@article{Iaccarino2022-wf,

title = {rPOP: Robust PET-only processing of community acquired 

 heterogeneous amyloid-PET data},

author = {Leonardo Iaccarino and Renaud La Joie and Robert Koeppe and Barry A Siegel and Bruce E Hillner and Constantine Gatsonis and Rachel A Whitmer and Maria C Carrillo and Charles Apgar and Monica R Camacho and Rachel Nosheny and Gil D Rabinovici and Alzheimer's Disease Neuroimaging Initiative},

year  = {2022},

date = {2022-02-01},

journal = {Neuroimage},

volume = {246},

number = {118775},

pages = {118775},

publisher = {Elsevier BV},

abstract = {The reference standard for amyloid-PET quantification requires 

 structural MRI (sMRI) for preprocessing in both multi-site 

 research studies and clinical trials. Here we describe rPOP 

 (robust PET-Only Processing), a MATLAB-based MRI-free pipeline 

 implementing non-linear warping and differential smoothing of 

 amyloid-PET scans performed with any of the FDA-approved 

 radiotracers (18F-florbetapir/FBP, 18F-florbetaben/FBB or 

 18F-flutemetamol/FLUTE). Each image undergoes spatial 

 normalization based on weighted PET templates and data-driven 

 differential smoothing, then allowing users to perform their 

 quantification of choice. Prior to normalization, users can 

 choose whether to automatically reset the origin of the image to 

 the center of mass or proceed with the pipeline with the image as it is. We validate rPOP with n = 740 (514 FBP, 182 FBB, 44 

 FLUTE) amyloid-PET scans from the Imaging Dementia-Evidence for 

 Amyloid Scanning - Brain Health Registry sub-study (IDEAS-BHR) and n = 1,518 scans from the Alzheimer's Disease Neuroimaging Initiative (n = 1,249 FB},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Apostolova2021-ik,

title = {The Longitudinal early-onset Alzheimer's disease Study 

 (LEADS): Framework and methodology},

author = {Liana G Apostolova and Paul Aisen and Ani Eloyan and Anne Fagan and Keith N Fargo and Tatiana Foroud and Constantine Gatsonis and Lea T Grinberg and Clifford R Jr Jack and Joel Kramer and Robert Koeppe and Walter A Kukull and Melissa E Murray and Kelly Nudelman and Malia Rumbaugh and Arthur Toga and Prashanthi Vemuri and Amy Trullinger and Leonardo Iaccarino and Gregory S Day and Neill R Graff-Radford and Lawrence S Honig and David T Jones and Joseph Masdeu and Mario Mendez and Erik Musiek and Chiadi U Onyike and Emily Rogalski and Steve Salloway and David A Wolk and Thomas S Wingo and Maria C Carrillo and Bradford C Dickerson and Gil D Rabinovici and LEADS Consortium},

year  = {2021},

date = {2021-12-01},

journal = {Alzheimers. Dement.},

volume = {17},

number = {12},

pages = {2043--2055},

publisher = {Wiley},

abstract = {Patients with early-onset Alzheimer's disease (EOAD) are 

 commonly excluded from large-scale observational and therapeutic 

 studies due to their young age, atypical presentation, or 

 absence of pathogenic mutations. The goals of the Longitudinal 

 EOAD Study (LEADS) are to (1) define the clinical, imaging, and 

 fluid biomarker characteristics of EOAD; (2) develop sensitive 

 cognitive and biomarker measures for future clinical and 

 research use; and (3) establish a trial-ready network. LEADS 

 will follow 400 amyloid beta (A$beta$)-positive EOAD, 200 

 A$beta$-negative EOnonAD that meet National Institute on 

 Aging-Alzheimer's Association (NIA-AA) criteria for mild 

 cognitive impairment (MCI) or AD dementia, and 100 age-matched 

 controls. Participants will undergo clinical and cognitive 

 assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben 

 and [18 F]Flortaucipir positron emission tomography (PET), 

 lumbar puncture, and blood draw for DNA, RNA, plasma, serum and 

 peripheral blood mononuclear cells, and post-mortem assessment. 

 To develop more effective AD treatments, scientists need to 

 understand the genetic, biological, and clinical processes 

 involved in EOAD. LEADS will develop a public resource that will 

 enable future planning and implementation of EOAD clinical 

 trials.},

keywords = {Alzheimer's disease; EOAD; LEADS; YOAD; early-onset; young onset},

pubstate = {published},

tppubtype = {article}

}

@article{Asken2021-no,

title = {Association of remote mild traumatic brain injury with cortical 

 amyloid burden in clinically normal older adults},

author = {Breton M Asken and William G Mantyh and Renaud La Joie and Amelia Strom and Kaitlin B Casaletto and Adam M Staffaroni and Alexandra C Apple and Cutter A Lindbergh and Leonardo Iaccarino and Michelle You and Harli Grant and Corrina Fonseca and Charles Windon and Kyan Younes and Jeremy Tanner and Gil D Rabinovici and Joel H Kramer and Raquel C Gardner},

year  = {2021},

date = {2021-10-01},

journal = {Brain Imaging Behav.},

volume = {15},

number = {5},

pages = {2417--2425},

publisher = {Springer Science and Business Media LLC},

abstract = {We investigated whether clinically normal older adults with 

 remote, mild traumatic brain injury (mTBI) show evidence of 

 higher cortical A$beta$ burden. Our study included 134 

 clinically normal older adults (age 74.1 $pm$ 6.8 years, 59.7% 

 female, 85.8% white) who underwent A$beta$ positron emission 

 tomography (A$beta$-PET) and who completed the Ohio State 

 University Traumatic Brain Injury Identification questionnaire. 

 We limited participants to those reporting injuries classified as mTBI. A subset (N = 30) underwent a second A$beta$-PET scan 

 (mean 2.7 years later). We examined the effect of remote mTBI on 

 A$beta$-PET burden, interactions between remote mTBI and age, 

 sex, and APOE status, longitudinal A$beta$ accumulation, and 

 the interaction between remote mTBI and A$beta$ burden on 

 memory and executive functioning. Of 134 participants, 48 (36%) reported remote mTBI (},

keywords = {Aging; Amyloid; Concussion; Dementia; Neurodegenerative; PET;   Traumatic brain injury},

pubstate = {published},

tppubtype = {article}

}

@article{Ljubenkov2021-tn,

title = {Effect of the histone deacetylase inhibitor FRM-0334 on 

 progranulin levels in patients with progranulin gene 

 haploinsufficiency: A randomized clinical trial},

author = {Peter A Ljubenkov and Lauren Edwards and Leonardo Iaccarino and Renaud La Joie and Julio C Rojas and Mary Koestler and Baruch Harris and Bradley F Boeve and Barbara Borroni and John C Swieten and Murray Grossman and Florence Pasquier and Giovanni B Frisoni and Catherine J Mummery and Rik Vandenberghe and Isabelle Le Ber and Didier Hannequin and Scott M McGinnis and Sophie Auriacombe and Marco Onofrj and Ira J Goodman and Henry J Riordan and Gary Wisniewski and Jacob Hesterman and Ken Marek and Beth Ann Haynes and Holger Patzke and Gerhard Koenig and Dana Hilt and Hans Moebius and Adam L Boxer},

year  = {2021},

date = {2021-09-01},

journal = {JAMA Netw. Open},

volume = {4},

number = {9},

pages = {e2125584},

publisher = {American Medical Association (AMA)},

abstract = {Importance: Histone deacetylase inhibitors have been repeatedly 

 shown to elevate progranulin levels in preclinical models. This 

 report describes the first randomized clinical trial of a 

 histone deacetylase inhibitor in frontotemporal dementia (FTD) 

 resulting from progranulin (GRN) gene variations. Objective: To 

 characterize the safety, tolerability, plasma pharmacokinetics, 

 and pharmacodynamic effects of oral FRM-0334 on plasma 

 progranulin and other exploratory biomarkers, including 

 fluorodeoxyglucose (FDG)-positron emission tomography (PET), in 

 individuals with GRN haploinsufficiency. Design, Setting, and 

 Participants: In this randomized, double-blind, 

 placebo-controlled, dose-escalating, phase 2a safety, 

 tolerability, and pharmacodynamic clinical study, 2 doses of a 

 histone deacetylase inhibitor (FRM-0334) were administered to 

 participants with prodromal to moderate FTD with granulin 

 variations. Participants were recruited from January 13, 2015, 

 to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) 

 and heterozygous pathogenic variations in GRN and was conducted 

 at multiple centers in North America, the UK, and the European 

 Union. Data were analyzed from June 9, 2019, to May 13, 2021. Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 

 days. Main Outcomes and Measures: Primary outcomes were safety 

 and tolerability of FRM-0334 and its peripheral pharmacodynamic 

 effect on plasma progranulin. Secondary outcomes were the plasma 

 pharmacokinetic profile of FRM-0334 and its pharmacodynamic 

 effect on cerebrospinal fluid progranulin. Exploratory outcomes 

 were FDG-PET, FTD clinical severity, and cerebrospinal fluid 

 biomarkers (neurofilament light chain [NfL], amyloid $beta$ 

 1-42, phosphorylated tau 181, and total tau [t-tau]). Results: A 

 total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 

 women [59.3%]; 26 White participants [96.3%]) with GRN 

 variations were randomized and completed treatment. FRM-0334 was 

 safe and well tolerated but did not affect plasma progranulin 

 (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or 

 exploratory pharmacodynamic measures. Plasma FRM-0334 exposure 

 did not increase proportionally with dose. Brain FDG-PET data 

 were available in 26 of 27 randomized participants. In a 

 cross-sectional analysis of 26 individuals, bifrontal cortical 

 FDG hypometabolism was associated with worse Clinical Dementia 

 Rating (CDR) plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration sum of boxes score (b = -3.6 

 $times$ 10-2 standardized uptake value ratio [SUVR] units/CDR 

 units; 95% CI, -4.9 $times$ 10-2 to -2.2 $times$ 10-2; P < .001), high cerebrospinal fluid NfL (b = -9.2 $times$ 10-5 SUVR 

 units/pg NfL/mL; 95% CI, -1.3 $times$ 10-4 to -5.6 $times$ 

 10-5; P < .001), and high CSF t-tau (-7.2 $times$ 10-4 SUVR 

 units/pg t-tau/mL; 95% CI, -1.4 $times$ 10-3 to -9.5 $times$ 10-5; P = .03). Conclusions and Relevance: In this randomized 

 clinical trial, the current formulation of FRM-0334 did not 

 elevate PRGN levels, which could reflect a lack of efficacy at 

 attained exposures, low bioavailability, or some combination of 

 the 2 factors. Bifrontal FDG-PET is a sensitive measure of 

 symptomatic GRN haploinsufficiency. International multicenter 

 clinical trials of FTD-GRN are feasible. Trial Registration: 

