/carbon metabolic pathways enriched among amyloid/tau-associated proteins. Key glucose/carbon metabolism protein associations independently replicated. CSF proteome outperformed other omics data in predicting amyloid/tau positivity. CSF metabolomics identified and replicated a succinylcarnitine–phosphorylated tau association. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
acylcarnitines;  Alzheimer’s disease;  amyloid;  biomarkers;  carbon metabolism;  glucose metabolism;  metabolism;  metabolomics;  multiomics;  neurodegeneration;  neuroinflammation;  proteomics;  tau

Funding details
5T32HL83806, T32LM012413
715986
1R01AG068398‐01, 1RF1AG074007, JPND2019‐466‐236, R01AG044546, R01AG058501, R01AG064614, R01AG064877, RF1AG053303, U01AG058922
P30AG017266
2019‐0228
720931
National Institutes of HealthNIHP30AG062715, P41GM108538, P50AG033514, R01AG021155, R01AG037639, R01AG054047, R01AG27161
National Institute on AgingNIAT32AG000213
U.S. National Library of MedicineNLM
Alzheimer’s AssociationAA2019‐AARF‐643973
Wisconsin Alumni Research FoundationWARF
Alzheimer’s Drug Discovery FoundationADDF201809‐2016862
National Center for Advancing Translational SciencesNCATSUL1TR000427
University of Wisconsin-MadisonUWP2CHD047873
Familjen Erling-Perssons Stiftelse
Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin-MadisonVCRGE, UW
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZIP01AG003991, P30AG066444
Cerveau Technologies
European Research CouncilERC681712
VetenskapsrådetVR2018‐02532
Horizon 2020860197
Alzheimerfonden2017‐0243, 742881
UK Dementia Research InstituteUK DRI2017‐00915, 201809‐2016615
Olav Thon Stiftelsen

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Comparing Tau PET Visual Interpretation with Tau PET Quantification, Cerebrospinal Fluid Biomarkers, and Longitudinal Clinical Assessment
(2023) Journal of Alzheimer’s Disease: JAD, 93 (2), pp. 765-777. 

Chen, C.D.^a , Ponisio, M.R.^a , Lang, J.A.^a , Flores, S.^a , Schindler, S.E.^b , Fagan, A.M.^b , Morris, J.C.^b , Benzinger, T.L.S.^a

^a Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: 18F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer’s disease (AD). However, manufacturer’s guidelines for visual interpretation of 18F-flortaucipir PET differ from how 18F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood. OBJECTIVE: We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n = 189, 23 were cognitively impaired). METHODS: Participants had tau PET, Aβ PET, MRI, and clinical and cognitive evaluation within 18 months (n = 189); the majority (n = 144) also underwent lumbar puncture. Two radiologists followed manufacturer’s guidelines for 18F-flortaucipir PET visual interpretation. RESULTS: Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases. CONCLUSION: Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals.

Author Keywords
Alzheimer’s disease;  cerebrospinal fluid;  positron emission tomography;  tauopathies

Document Type: Article
Publication Stage: Final
Source: Scopus