 ClinicalTrials.gov Identifier: NCT02149160.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Thijssen2021-wf,

title = {Plasma phosphorylated tau 217 and phosphorylated tau 181 as 

 biomarkers in Alzheimer's disease and frontotemporal lobar 

 degeneration: a retrospective diagnostic performance study},

author = {Elisabeth H Thijssen and Renaud La Joie and Amelia Strom and Corrina Fonseca and Leonardo Iaccarino and Amy Wolf and Salvatore Spina and Isabel E Allen and Yann Cobigo and Hilary Heuer and Lawren VandeVrede and Nicholas K Proctor and Argentina Lario Lago and Suzanne Baker and Rajeev Sivasankaran and Agnieszka Kieloch and Arvind Kinhikar and Lili Yu and Marie-Anne Valentin and Andreas Jeromin and Henrik Zetterberg and Oskar Hansson and Niklas Mattsson-Carlgren and Danielle Graham and Kaj Blennow and Joel H Kramer and Lea T Grinberg and William W Seeley and Howard Rosen and Bradley F Boeve and Bruce L Miller and Charlotte E Teunissen and Gil D Rabinovici and Julio C Rojas and Jeffrey L Dage and Adam L Boxer and Advancing Research and Treatment investigators},

year  = {2021},

date = {2021-09-01},

journal = {Lancet Neurol.},

volume = {20},

number = {9},

pages = {739--752},

publisher = {Elsevier BV},

abstract = {BACKGROUND: Plasma tau phosphorylated at threonine 217 

 (p-tau217) and plasma tau phosphorylated at threonine 181 

 (p-tau181) are associated with Alzheimer's disease tau 

 pathology. We compared the diagnostic value of both biomarkers 

 in cognitively unimpaired participants and patients with a 

 clinical diagnosis of mild cognitive impairment, Alzheimer's 

 disease syndromes, or frontotemporal lobar degeneration (FTLD) 

 syndromes. METHODS: In this retrospective multicohort diagnostic 

 performance study, we analysed plasma samples, obtained from 

 patients aged 18-99 years old who had been diagnosed with 

 Alzheimer's disease syndromes (Alzheimer's disease dementia, 

 logopenic variant primary progressive aphasia, or posterior 

 cortical atrophy), FTLD syndromes (corticobasal syndrome, 

 progressive supranuclear palsy, behavioural variant 

 frontotemporal dementia, non-fluent variant primary progressive 

 aphasia, or semantic variant primary progressive aphasia), or 

 mild cognitive impairment; the participants were from the 

 University of California San Francisco (UCSF) Memory and Aging 

 Center, San Francisco, CA, USA, and the Advancing Research and 

 Treatment for Frontotemporal Lobar Degeneration Consortium 

 (ARTFL; 17 sites in the USA and two in Canada). Participants 

 from both cohorts were carefully characterised, including 

 assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), 

 and clinical and cognitive evaluations. Plasma p-tau181 and 

 p-tau217 were measured using electrochemiluminescence-based 

 assays, which differed only in the biotinylated antibody epitope 

 specificity. Receiver operating characteristic analyses were 

 used to determine diagnostic accuracy of both plasma markers 

 using clinical diagnosis, neuropathological findings, and 

 amyloid-PET and tau-PET measures as gold standards. Difference 

 between two area under the curve (AUC) analyses were tested with 

 the Delong test. FINDINGS: Data were collected from 593 

 participants (443 from UCSF and 150 from ARTFL, mean age 64 

 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, 

 p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, 

 mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau21},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Edwards2021-za,

title = {Multimodal neuroimaging of sex differences in cognitively 

 impaired patients on the Alzheimer's continuum: greater 

 tau-PET retention in females},

author = {Lauren Edwards and Renaud La Joie and Leonardo Iaccarino and Amelia Strom and Suzanne L Baker and Kaitlin B Casaletto and Yann Cobigo and Harli Grant and Minseon Kim and Joel H Kramer and Taylor J Mellinger and Julie Pham and Katherine L Possin and Howard J Rosen and David N Soleimani-Meigooni and Amy Wolf and Bruce L Miller and Gil D Rabinovici},

year  = {2021},

date = {2021-09-01},

journal = {Neurobiol. Aging},

volume = {105},

pages = {86--98},

publisher = {Elsevier BV},

abstract = {We assessed sex differences in amyloid- and tau-PET retention in 

 119 amyloid positive patients with mild cognitive impairment or 

 Alzheimer's disease (AD) dementia. Patients underwent 3T-MRI, 

 11C-PIB amyloid-PET and 18F-Flortaucipir tau-PET. Linear 

 ordinary least squares regression models tested sex differences 

 in Flortaucipir-PET SUVR in a summary temporal region of 

 interest as well as global PIB-PET. No sex differences were 

 observed in demographics, Clinical Dementia Rating Sum of Boxes 

 (CDR-SoB), Mini-Mental State Exam (MMSE), raw episodic memory 

 scores, or cortical thickness. Females had higher global PIB SUVR ($eta$p²=.04},

keywords = {Alzheimer's disease; Amyloid; Apolipoprotein E; Positron   emission tomography; Sex differences; Tau},

pubstate = {published},

tppubtype = {article}

}

@article{Provost2021-wl,

title = {Crossed cerebellar diaschisis on 18F-FDG PET: Frequency 

 across neurodegenerative syndromes and association with 

 11C-PIB and 18F-Flortaucipir},

author = {Karine Provost and Renaud La Joie and Amelia Strom and Leonardo Iaccarino and Lauren Edwards and Taylor J Mellinger and Julie Pham and Suzanne L Baker and Bruce L Miller and William J Jagust and Gil D Rabinovici},

year  = {2021},

date = {2021-09-01},

journal = {J. Cereb. Blood Flow Metab.},

volume = {41},

number = {9},

pages = {2329--2343},

publisher = {SAGE Publications},

abstract = {We used 18F-FDG-PET to investigate the frequency of crossed 

 cerebellar diaschisis (CCD) in 197 patients with various 

 syndromes associated with neurodegenerative diseases. In a 

 subset of 117 patients, we studied relationships between CCD and 

 cortical asymmetry of Alzheimer's pathology ($beta$-amyloid 

 (11C-PIB) and tau (18F-Flortaucipir)). PET images were processed 

 using MRIs to derive parametric SUVR images and define regions 

 of interest. Indices of asymmetry were calculated in the 

 cerebral cortex, basal ganglia and cerebellar cortex. Across all 

 patients, cerebellar 18F-FDG asymmetry was associated with 

 reverse asymmetry of 18F-FDG in the cerebral cortex (especially 

 frontal and parietal areas) and basal ganglia. Based on our 

 operational definition (cerebellar asymmetry >3% with 

 contralateral supratentorial hypometabolism), significant CCD 

 was present in 47/197 (24%) patients and was most frequent in 

 corticobasal syndrome and semantic and logopenic variants of 

 primary progressive aphasia. In $beta$-amyloid-positive 

 patients, mediation analyses showed that 18F-Flortaucipir 

 cortical asymmetry was associated with cerebellar 18F-FDG 

 asymmetry, but that cortical 18F-FDG asymmetry mediated this 

 relationship. Analysis of 18F-FDG-SUVR values suggested that CCD 

 might also occur in the absence of frank cerebellar 18F-FDG 

 asymmetry due to symmetrical supratentorial degeneration 

 resulting in a bilateral diaschisis process.},

keywords = {Alzheimer's; FDG; PET; Tau; diaschisis},

pubstate = {published},

tppubtype = {article}

}

@article{Strom2021-eo,

title = {Cortical hypometabolism reflects local atrophy and tau pathology 

 in symptomatic Alzheimer's disease},

author = {Amelia Strom and Leonardo Iaccarino and Lauren Edwards and Orit H Lesman-Segev and David N Soleimani-Meigooni and Julie Pham and Suzanne L Baker and Susan Landau and William J Jagust and Bruce L Miller and Howard J Rosen and Maria Luisa Gorno-Tempini and Gil D Rabinovici and Renaud La Joie and Alzheimer's Disease Neuroimaging Initiative},

year  = {2021},

date = {2021-08-01},

journal = {Brain},

publisher = {Oxford University Press (OUP)},

abstract = {Posterior cortical hypometabolism measured with 

 [18F]-Fluorodeoxyglucose (FDG)-PET is a well-known marker of 

 Alzheimer's disease-related neurodegeneration, but its 

 associations with underlying neuropathological processes are 

 unclear. We assessed cross-sectionally the relative 

 contributions of three potential mechanisms causing 

 hypometabolism in the retrosplenial and inferior parietal 

 cortices: local molecular (amyloid and tau) pathology and 

 atrophy, distant factors including contributions from the 

 degenerating medial temporal lobe or molecular pathology in 

 functionally connected regions, and the presence of the 

 apolipoprotein E (APOE) $epsilon$4 allele. Two hundred and 

 thirty-two amyloid-positive cognitively impaired patients from 

 two cohorts (University of California, San Francisco, UCSF, and 

 Alzheimer's Disease Neuroimaging Initiative, ADNI) underwent MRI 

 and PET with FDG, amyloid-PET using [11C]-Pittsburgh Compound B, 

 [18F]-Florbetapir, or [18F]-Florbetaben, and [18F]-Flortaucipir 

 tau-PET within one year. Standard uptake value ratios (SUVR) 

 were calculated using tracer-specific reference regions. 

 Regression analyses were run within cohorts to identify 

 variables associated with retrosplenial or inferior parietal FDG 

 SUVR. On average, ADNI patients were older and were less 

 impaired than UCSF patients. Regional patterns of hypometabolism 

 were similar between cohorts, though there were cohort 

 differences in regional gray matter atrophy. Local cortical 

 thickness and tau-PET (but not amyloid-PET) were independently 

 associated with both retrosplenial and inferior parietal FDG SUVR ($Delta$R2 = .09 to .21) across cohorts in models that 

 also included age and disease severity (local model). Including 

 medial temporal lobe volume improved the retrosplenial FDG model in ADNI ($Delta$R2 = .0},

keywords = {Alzheimer's disease; PET; amyloid; hypometabolism; tau},

pubstate = {published},

tppubtype = {article}

}

@article{Ossenkoppele2021-xp,

title = {Accuracy of tau positron emission tomography as a prognostic 

 marker in preclinical and prodromal Alzheimer disease: A 

 head-to-head comparison against amyloid positron emission 

 tomography and magnetic resonance imaging},

author = {Rik Ossenkoppele and Ruben Smith and Niklas Mattsson-Carlgren and Colin Groot and Antoine Leuzy and Olof Strandberg and Sebastian Palmqvist and Tomas Olsson and Jonas Jögi and Erik Stormrud and Hanna Cho and Young Hoon Ryu and Jae Yong Choi and Adam L Boxer and Maria L Gorno-Tempini and Bruce L Miller and David Soleimani-Meigooni and Leonardo Iaccarino and Renaud La Joie and Suzanne Baker and Edilio Borroni and Gregory Klein and Michael J Pontecorvo and Michael D Sr Devous and William J Jagust and Chul Hyoung Lyoo and Gil D Rabinovici and Oskar Hansson},

year  = {2021},

date = {2021-08-01},

journal = {JAMA Neurol.},

volume = {78},

number = {8},

pages = {961--971},

publisher = {American Medical Association (AMA)},

abstract = {Importance: Tau positron emission tomography (PET) tracers have 

 proven useful for the differential diagnosis of dementia, but 

 their utility for predicting cognitive change is unclear. 

 Objective: To examine the prognostic accuracy of baseline 

 fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in 

 individuals across the Alzheimer disease (AD) clinical spectrum 

 and to perform a head-to-head comparison against established 

 magnetic resonance imaging (MRI) and amyloid PET markers. 

 Design, Setting, and Participants: This prognostic study 

 collected data from 8 cohorts in South Korea, Sweden, and the US 

 from June 1, 2014, to February 28, 2021, with a mean (SD) 

 follow-up of 1.9 (0.8) years. A total of 1431 participants were 

 recruited from memory clinics, clinical trials, or cohort 

 studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] 

 positive for amyloid-$beta$ [A$beta$]), 443 had mild cognitive 

 impairment (MCI group; 271 [61.2%] positive for A$beta$), and 

 315 had a clinical diagnosis of AD dementia (315 [100%] 

 positive for A$beta$). Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination 

 (MMSE) evaluation. Main Outcomes and Measures: Baseline 

 [18F]flortaucipir/[18F]RO948 PET retention within a temporal 

 region of interest, MRI-based AD-signature cortical thickness, 

 and amyloid PET Centiloids were used to predict changes in MMSE 

 using linear mixed-effects models adjusted for age, sex, 

 education, and cohort. Mediation/interaction analyses tested 

 whether associations between baseline tau PET and cognitive 

 change were mediated by baseline MRI measures and whether age, 

 sex, and APOE genotype modified these associations. Results: 

 Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 

 751 (52.5%) were male. Findings for [18F]flortaucipir PET 

 predicted longitudinal changes in MMSE, and effect sizes were 

 stronger than for AD-signature cortical thickness and amyloid 

 PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 

 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in 

 the A$beta$-positive MCI group (R2, 0.25 [tau PET] vs 0.15 

 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for 

 difference) and in the A$beta$-positive CU group (R2, 0.16 [tau 

 PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped 

 for difference). These findings were replicated in the 

 [18F]RO948 PET cohort. MRI mediated the association between 

 [18F]flortaucipir PET and MMSE in the groups with AD dementia 

 (33.4% [95% CI, 15.5%-60.0%] of the total effect) and 

 A$beta$-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the 

 total effect), but not the A$beta$-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline 

 [18F]flortaucipir PET and cognitive change, such that older 

 individuals showed faster cognitive decline at similar tau PET 

 levels. Conclusions and Relevance: The findings of this 

 prognostic study suggest that tau PET is a promising tool for 

 predicting cognitive change that is superior to amyloid PET and 

 MRI and may support the prognostic process in preclinical and 

 prodromal stages of AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Provost2021-rw,

title = {Comparing ATN-T designation by tau PET visual reads, tau 

 PET quantification, and CSF PTau181 across three cohorts},

author = {Karine Provost and Leonardo Iaccarino and David N Soleimani-Meigooni and Suzanne Baker and Lauren Edwards and Udo Eichenlaub and Oskar Hansson and William Jagust and Mustafa Janabi and Renaud La Joie and Orit Lesman-Segev and Taylor J Mellinger and Bruce L Miller and Rik Ossenkoppele and Julie Pham and Ruben Smith and Ida Sonni and Amelia Strom and Niklas Mattsson-Carlgren and Gil D Rabinovici and Alzheimer's Disease Neuroimaging Initiative (ADNI)},

year  = {2021},

date = {2021-07-01},

journal = {Eur. J. Nucl. Med. Mol. Imaging},

volume = {48},

number = {7},

pages = {2259--2271},

publisher = {Springer Science and Business Media LLC},

abstract = {PURPOSE: To compare rates of tau biomarker positivity (T-status) 

 per the 2018 Alzheimer's Disease (AD) Research Framework derived 

 from [18F]flortaucipir (FTP) PET visual assessment, FTP 

 quantification, and cerebrospinal fluid (CSF) phosphorylated 

 Tau-181 (PTau181). METHODS: We included 351 subjects with 

 varying clinical diagnoses from three cohorts with available FTP 

 PET and CSF PTau181 within 18 months. T-status was derived from 

 (1) FTP visual assessment by two blinded raters; (2) FTP 

 standardized uptake value ratio (SUVR) quantification from a 

 temporal meta-ROI (threshold: SUVR $geq$1.27); and (3) 

 Elecsystextregistered Phospho-Tau (181P) CSF (Roche 

 Diagnostics) concentrations (threshold: PTau181 $geq$ 24.5 

 pg/mL). RESULTS: FTP visual reads yielded the highest rates of 

 T+, while T+ by SUVR increased progressively from cognitively 

 normal (CN) through mild cognitive impairment (MCI) and AD 

 dementia. T+ designation by CSF PTau181 was intermediate between 

 FTP visual reads and SUVR values in CN, similar to SUVR in MCI, 

 and lower in AD dementia. Concordance in T-status between 

 modality pairs ranged from 68 to 76% and varied by clinical 

 diagnosis, being highest in patients with AD dementia. In 

 discriminating A$beta$ + MCI and AD subjects from healthy 

 controls and non-AD participants, FTP visual assessment was most 

 sensitive (0.96) but least specific (0.60). Specificity was 

 highest with FTP SUVR (0.91) with sensitivity of 0.89. 

 Sensitivity (0.73) and specificity (0.72) were balanced for 

 PTau181. CONCLUSION: The choice of tau biomarker may differ by 

 disease stage and research goals that seek to maximize 

 sensitivity or specificity. Visual interpretations of tau PET 

 enhance sensitivity compared to quantification alone, 

 particularly in early disease stages.},

keywords = {Alzheimer's disease; Biomarkers; CSF; Flortaucipir; PET; Tau},

pubstate = {published},

tppubtype = {article}

}

@article{Ossenkoppele2021-ok,

title = {The impact of demographic, clinical, genetic, and imaging 

 variables on tau PET status},

author = {Rik Ossenkoppele and Antoine Leuzy and Hanna Cho and Carole H Sudre and Olof Strandberg and Ruben Smith and Sebastian Palmqvist and Niklas Mattsson-Carlgren and Tomas Olsson and Jonas Jögi and Erik Stormrud and Young Hoon Ryu and Jae Yong Choi and Alzheimer's Disease Neuroimaging Initiative and PREVENT-AD group and Adam L Boxer and Maria L Gorno-Tempini and Bruce L Miller and David Soleimani-Meigooni and Leonardo Iaccarino and Renaud La Joie and Edilio Borroni and Gregory Klein and Michael J Pontecorvo and Michael D Sr Devous and Sylvia Villeneuve and Chul Hyoung Lyoo and Gil D Rabinovici and Oskar Hansson},

year  = {2021},

date = {2021-07-01},

journal = {Eur. J. Nucl. Med. Mol. Imaging},

volume = {48},

number = {7},

pages = {2245--2258},

publisher = {Springer Science and Business Media LLC},

abstract = {PURPOSE: A substantial proportion of amyloid-$beta$ (A$beta$)+ 

 patients with clinically diagnosed Alzheimer's disease (AD) 

 dementia and mild cognitive impairment (MCI) are tau 

 PET-negative, while some clinically diagnosed non-AD 

 neurodegenerative disorder (non-AD) patients or cognitively 

 unimpaired (CU) subjects are tau PET-positive. We investigated 

 which demographic, clinical, genetic, and imaging variables 

 contributed to tau PET status. METHODS: We included 2338 

 participants (430 A$beta$+ AD dementia, 381 A$beta$+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined 

 in the entorhinal cortex, temporal meta-ROI, and Braak V-VI 

 regions using previously established cutoffs. We performed 

 bivariate binary logistic regression models with tau PET status 

 (positive/negative) as dependent variable and age, sex, 

 APOE$epsilon$4, A$beta$ status (only in CU and non-AD 

 analyses), MMSE, global white matter hyperintensities (WMH), and 

 AD-signature cortical thickness as predictors. Additionally, we 

 performed multivariable binary logistic regression models to 

 account for all other predictors in the same model. RESULTS: Tau 

 PET positivity in the temporal meta-ROI was 88.6% for AD 

 dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. 

 Among A$beta$+ participants with AD dementia and MCI, lower 

 age, MMSE score, and AD-signature cortical thickness showed the 

 strongest associations with tau PET positivity. In non-AD and CU 

 participants, presence of A$beta$ was the strongest predictor 

 of a positive tau PET scan. CONCLUSION: We identified several 

 demographic, clinical, and neurobiological factors that are 

 important to explain the variance in tau PET retention observed 

 across the AD pathological continuum, non-AD neurodegenerative 

 disorders, and cognitively unimpaired persons.},

keywords = {Alzheimer's disease; A$beta$; Dementia; MCI; PET; Tau},

pubstate = {published},

tppubtype = {article}

}

@article{Singleton2021-pu,

title = {Heterogeneous distribution of tau pathology in the behavioural 

 variant of Alzheimer's disease},

author = {Ellen Singleton and Oskar Hansson and Yolande A L Pijnenburg and Renaud La Joie and William G Mantyh and Pontus Tideman and Erik Stomrud and Antoine Leuzy and Maurits Johansson and Olof Strandberg and Ruben Smith and Evi Berendrecht and Bruce L Miller and Leonardo Iaccarino and Lauren Edwards and Amelia Strom and Emma E Wolters and Emma Coomans and Denise Visser and Sandeep S V Golla and Hayel Tuncel and Femke Bouwman and John Cornelis Van Swieten and Janne M Papma and Bart Berckel and Philip Scheltens and Anke A Dijkstra and Gil D Rabinovici and Rik Ossenkoppele},

year  = {2021},

date = {2021-04-01},

journal = {J. Neurol. Neurosurg. Psychiatry},

volume = {92},

number = {8},

pages = {872--880},

publisher = {BMJ},

abstract = {OBJECTIVE: The clinical phenotype of the rare behavioural 

 variant of Alzheimer's disease (bvAD) is insufficiently 

 understood. Given the strong clinico-anatomical correlations of 

 tau pathology in AD, we investigated the distribution of tau 

 deposits in bvAD, in-vivo and ex-vivo, using positron emission 

 tomography (PET) and postmortem examination. METHODS: For the 

 tau PET study, seven amyloid-$beta$ positive bvAD patients 

 underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau 

 PET uptake values into standardised (W-)scores, adjusting for 

 age, sex and mini mental state examination in a 'typical' memory-predominant AD (n=205) group. W-scores were computed 

 within entorhinal, temporoparietal, medial and lateral 

 prefrontal, insular and whole-brain regions-of-interest, 

 frontal-to-entorhinal and frontal-to-parietal ratios and within 

 intrinsic functional connectivity network templates. For the 

 postmortem study, the percentage of AT8 (tau)-positive area in 

 hippocampus CA1, temporal, parietal, frontal and insular 

 cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7). RESULTS: Individual 

 regional W-scores $geq$1.96 (corresponding to p0.05). 

 CONCLUSIONS: Both in-vivo and ex-vivo, patients with bvAD showed 

 heterogeneous distributions of tau pathology. Since key regions 

 involved in behavioural regulation were not consistently 

 disproportionally affected by tau pathology, other factors are 

 more likely driving the clinical phenotype in bvAD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Tsoy2021-um,

title = {Detecting Alzheimer's disease biomarkers with a brief 

 tablet-based cognitive battery: sensitivity to A$beta$ and 

 tau PET},

author = {Elena Tsoy and Amelia Strom and Leonardo Iaccarino and Sabrina J Erlhoff and Collette A Goode and Anne-Marie Rodriguez and Gil D Rabinovici and Bruce L Miller and Joel H Kramer and Katherine P Rankin and Renaud La Joie and Katherine L Possin},

year  = {2021},

date = {2021-02-01},

journal = {Alzheimers. Res. Ther.},

volume = {13},

number = {1},

pages = {36},

publisher = {Springer Science and Business Media LLC},

abstract = {BACKGROUND: $beta$-amyloid (A$beta$) and tau positron emission 

 tomography (PET) detect the pathological changes that define 

 Alzheimer's disease (AD) in living people. Cognitive measures 

 sensitive to A$beta$ and tau burden may help streamline 

 identification of cases for confirmatory AD biomarker testing. 

 METHODS: We examined the association of Brain Health Assessment 

 (BHA) tablet-based cognitive measures with dichotomized A$beta$ 

 -PET status using logistic regression models in individuals with mild cognitive impairment (MCI) or dementia (N = 140; 43 

 A$beta$-, 97 A$beta$+). We also investigated the relationship 

 between the BHA tests and regional patterns of tau-PET signal 

 using voxel-wise regression analyses in a subsample of 60 

 A$beta$+ individuals with MCI or dementia. RESULTS: Favorites 

 (associative memory), Match (executive functions and speed), and 

 Everyday Cognition Scale scores were significantly associated with A$beta$ positivity (area under the curve [AUC] = 0.75 

 [95% CI 0.66-0.85]). We found significant associations with 

 tau-PET signal in mesial temporal regions for Favorites, 

 frontoparietal regions for Match, and occipitoparietal regions 

 for Line Orientation (visuospatial skills) in a subsample of 

 individuals with MCI and dementia. CONCLUSION: The BHA measures 

 are significantly associated with both A$beta$ and regional tau 

 in vivo imaging markers and could be used for the identification 

 of patients with suspected AD pathology in clinical practice.},

keywords = {Alzheimer's disease; Biomarkers; Mild cognitive impairment;   Neuropsychology; Positron emission tomography; Psychometrics},

pubstate = {published},

tppubtype = {article}

}

@article{La_Joie2021-zv,

title = {Association of APOE4 and clinical variability in Alzheimer 

 disease with the pattern of tau- and amyloid-PET},

author = {Renaud La Joie and Adrienne V Visani and Orit H Lesman-Segev and Suzanne L Baker and Lauren Edwards and Leonardo Iaccarino and David N Soleimani-Meigooni and Taylor Mellinger and Mustafa Janabi and Zachary A Miller and David C Perry and Julie Pham and Amelia Strom and Maria Luisa Gorno-Tempini and Howard J Rosen and Bruce L Miller and William J Jagust and Gil D Rabinovici},

year  = {2021},

date = {2021-02-01},

journal = {Neurology},

volume = {96},

number = {5},

pages = {e650--e661},

publisher = {Ovid Technologies (Wolters Kluwer Health)},

abstract = {OBJECTIVE: To assess whether Alzheimer disease (AD) clinical 

 presentation and APOE4 relate to the burden and topography of 

 $beta$-amyloid (A$beta$) and tau pathologies using in vivo PET 

 imaging. METHODS: We studied 119 A$beta$-positive symptomatic 

 patients aged 48-95 years, including 29 patients with logopenic 

 variant primary progressive aphasia (lvPPA) and 21 with 

 posterior cortical atrophy (PCA). Pittsburgh compound B 

 (PiB)-A$beta$ and flortaucipir (tau)-PET standardized uptake 

 value ratio (SUVR) images were created. General linear models 

 assessed relationships between demographic/clinical variables 

 (phenotype, age), APOE4, and PET (including global cortical and 

 voxelwise SUVR values) while controlling for disease severity 

 using the Clinical Dementia Rating Sum of Boxes. RESULTS: 

 PiB-PET binding showed a widespread cortical distribution with 

 subtle differences across phenotypes and was unrelated to 

 demographic/clinical variables or APOE4. Flortaucipir-PET was 

 commonly elevated in temporoparietal regions, but showed marked 

 phenotype-associated differences, with higher binding observed 

 in occipito-parietal areas for PCA, in left temporal and 

 inferior frontal for lvPPA, and in medial temporal areas for 

 other AD. Cortical flortaucipir-PET binding was higher in younger patients across phenotypes (r = -0.63, 95% confidence 

 interval [CI] -0.72, -0.50), especially in parietal and dorsal 

 prefrontal cortices. The presence of APOE4 was associated with a 

 focal medial temporal flortaucipir-SUVR increase, controlling 

 for all other variables (entorhinal: + 0.310 SUVR, 95% CI 

 0.091, 0.530). CONCLUSIONS: Clinical phenotypes are associated 

 with differential patterns of tau but not amyloid pathology. 

 Older age and APOE4 are not only risk factors for AD but also 

 seem to affect disease expression by promoting a more medial 

 temporal lobe-predominant pattern of tau pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2021-ex,

title = {Association between ambient air pollution and amyloid positron 

 emission tomography positivity in older adults with cognitive 

 impairment},

author = {Leonardo Iaccarino and Renaud La Joie and Orit H Lesman-Segev and Eunice Lee and Lucy Hanna and Isabel E Allen and Bruce E Hillner and Barry A Siegel and Rachel A Whitmer and Maria C Carrillo and Constantine Gatsonis and Gil D Rabinovici},

year  = {2021},

date = {2021-02-01},

journal = {JAMA Neurol.},

volume = {78},

number = {2},

pages = {197--207},

publisher = {American Medical Association (AMA)},

abstract = {Importance: Amyloid-$beta$ (A$beta$) deposition is a feature 

 of Alzheimer disease (AD) and may be promoted by exogenous 

 factors, such as ambient air quality. Objective: To examine the 

 association between the likelihood of amyloid positron emission 

 tomography (PET) scan positivity and ambient air quality in 

 individuals with cognitive impairment. Design, Setting, and 

 Participants: This cross-sectional study used data from the 

 Imaging Dementia-Evidence for Amyloid Scanning Study, which 

 included more than 18 000 US participants with cognitive 

 impairment who received an amyloid PET scan with 1 of 3 A$beta$ 

 tracers (fluorine 18 [18F]-labeled florbetapir, 18F-labeled 

 florbetaben, or 18F-labeled flutemetamol) between February 16, 

 2016, and January 10, 2018. A sample of older adults with mild 

 cognitive impairment (MCI) or dementia was selected. Exposures: 

 Air pollution was estimated at the patient residence using 

 predicted fine particulate matter (PM2.5) and ground-level ozone 

 (O3) concentrations from the Environmental Protection Agency 

 Downscaler model. Air quality was estimated at 2002 to 2003 

 (early, or approximately 14 [range, 13-15] years before amyloid 

 PET scan) and 2015 to 2016 (late, or approximately 1 [range, 

 0-2] years before amyloid PET scan). Main Outcomes and Measures: 

 Primary outcome measure was the association between air 

 pollution and the likelihood of amyloid PET scan positivity, 

 which was measured as odds ratios (ORs) and marginal effects, 

 adjusting for demographic, lifestyle, and socioeconomic factors 

 and medical comorbidities, including respiratory, 

 cardiovascular, cerebrovascular, psychiatric, and neurological 

 conditions. Results: The data set included 18 178 patients, of 

 which 10 991 (60.5%) had MCI and 7187 (39.5%) had dementia 

 (mean [SD] age, 75.8 [6.3] years; 9333 women [51.3%]). Living 

 in areas with higher estimated biennial PM2.5 concentrations in 

 2002 to 2003 was associated with a higher likelihood of amyloid 

 PET scan positivity (adjusted OR, 1.10; 95% CI, 1.05-1.15; z score = 3.93; false discovery rate [FDR]-corrected P < .001; per 

 4-$mu$g/m3 increments). Results were similar for 2015 to 2016 data (OR, 1.15; 95% CI, 1.05-1.26, z score = 3.14; FDR-corrected P = .003). An average marginal effect (AME) of +0.5% (SE = 0.1%; z score, 3.93; 95% CI, 0.3%-0.7%; 

 FDR-corrected P < .001) probability of amyloid PET scan 

 positivity for each 1-$mu$g/m3 increase in PM2.5 was observed for 2002 to 2003, whereas an AME of +0.8% (SE = 0.2%; z score = 3.15; 95% CI, 0.3%-1.2%; FDR-corrected P = .002) 

 probability was observed for 2015 to 2016. Post hoc analyses 

 showed no effect modification by sex (2002-2003: interaction term $beta$ = 1.01 [95% CI, 0.99-1.04; z score = 1.13; FDR-corrected P = .56]; 2015-2016: $beta$ = 1.02 [95% CI, 0.98-1.07; z score = 0.91; FDR-corrected P = .56]) or clinical stage (2002-2003: interaction term $beta$ = 1.01 [95% CI, 0.99-1.03; z score = 0.77; FDR-corrected P = .58]; 2015-2016: $beta$ = 1.03; 95% CI, 0.99-1.08; z score = 1.46; FDR-corrected P = .47]). Exposure to higher O3 concentrations 

 was not associated with amyloid PET scan positivity in both time 

 windows. Conclusions and Relevance: This study found that higher 

 PM2.5 concentrations appeared to be associated with brain 

 A$beta$ plaques. These findings suggest the need to consider 

 airborne toxic pollutants associated with A$beta$ pathology in 

 public health policy decisions and to inform individual lifetime 

 risk of developing AD and dementia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lesman-Segev2021-jh,

title = {Diagnostic accuracy of amyloid versus 18 F-fluorodeoxyglucose 

 positron emission tomography in autopsy-confirmed dementia},

author = {Orit H Lesman-Segev and Renaud La Joie and Leonardo Iaccarino and Iryna Lobach and Howard J Rosen and Sang Won Seo and Mustafa Janabi and Suzanne L Baker and Lauren Edwards and Julie Pham and John Olichney and Adam Boxer and Eric Huang and Marilu Gorno-Tempini and Charles DeCarli and Mackenzie Hepker and Ji-Hye L Hwang and Bruce L Miller and Salvatore Spina and Lea T Grinberg and William W Seeley and William J Jagust and Gil D Rabinovici},

year  = {2021},

date = {2021-02-01},

journal = {Ann. Neurol.},

volume = {89},

number = {2},

pages = {389--401},

publisher = {Wiley},

abstract = {OBJECTIVE: The purpose of this study was to compare the 

 diagnostic accuracy of antemortem 11 C-Pittsburgh compound B 

 (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission 

 tomography (PET) versus autopsy diagnosis in a heterogenous 

 sample of patients. METHODS: One hundred one participants 

 underwent PIB and FDG PET during life and neuropathological 

 assessment. PET scans were visually interpreted by 3 raters 

 blinded to clinical information. PIB PET was rated as positive 

 or negative for cortical retention, whereas FDG scans were read 

 as showing an Alzheimer disease (AD) or non-AD pattern. 

 Neuropathological diagnoses were assigned using research 

 criteria. Majority visual reads were compared to 

 intermediate-high AD neuropathological change (ADNC). RESULTS: One hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients 

 showed primary AD, 56 showed non-AD neuropathology (primarily 

 frontotemporal lobar degeneration [FTLD]), and 13 showed mixed 

 AD/FTLD pathology. PIB showed higher sensitivity than FDG for 

 detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2021-yr,

title = {Spatial relationships between molecular pathology and 

 neurodegeneration in the Alzheimer's disease continuum},

author = {Leonardo Iaccarino and Renaud La Joie and Lauren Edwards and Amelia Strom and Daniel R Schonhaut and Rik Ossenkoppele and Julie Pham and Taylor Mellinger and Mustafa Janabi and Suzanne L Baker and David Soleimani-Meigooni and Howard J Rosen and Bruce L Miller and William J Jagust and Gil D Rabinovici},

year  = {2021},

date = {2021-01-01},

journal = {Cereb. Cortex},

volume = {31},

number = {1},

pages = {1--14},

publisher = {Oxford University Press (OUP)},

abstract = {A deeper understanding of the spatial relationships of 

 $beta$-amyloid (A$beta$), tau, and neurodegeneration in 

 Alzheimer's disease (AD) could provide insight into pathogenesis 

 and clinical trial design. We included 81 amyloid-positive 

 patients (age 64.4 $pm$ 9.5) diagnosed with AD dementia or mild 

 cognitive impairment due to AD and available 11C-PiB (PIB), 

 18F-Flortaucipir (FTP),18F-FDG-PET, and 3T-MRI, and 31 

 amyloid-positive, cognitively normal participants (age 77.3 

 $pm$ 6.5, no FDG-PET). W-score voxel-wise deviation maps were 

 created and binarized for each imaging-modality (W > 1.64, P tau 

 > neurodegeneration was the most frequent hierarchy for both 

 groups (79-77%, respectively), followed by tau > amyloid > 

 neurodegeneration (13-10%) and amyloid > neurodegeneration > 

 tau (6-13%). For symptomatic participants, most abnormal voxels 

 were PIB+/FTP+/ND- (median 35%), and the great majority of ND+ 

 voxels (91%) colocalized with molecular pathology. Amyloid 

 spatially exceeded tau and neurodegeneration, with individual 

 heterogeneities. Molecular pathology and neurodegeneration 

 showed a progressive overlap along AD course, indicating shared 

 vulnerabilities or synergistic toxic mechanisms.},

keywords = {amyloid; neurodegeneration; spatial extent; tau; topography},

pubstate = {published},

tppubtype = {article}

}

@article{Soleimani-Meigooni2020-th,

title = {18F-flortaucipir PET to autopsy comparisons in Alzheimer's 

 disease and other neurodegenerative diseases},

author = {David N Soleimani-Meigooni and Leonardo Iaccarino and Renaud La Joie and Suzanne Baker and Viktoriya Bourakova and Adam L Boxer and Lauren Edwards and Rana Eser and Maria-Luisa Gorno-Tempini and William J Jagust and Mustafa Janabi and Joel H Kramer and Orit H Lesman-Segev and Taylor Mellinger and Bruce L Miller and Julie Pham and Howard J Rosen and Salvatore Spina and William W Seeley and Amelia Strom and Lea T Grinberg and Gil D Rabinovici},

year  = {2020},

date = {2020-12-01},

journal = {Brain},

volume = {143},

number = {11},

pages = {3477--3494},

publisher = {Oxford University Press (OUP)},

abstract = {Few studies have evaluated the relationship between in 

 vivo18F-flortaucipir PET and post-mortem pathology. We sought to 

 compare antemortem 18F-flortaucipir PET to neuropathology in a 

 consecutive series of patients with a broad spectrum of 

 neurodegenerative conditions. Twenty patients were included 

 [mean age at PET 61 years (range 34-76); eight female; median 

 PET-to-autopsy interval of 30 months (range 4-59 months)]. Eight 

 patients had primary Alzheimer's disease pathology, nine had 

 non-Alzheimer tauopathies (progressive supranuclear palsy, 

 corticobasal degeneration, argyrophilic grain disease, and 

 frontotemporal lobar degeneration with MAPT mutations), and 

 three had non-tau frontotemporal lobar degeneration. Using an 

 inferior cerebellar grey matter reference, 80-100-min 

 18F-flortaucipir PET standardized uptake value ratio (SUVR) 

 images were created. Mean SUVRs were calculated for progressive 

 supranuclear palsy, corticobasal degeneration, and 

 neurofibrillary tangle Braak stage regions of interest, and 

 these values were compared to SUVRs derived from young, 

 non-autopsy, cognitively normal controls used as a standard for 

 tau negativity. W-score maps were generated to highlight areas 

 of increased tracer retention compared to cognitively normal 

 controls, adjusting for age as a covariate. Autopsies were 

 performed blinded to PET results. There was excellent 

 correspondence between areas of 18F-flortaucipir retention, on 

 both SUVR images and W-score maps, and neurofibrillary tangle 

 distribution in patients with primary Alzheimer's disease 

 neuropathology. Patients with non-Alzheimer tauopathies and 

 non-tau frontotemporal lobar degeneration showed a range of 

 tracer retention that was less than Alzheimer's disease, though 

 higher than age-matched, cognitively normal controls. Overall, 

 binding across both tau-positive and tau-negative non-Alzheimer 

 disorders did not reliably correspond with post-mortem tau 

 pathology. 18F-flortaucipir SUVRs in subcortical regions were 

 higher in autopsy-confirmed progressive supranuclear palsy and 

 corticobasal degeneration than in controls, but were similar to 

 values measured in Alzheimer's disease and tau-negative 

 neurodegenerative pathologies. Quantification of 

 18F-flortaucipir SUVR images at Braak stage regions of interest 

 reliably detected advanced Alzheimer's (Braak VI) pathology. 

 However, patients with earlier Braak stages (Braak I-IV) did not 

 show elevated tracer uptake in these regions compared to young, 

 tau-negative controls. In summary, PET-to-autopsy comparisons 

 confirm that 18F-flortaucipir PET is a reliable biomarker of 

 advanced Braak tau pathology in Alzheimer's disease. The tracer 

 cannot reliably differentiate non-Alzheimer tauopathies and may 

 not detect early Braak stages of neurofibrillary tangle 

 pathology.},

keywords = {Alzheimer's disease; neurofibrillary tangle; neuropathology;   positron emission tomography; tau},

pubstate = {published},

tppubtype = {article}

}

@article{Sonni2020-kb,

title = {Evaluation of a visual interpretation method for tau-PET with 

 18F-flortaucipir},

author = {Ida Sonni and Orit H Lesman Segev and Suzanne L Baker and Leonardo Iaccarino and Deniz Korman and Gil D Rabinovici and William J Jagust and Susan M Landau and Renaud La Joie and Alzheimer's Disease Neuroimaging Initiative},

year  = {2020},

date = {2020-11-01},

journal = {Alzheimers Dement. (Amst.)},

volume = {12},

number = {1},

pages = {e12133},

publisher = {Wiley},

abstract = {Introduction: Positron emission tomography targeting tau 

 (tau-PET) is a promising diagnostic tool for the identification 

 of Alzheimer's disease (AD). Currently available data rely on 

 quantitative measures, and a visual interpretation method, 

 critical for clinical translation, is needed. Methods: We 

 developed a visual interpretation method for 18F-flortaucipir 

 tau-PET and tested it on 274 individuals (cognitively normal 

 controls, patients with mild cognitive impairment [MCI], AD 

 dementia, and non-AD diagnoses). Two readers interpreted 

 18F-flortaucipir PET using two complementary indices: a global 

 visual score and a visual distribution pattern. Results: Global 

 visual scores were reliable, correlated with global cortical 

 18F-flortaucipir standardized uptake value ratio (SUVR) and were 

 associated with clinical diagnosis and amyloid status. The 

 AD-like 18F-flortaucipir pattern had good sensitivity and 

 specificity to identify amyloid-positive patients with AD 

 dementia or MCI. Discussion: This 18F-flortaucipir visual rating 

 scheme is associated with SUVR quantification, clinical 

 diagnosis, and amyloid status, and constitutes a promising 

 approach to tau measurement in clinical settings.},

keywords = {Alzheimer's disease; flortaucipir; qualitative assessment; tau   positron emission tomography; visual assessment},

pubstate = {published},

tppubtype = {article}

}

@article{Europa2020-gu,

title = {Diagnostic assessment in primary progressive aphasia: An 

 illustrative case example},

author = {Eduardo Europa and Leonardo Iaccarino and David C Perry and Elizabeth Weis and Ariane E Welch and Gil D Rabinovici and Bruce L Miller and Maria Luisa Gorno-Tempini and Maya L Henry},

year  = {2020},

date = {2020-11-01},

journal = {Am. J. Speech. Lang. Pathol.},

volume = {29},

number = {4},

pages = {1833--1849},

publisher = {American Speech Language Hearing Association},

abstract = {Purpose Diagnosis and classification of primary progressive 

 aphasia (PPA) requires confirmation of specific speech and 

 language symptoms, highlighting the important role of 

 speech-language pathologists in the evaluation process. The 

 purpose of this case report is to inform speech-language 

 pathologists regarding current practices for diagnostic 

 assessment in PPA, describing standard approaches as well as 

 complementary, state-of-the-art procedures that may improve 

 diagnostic precision. Method We describe the diagnostic 

 evaluation of a 49-year-old woman with complaints of progressive 

 word-finding difficulty. She completed standard neurological, 

 neuropsychological, and speech-language evaluations, as well as 

 magnetic resonance and positron emission tomography imaging of 

 her brain. In addition, a history of developmental speech, 

 language, and learning abilities was obtained, as well as 

 genetic testing and assessment of cerebrospinal fluid 

 biomarkers. We discuss the evaluation results in the context of 

 the most current research related to PPA diagnosis. Conclusion 

 Detailed behavioral assessment, thorough intake of symptom 

 history and neurodevelopmental differences, multimodal 

 neuroimaging, and comprehensive examination of genes and 

 biomarkers are of paramount importance for detecting and 

 characterizing PPA, with ramifications for early behavioral 

 and/or pharmacological intervention. Supplemental Material 

 https://doi.org/10.23641/asha.12771113.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lindbergh2020-bs,

title = {Sex-related differences in the relationship between 

 $beta$-amyloid and cognitive trajectories in older adults},

author = {Cutter A Lindbergh and Kaitlin B Casaletto and Adam M Staffaroni and Renaud La Joie and Leonardo Iaccarino and Lauren Edwards and Elena Tsoy and Fanny Elahi and Samantha M Walters and Devyn Cotter and Michelle You and Alexandra C Apple and Breton Asken and John Neuhaus and Jessica E Rexach and Kevin J Wojta and Gil Rabinovici and Joel H Kramer and Hillblom Aging Network},

year  = {2020},

date = {2020-11-01},

journal = {Neuropsychology},

volume = {34},

number = {8},

pages = {835--850},

publisher = {American Psychological Association (APA)},

abstract = {Objective: We aimed to test the hypothesis that elevated 

 neocortical $beta$-amyloid (A$beta$), a hallmark feature of 

 Alzheimer's disease (AD), predicts sex-specific cognitive 

 trajectories in clinically normal older adults, with women 

 showing greater risk of decline than men. Method: Florbetapir 

 A$beta$ positron emission tomography (PET) was acquired in 149 clinically normal older adults (52% femal},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Tondo2020-om,

title = {11 C-PK11195 PET-based molecular study of microglia 

 activation in SOD1 amyotrophic lateral sclerosis},

author = {Giacomo Tondo and Leonardo Iaccarino and Chiara Cerami and Giovanna Emilia Vanoli and Luca Presotto and Valeria Masiello and Angela Coliva and Fabrizio Salvi and Ilaria Bartolomei and Lorena Mosca and Christian Lunetta and Daniela Perani},

year  = {2020},

date = {2020-09-01},

journal = {Ann. Clin. Transl. Neurol.},

volume = {7},

number = {9},

pages = {1513--1523},

publisher = {Wiley},

abstract = {OBJECTIVE: Neuroinflammation is considered a key driver for 

 neurodegeneration in several neurological diseases, including 

 amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 

 20% of familial ALS, and related pathology might generate 

 microglial activation triggering neurodegeneration. 11 C-PK11195 

 is the prototypical and most validated PET radiotracer, 

 targeting the 18-kDa translocator protein which is overexpressed 

 in activated microglia. In this study, we investigated microglia 

 activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 

 mutated carriers, by using 11 C-PK11195 and PET imaging. 

 METHODS: We included 20 subjects: 4 ASYM-carriers, 

 neurologically normal, 6 SYM-carriers with probable ALS, and 10 

 healthy controls. A receptor parametric mapping procedure 

 estimated 11 C-PK11195 binding potentials and voxel-wise 

 statistical comparisons were performed at group and 

 single-subject levels. RESULTS: Both the SYM- and ASYM-carriers 

 showed significant microglia activation in cortical and 

 subcortical structures, with variable patterns at individual 

 level. Clusters of activation were present in occipital and 

 temporal regions, cerebellum, thalamus, and medulla oblongata. 

 Notably, SYM-carriers showed microglia activation also in 

 supplementary and primary motor cortices and in the 

 somatosensory regions. INTERPRETATION: In vivo neuroinflammation 

 occurred in all SOD1 mutated cases since the presymptomatic 

 stages, as shown by a significant cortical and subcortical 

 microglia activation. The involvement of sensorimotor cortex 

 became evident at the symptomatic disease stage. Although our 

 data indicate the role of in vivo PET imaging for assessing 

 resident microglia in the investigation of SOD1-ALS 

 pathophysiology, further studies are needed to clarify the 

 temporal and spatial dynamics of microglia activation and its 

 relationship with neurodegeneration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bejanin2020-nj,

title = {Longitudinal structural and metabolic changes in frontotemporal 

 dementia},

author = {Alexandre Bejanin and Gautam Tammewar and Gabe Marx and Yann Cobigo and Leonardo Iaccarino and John Kornak and Adam M Staffaroni and Bradford C Dickerson and Bradley F Boeve and David S Knopman and Marilu Gorno-Tempini and Bruce L Miller and William J Jagust and Adam L Boxer and Howard J Rosen and Gil D Rabinovici},

year  = {2020},

date = {2020-07-01},

journal = {Neurology},

volume = {95},

number = {2},

pages = {e140--e154},

publisher = {Ovid Technologies (Wolters Kluwer Health)},

abstract = {OBJECTIVE: To compare the sensitivity of structural MRI and 

 18F-fludeoxyglucose PET (18FDG-PET) to detect longitudinal 

 changes in frontotemporal dementia (FTD). METHODS: Thirty 

 patients with behavioral variant FTD (bvFTD), 7 with 

 nonfluent/agrammatic variant primary progressive aphasia 

 (nfvPPA), 16 with semantic variant primary progressive aphasia 

 (svPPA), and 43 cognitively normal controls underwent 2-4 MRI and 18FDG-PET scans (total scans/visit = 270) as part of the 

 Frontotemporal Lobar Degeneration Neuroimaging Initiative study. 

 Linear mixed-effects models were carried out voxel-wise and in 

 regions of interest to identify areas showing decreased volume 

 or metabolism over time in patients as compared to controls. 

 RESULTS: At baseline, patients with bvFTD showed bilateral 

 temporal, dorsolateral, and medial prefrontal 

 atrophy/hypometabolism that extended with time into adjacent 

 structures and parietal lobe. In nfvPPA, baseline 

 atrophy/hypometabolism in supplementary motor cortex extended 

 with time into left greater than right precentral, dorsolateral, 

 and dorsomedial prefrontal cortex. In svPPA, baseline 

 atrophy/hypometabolism encompassed the anterior temporal and 

 medial prefrontal cortex and longitudinal changes were found in 

 temporal, orbitofrontal, and lateral parietal cortex. Across 

 syndromes, there was substantial overlap in the brain regions 

 showing volume and metabolism loss. Even though the pattern of 

 metabolic decline was more extensive, metabolic changes were 

 also more variable and sample size estimates were similar or 

 higher for 18FDG-PET compared to MRI. CONCLUSION: Our findings 

 demonstrated the sensitivity of 18FDG-PET and structural MRI for 

 tracking disease progression in FTD. Both modalities showed 

 highly overlapping patterns of longitudinal change and 

 comparable sample size estimates to detect longitudinal changes 

 in future clinical trials.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Tondo2020-sv,

title = {The combined effects of microglia activation and brain glucose 

 hypometabolism in early-onset Alzheimer's disease},

author = {Giacomo Tondo and Leonardo Iaccarino and Silvia Paola Caminiti and Luca Presotto and Roberto Santangelo and Sandro Iannaccone and Giuseppe Magnani and Daniela Perani},

year  = {2020},

date = {2020-04-01},

journal = {Alzheimers. Res. Ther.},

volume = {12},

number = {1},

pages = {50},

publisher = {Springer Science and Business Media LLC},

abstract = {BACKGROUND: Early-onset Alzheimer's disease (EOAD) is 

 characterized by young age of onset (< 65 years), severe 

 neurodegeneration, and rapid disease progression, thus differing 

 significantly from typical late-onset Alzheimer's disease. 

 Growing evidence suggests a primary role of neuroinflammation in 

 AD pathogenesis. However, the role of microglia activation in 

 EOAD remains a poorly explored field. Investigating microglial 

 activation and its influence on the development of synaptic 

 dysfunction and neuronal loss in EOAD may contribute to the 

 understanding of its pathophysiology and to subject selection in 

 clinical trials. In our study, we aimed to assess the amount of 

 neuroinflammation and neurodegeneration and their relationship 

 in EOAD patients, through positron emission tomography (PET) 

 measures of microglia activation and brain metabolic changes. 

 METHODS: We prospectively enrolled 12 EOAD patients, classified 

 according to standard criteria, who underwent standard 

 neurological and neuropsychological evaluation, CSF analysis, 

 brain MRI, and both [18F]-FDG PET and [11C]-(R)-PK11195 PET. 

 Healthy controls databases were used for statistical comparison. 

 [18F]-FDG PET brain metabolism in single subjects and as a group 

 was assessed by an optimized SPM voxel-wise single-subject 

 method. [11C]-PK11195 PET binding potentials were obtained using 

 reference regions selected with an optimized clustering 

 procedure followed by a parametric analysis. We performed a 

 topographic interaction analysis and correlation analysis in 

 AD-signature metabolic dysfunctional regions and regions of 

 microglia activation. A network connectivity analysis was 

 performed using the interaction regions of hypometabolism and 

 [11C]-PK11195 PET BP increases. RESULTS: EOAD patients showed a 

 significant and extended microglia activation, as [11C]-PK11195 

 PET binding potential increases, and hypometabolism in typical 

 AD-signature brain regions, i.e., temporo-parietal cortex, with 

 additional variable frontal and occipital hypometabolism in the 

 EOAD variants. There was a spatial concordance in the 

 interaction areas and significant correlations between the two 

 biological changes. The network analysis showed a disruption of 

 frontal connectivity induced by the metabolic/microglia effects. 

 CONCLUSION: The severe microglia activation characterizing EOAD 

 and contributing to neurodegeneration may be a marker of rapid 

 disease progression. The coupling between brain glucose 

 hypometabolism and local immune response in AD-signature regions 

 supports their biological interaction.},

keywords = {Early-onset Alzheimer's disease; Microglia activation; Positron   emission tomography; [11C]-(R)-PK11195 PET; [18F]-FDG PET},

pubstate = {published},

tppubtype = {article}

}

@article{Mantyh2020-ue,

title = {Tau positron emission tomographic findings in a former US 

 football player with pathologically confirmed chronic traumatic 

 encephalopathy},

author = {William G Mantyh and Salvatore Spina and Alex Lee and Leonardo Iaccarino and David Soleimani-Meigooni and Elena Tsoy and Taylor J Mellinger and Harli Grant and Lawren Vandevrede and Renaud La Joie and Orit Lesman-Segev and Stephanie Gaus and Katherine L Possin and Lea T Grinberg and Bruce L Miller and William W Seeley and Gil D Rabinovici},

year  = {2020},

date = {2020-04-01},

journal = {JAMA Neurol.},

volume = {77},

number = {4},

pages = {517--521},

publisher = {American Medical Association (AMA)},

abstract = {Importance: Biomarkers for chronic traumatic encephalopathy 

 (CTE) are currently lacking. The radiotracer fluorine F 

 18-labeled (18F)-flortaucipir (FTP) detects tau pathology in 

 Alzheimer disease, and positron emission tomography (PET) with 

 FTP shows elevated binding in individuals at risk for CTE. No 

 study, however, has assessed the correlation between in vivo FTP 

 PET and postmortem tau in CTE. Objective: To assess the regional 

 association between in vivo FTP binding and postmortem tau 

 pathology in a patient with pathologically confirmed CTE. 

 Design, Setting, and Participants: A white male former National 

 Football League player with 17 years of US football exposure was 

 clinically diagnosed with traumatic encephalopathy syndrome at a 

 neurology tertiary referral center. 18F-Fludeoxyglucose, carbon 

 11-labeled Pittsburgh compound B, and FTP PET were performed 52 

 months prior to death, and magnetic resonance imaging, 50 months 

 prior to death. Brain images were assessed qualitatively for 

 abnormalities blinded to autopsy data. Autopsy was performed 

 using a neurodegenerative research protocol. The FTP 

 standardized uptake value ratios (inferior cerebellar gray 

 reference region) and W-score (age-adjusted z-score) maps were 

 compared with phosphorylated tau immunohistochemical analysis 

 with monoclonal antibody CP13. Main Outcomes and Measures: 

 Qualitative and quantitative comparisons between antemortem FTP 

 PET and tau pathology at autopsy. Results: Flortaucipir uptake 

 was distributed in a patchy, frontotemporal-predominant pattern 

 that overlapped with regions showing neurodegeneration on 

 magnetic resonance imaging and hypometabolism on 

 18F-fludeoxyglucose PET. Pathological assessment revealed stage 

 4 CTE; limbic argyrophilic grain disease; stage 2 

 limbic-predominant, age-related transactive response DNA-binding 

 protein 43 encephalopathy; and Braak neurofibrillary tangle 

 stage 3. 18F-Flortaucipir W-maps matched areas of high 

 postmortem tau burden in left fusiform and inferior temporal 

 gyri and juxtacortical frontal white matter. High FTP W-scores 

 with low tau burden were found in the basal ganglia, thalamus, 

 motor cortex, and calcarine cortex. No regions with low FTP 

 W-scores corresponded to areas with high pathological tau 

 burden. A modest correlation, which did not reach statistical significance ($rho$ = 0.3},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ranasinghe2020-cw,

title = {Neurophysiological signatures in Alzheimer's disease are 

 distinctly associated with TAU, amyloid-$beta$ accumulation, 

 and cognitive decline},

author = {Kamalini G Ranasinghe and Jungho Cha and Leonardo Iaccarino and Leighton B Hinkley and Alexander J Beagle and Julie Pham and William J Jagust and Bruce L Miller and Katherine P Rankin and Gil D Rabinovici and Keith A Vossel and Srikantan S Nagarajan},

year  = {2020},

date = {2020-03-01},

journal = {Sci. Transl. Med.},

volume = {12},

number = {534},

pages = {eaaz4069},

publisher = {American Association for the Advancement of Science (AAAS)},

abstract = {Neural synchrony is intricately balanced in the normal resting 

 brain but becomes altered in Alzheimer's disease (AD). To 

 determine the neurophysiological manifestations associated with 

 molecular biomarkers of AD neuropathology, in patients with AD, 

 we used magnetoencephalographic imaging (MEGI) and positron 

 emission tomography with amyloid-beta (A$beta$) and TAU 

 tracers. We found that alpha oscillations (8 to 12 Hz) were 

 hyposynchronous in occipital and posterior temporoparietal 

 cortices, whereas delta-theta oscillations (2 to 8 Hz) were 

 hypersynchronous in frontal and anterior temporoparietal 

 cortices, in patients with AD compared to age-matched controls. 

 Regional patterns of alpha hyposynchrony were unique in each 

 neurobehavioral phenotype of AD, whereas the regional patterns 

 of delta-theta hypersynchrony were similar across the 

 phenotypes. Alpha hyposynchrony strongly colocalized with TAU 

 deposition and was modulated by the degree of TAU tracer uptake. 

 In contrast, delta-theta hypersynchrony colocalized with both 

 TAU and A$beta$ depositions and was modulated by both TAU and 

 A$beta$ tracer uptake. Furthermore, alpha hyposynchrony but not 

 delta-theta hypersynchrony was correlated with the degree of 

 global cognitive dysfunction in patients with AD. The current 

 study demonstrates frequency-specific neurophysiological 

 signatures of AD pathophysiology and suggests that 

 neurophysiological measures from MEGI are sensitive indices of 

 network disruptions mediated by TAU and A$beta$ and associated 

 cognitive decline. These findings facilitate the pursuit of 

 novel therapeutic approaches toward normalizing network 

 synchrony in AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Thijssen2020-id,

title = {Diagnostic value of plasma phosphorylated tau181 in Alzheimer's 

 disease and frontotemporal lobar degeneration},

author = {Elisabeth H Thijssen and Renaud La Joie and Amy Wolf and Amelia Strom and Ping Wang and Leonardo Iaccarino and Viktoriya Bourakova and Yann Cobigo and Hilary Heuer and Salvatore Spina and Lawren VandeVrede and Xiyun Chai and Nicholas K Proctor and David C Airey and Sergey Shcherbinin and Cynthia Duggan Evans and John R Sims and Henrik Zetterberg and Kaj Blennow and Anna M Karydas and Charlotte E Teunissen and Joel H Kramer and Lea T Grinberg and William W Seeley and Howie Rosen and Bradley F Boeve and Bruce L Miller and Gil D Rabinovici and Jeffrey L Dage and Julio C Rojas and Adam L Boxer and Advancing Research and Treatment investigators},

year  = {2020},

date = {2020-03-01},

journal = {Nat. Med.},

volume = {26},

number = {3},

pages = {387--397},

publisher = {Springer Science and Business Media LLC},

abstract = {With the potential development of new disease-modifying 

 Alzheimer's disease (AD) therapies, simple, widely available 

 screening tests are needed to identify which individuals, who 

 are experiencing symptoms of cognitive or behavioral decline, 

 should be further evaluated for initiation of treatment. A 

 blood-based test for AD would be a less invasive and less 

 expensive screening tool than the currently approved 

 cerebrospinal fluid or amyloid $beta$ positron emission 

 tomography (PET) diagnostic tests. We examined whether plasma 

 tau phosphorylated at residue 181 (pTau181) could differentiate 

 between clinically diagnosed or autopsy-confirmed AD and 

 frontotemporal lobar degeneration. Plasma pTau181 concentrations 

 were increased by 3.5-fold in AD compared to controls and 

 differentiated AD from both clinically diagnosed (receiver 

 operating characteristic area under the curve of 0.894) and 

 autopsy-confirmed frontotemporal lobar degeneration (area under 

 the curve of 0.878). Plasma pTau181 identified individuals who 

 were amyloid $beta$-PET-positive regardless of clinical 

 diagnosis and correlated with cortical tau protein deposition 

 measured by 18F-flortaucipir PET. Plasma pTau181 may be useful 

 to screen for tau pathology associated with AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{La_Joie2020-yl,

title = {Prospective longitudinal atrophy in Alzheimer's disease 

 correlates with the intensity and topography of baseline 

 tau-PET},

author = {Renaud La Joie and Adrienne V Visani and Suzanne L Baker and Jesse A Brown and Viktoriya Bourakova and Jungho Cha and Kiran Chaudhary and Lauren Edwards and Leonardo Iaccarino and Mustafa Janabi and Orit H Lesman-Segev and Zachary A Miller and David C Perry and James P O'Neil and Julie Pham and Julio C Rojas and Howard J Rosen and William W Seeley and Richard M Tsai and Bruce L Miller and William J Jagust and Gil D Rabinovici},

year  = {2020},

date = {2020-01-01},

journal = {Sci. Transl. Med.},

volume = {12},

number = {524},

pages = {eaau5732},

publisher = {American Association for the Advancement of Science (AAAS)},

abstract = {$beta$-Amyloid plaques and tau-containing neurofibrillary 

 tangles are the two neuropathological hallmarks of Alzheimer's 

 disease (AD) and are thought to play crucial roles in a 

 neurodegenerative cascade leading to dementia. Both lesions can 

 now be visualized in vivo using positron emission tomography 

 (PET) radiotracers, opening new opportunities to study disease 

 mechanisms and improve patients' diagnostic and prognostic 

 evaluation. In a group of 32 patients at early symptomatic AD 

 stages, we tested whether $beta$-amyloid and tau-PET could 

 predict subsequent brain atrophy measured using longitudinal 

 magnetic resonance imaging acquired at the time of PET and 15 

 months later. Quantitative analyses showed that the global 

 intensity of tau-PET, but not $beta$-amyloid-PET, signal 

 predicted the rate of subsequent atrophy, independent of 

 baseline cortical thickness. Additional investigations 

 demonstrated that the specific distribution of tau-PET signal 

 was a strong indicator of the topography of future atrophy at 

 the single patient level and that the relationship between 

 baseline tau-PET and subsequent atrophy was particularly strong 

 in younger patients. These data support disease models in which 

 tau pathology is a major driver of local neurodegeneration and 

 highlight the relevance of tau-PET as a precision medicine tool 

 to help predict individual patient's progression and design 

 future clinical trials.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2020-gy,

title = {In vivo MRI structural and PET metabolic connectivity study 

 of dopamine pathways in Alzheimer's disease},

author = {Leonardo Iaccarino and Arianna Sala and Silvia Paola Caminiti and Luca Presotto and Daniela Perani and Alzheimer's Disease Neuroimaging Initiative},

year  = {2020},

date = {2020-01-01},

journal = {J. Alzheimers. Dis.},

volume = {75},

number = {3},

pages = {1003--1016},

publisher = {IOS Press},

abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by an 

 involvement of brain dopamine (DA) circuitry, the presence of 

 which has been associated with emergence of both 

 neuropsychiatric symptoms and cognitive deficits. OBJECTIVE: In 

 order to investigate whether and how the DA pathways are 

 involved in the pathophysiology of AD, we assessed by in vivo 

 neuroimaging the structural and metabolic alterations of 

 subcortical and cortical DA pathways and targets. METHODS: We 

 included 54 healthy control participants, 53 amyloid-positive 

 subjects with mild cognitive impairment due to AD (MCI-AD), and 

 60 amyloid-positive patients with probable dementia due to AD 

 (ADD), all with structural 3T MRI and 18F-FDG-PET scans. We 

 assessed MRI-based gray matter reductions in the MCI-AD and ADD 

 groups within an anatomical a priori-defined Nigrostriatal and 

 Mesocorticolimbic DA pathways, followed by 18F-FDG-PET metabolic 

 connectivity analyses to evaluate network-level metabolic 

 connectivity changes. RESULTS: We found significant tissue loss 

 in the Mesocorticolimbic over the Nigrostriatal pathway. Atrophy 

 was evident in the ventral striatum, orbitofrontal cortex, and 

 medial temporal lobe structures, and already plateaued in the 

 MCI-AD stage. Degree of atrophy in Mesocorticolimbic regions 

 positively correlated with the severity of depression, anxiety, 

 and apathy in MCI-AD and ADD subgroups. Additionally, we 

 observed significant alterations of metabolic connectivity 

 between the ventral striatum and fronto-cingulate regions in 

 ADD, but not in MCI-AD. There were no metabolic connectivity 

 changes within the Nigrostriatal pathway. CONCLUSION: Our 

 cross-sectional data support a clinically-meaningful, yet 

 stage-dependent, involvement of the Mesocorticolimbic system in 

 AD. Longitudinal and clinical correlation studies are needed to 

 further establish the relevance of DA system involvement in AD.},

keywords = {Alzheimer's disease; connectivity; dementia; dopamine systems;   mild cognitive impairment; ventro-tegmental area},

pubstate = {published},

tppubtype = {article}

}

@article{Perani2019-mp,

title = {Application of advanced brain positron emission tomography-based 

 molecular imaging for a biological framework in 

 neurodegenerative proteinopathies},

author = {Daniela Perani and Leonardo Iaccarino and Andreas H Jacobs and IMBI Brain Imaging Working Group},

year  = {2019},

date = {2019-12-01},

journal = {Alzheimers Dement. (Amst.)},

volume = {11},

number = {1},

pages = {327--332},

publisher = {Wiley},

abstract = {Introduction: A rapid transition from a clinical-based 

 classification to a pathology-based classification of 

 neurodegenerative conditions, largely promoted by the increasing 

 availability of imaging biomarkers, is emerging. The Framework 

 for Innovative Multi-tracer molecular Brain Imaging, funded by 

 the EU Joint Program - Neurodegenerative Disease Research 2016 

 ``Working Groups for Harmonisation and Alignment in Brain 

 Imaging Methods for Neurodegeneration,'' aimed at providing a 

 roadmap for the applications of established and new molecular 

 imaging techniques in dementia. Methods: We consider current and 

 future implications of adopting a pathology-based framework for 

 the use and development of positron emission tomography 

 techniques. Results: This approach will enhance efforts to 

 understand the multifactorial etiology of Alzheimer's disease 

 and other dementias. Discussion: The availability of pathology 

 biomarkers will soon transform clinical and research practice. 

 Crucially, a comprehensive understanding of strengths and 

 caveats of these techniques will promote an informed use to take 

 full advantage of these tools.},

keywords = {Amyloid; Neuroinflammation; PET molecular imaging;   Protheinopathies; Radiotracers; Tau},

pubstate = {published},

tppubtype = {article}

}

@article{Sala2019-zu,

title = {Vulnerability of multiple large-scale brain networks in dementia 

 with Lewy bodies},

author = {Arianna Sala and Silvia Paola Caminiti and Leonardo Iaccarino and Luca Beretta and Sandro Iannaccone and Giuseppe Magnani and Alessandro Padovani and Luigi Ferini-Strambi and Daniela Perani},

year  = {2019},

date = {2019-10-01},

journal = {Hum. Brain Mapp.},

volume = {40},

number = {15},

pages = {4537--4550},

publisher = {Wiley},

abstract = {Aberrations of large-scale brain networks are found in the 

 majority of neurodegenerative disorders. The brain connectivity 

 alterations underlying dementia with Lewy bodies (DLB) remain, 

 however, still elusive, with contrasting results possibly due to 

 the pathological and clinical heterogeneity characterizing this 

 disorder. Here, we provide a molecular assessment of brain 

 network alterations, based on cerebral metabolic measurements as 

 proxies of synaptic activity and density, in a large cohort of DLB patients (N = 72). We applied a seed-based interregional 

 correlation analysis approach (p < .01, false discovery rate 

 corrected) to evaluate large-scale resting-state networks' 

 integrity and their interactions. We found both local and 

 long-distance metabolic connectivity alterations, affecting the 

 posterior cortical networks, that is, primary visual and the 

 posterior default mode network, as well as the limbic and 

 attention networks, suggesting a widespread derangement of the 

 brain connectome. Notably, patients with the lowest visual and 

 attention cognitive scores showed the most severe connectivity 

 derangement in regions of the primary visual network. In 

 addition, network-level alterations were differentially 

 associated with the core clinical manifestations, namely, 

 hallucinations with more severe metabolic dysfunction of the 

 attention and visual networks, and rapid eye movement sleep 

 behavior disorder with alterations of connectivity of attention 

 and subcortical networks. These multiple network-level 

 vulnerabilities may modulate the core clinical and cognitive 

 features of DLB and suggest that DLB should be considered as a 

 complex multinetwork disorder.},

keywords = {FDG; PET; connectivity; default mode network; resting-state   network; synuclein},

pubstate = {published},

tppubtype = {article}

}

@article{Perani2019-vw,

title = {A new perspective for advanced positron emission 

 tomography-based molecular imaging in neurodegenerative 

 proteinopathies},

author = {Daniela Perani and Leonardo Iaccarino and Adriaan A Lammertsma and Albert D Windhorst and Paul Edison and Ronald Boellaard and Oskar Hansson and Agneta Nordberg and Andreas H Jacobs and IMBI Project},

year  = {2019},

date = {2019-08-01},

journal = {Alzheimers. Dement.},

volume = {15},

number = {8},

pages = {1081--1103},

publisher = {Wiley},

abstract = {Recent studies in neurodegenerative conditions have increasingly 

 highlighted that the same neuropathology can trigger different 

 clinical phenotypes or, vice-versa, that similar phenotypes can 

 be triggered by different neuropathologies. This evidence has 

 called for the adoption of a pathology spectrum-based approach 

 to study neurodegenerative proteinopathies. These conditions 

 share brain deposition of abnormal protein aggregates, leading 

 to aberrant biochemical, metabolic, functional, and structural 

 changes. Positron emission tomography (PET) is a well-recognized 

 and unique tool for the in vivo assessment of brain 

 neuropathology, and novel PET techniques are emerging for the 

 study of specific protein species. Today, key applications of 

 PET range from early research and clinical diagnostic tools to 

 their use in clinical trials for both participants screening and 

 outcome evaluation. This position article critically reviews the 

 role of distinct PET molecular tracers for different 

 neurodegenerative proteinopathies, highlighting their strengths, 

 weaknesses, and opportunities, with special emphasis on 

 methodological challenges and future applications.},

keywords = {Amyloid; Neuroinflammation; PET molecular imaging;   Protheinopathies; Radiotracers; Tau},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2019-jz,

title = {Predicting long-term clinical stability in amyloid-positive 

 subjects by FDG-PET},

author = {Leonardo Iaccarino and Arianna Sala and Daniela Perani and Alzheimer's Disease Neuroimaging Initiative},

year  = {2019},

date = {2019-06-01},

journal = {Ann. Clin. Transl. Neurol.},

volume = {6},

number = {6},

pages = {1113--1120},

publisher = {Wiley},

abstract = {Imaging biomarkers can be used to screen participants for 

 Alzheimer's disease clinical trials. To test the predictive 

 values in clinical progression of neuropathology change 

 (amyloid-PET) or brain metabolism as neurodegeneration biomarker ([18F]FDG-PET), we evaluated data from N = 268 healthy controls and N = 519 mild cognitive impairment subjects. Despite being a 

 significant risk factor, amyloid positivity was not associated 

 with clinical progression in the majority ($geq$60%) of 

 subjects. Notably, a negative [18F]FDG-PET scan at baseline 

 strongly predicted clinical stability with high negative 

 predictive values (>0.80) for both groups. We suggest 

 [18F]FDG-PET brain metabolism or other neurodegeneration 

 measures should be coupled to amyloid-PET to exclude clinically 

 stable individuals from clinical trials.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ossenkoppele2019-dl,

title = {Tau covariance patterns in Alzheimer's disease patients match 

 intrinsic connectivity networks in the healthy brain},

author = {Rik Ossenkoppele and Leonardo Iaccarino and Daniel R Schonhaut and Jesse A Brown and Renaud La Joie and James P O'Neil and Mustafa Janabi and Suzanne L Baker and Joel H Kramer and Maria-Luisa Gorno-Tempini and Bruce L Miller and Howard J Rosen and William W Seeley and William J Jagust and Gil D Rabinovici},

year  = {2019},

date = {2019-05-01},

journal = {NeuroImage Clin.},

volume = {23},

number = {101848},

pages = {101848},

publisher = {Elsevier BV},

abstract = {According to the network model of neurodegeneration, the spread 

 of pathogenic proteins occurs selectively along connected brain 

 regions. We tested in vivo whether the distribution of 

 filamentous tau (measured with [18F]flortaucipir-PET), fibrillar 

 amyloid-$beta$ ([11C]PIB-PET) and glucose hypometabolism 

 ([18F]FDG-PET) follows the intrinsic functional organization of 

 the healthy brain. We included 63 patients with Alzheimer's 

 disease (AD; 30 male, 63 $pm$ 8 years) who underwent 

 [18F]flortaucipir, [11C]PIB and [18F]FDG PET, and 1000 young 

 adults (427 male, 21 $pm$ 3 years) who underwent task-free 

 fMRI. We selected six predefined disease epicenters as seeds for 

 whole-brain voxelwise covariance analyses to compare correlated 

 patterns of tracer uptake across AD patients against fMRI 

 intrinsic connectivity patterns in young adults. We found a 

 striking convergence between [18F]flortaucipir covariance 

 patterns and intrinsic connectivity maps (range Spearman rho's: 

 0.32-0.78, p < .001), which corresponded with expected 

 functional networks (range goodness-of-fit: 3.8-8.2). The 

 topography of amyloid-$beta$ covariance patterns was more 

 diffuse and less network-specific, while glucose hypometabolic 

 patterns were more spatially restricted than tau but overlapped 

 with functional networks. These findings suggest that the 

 spatial patterns of tau and glucose hypometabolism observed in 

 AD resemble the functional organization of the healthy brain, 

 supporting the notion that tau pathology spreads through 

 circumscribed brain networks and drives neurodegeneration.},

keywords = {Alzheimer's disease; Amyloid; Flortaucipir; Functional   connectivity; PET; Tau},

pubstate = {published},

tppubtype = {article}

}

@article{Sala2019-sv,

title = {Testing the diagnostic accuracy of [18F]FDG-PET in 

 discriminating spinal- and bulbar-onset amyotrophic lateral 

 sclerosis},

author = {Arianna Sala and Leonardo Iaccarino and Piercarlo Fania and Emilia G Vanoli and Federico Fallanca and Caterina Pagnini and Chiara Cerami and Andrea Calvo and Antonio Canosa and Marco Pagani and Adriano Chi`o and Angelina Cistaro and Daniela Perani},

year  = {2019},

date = {2019-05-01},

journal = {Eur. J. Nucl. Med. Mol. Imaging},

volume = {46},

number = {5},

pages = {1117--1131},

publisher = {Springer Science and Business Media LLC},

abstract = {PURPOSE: The role for [18F]FDG-PET in supporting amyotrophic 

 lateral sclerosis (ALS) diagnosis is not fully established. In 

 this study, we aim at evaluating [18F]FDG-PET hypo- and 

 hyper-metabolism patterns in spinal- and bulbar-onset ALS cases, 

 at the single-subject level, testing the diagnostic value in 

 discriminating the two conditions, and the correlations with 

 core clinical symptoms severity. METHODS: We included 95 

 probable-ALS patients with [18F]FDG-PET scan and clinical 

 follow-up. [18F]FDG-PET images were analyzed with an optimized 

 voxel-based-SPM method. The resulting single-subject SPM-t maps 

 were used to: (a) assess brain regional hypo- and 

 hyper-metabolism; (b) evaluate the accuracy of regional hypo- 

 and hyper metabolism in discriminating spinal vs. bulbar-onset 

 ALS; (c) perform correlation analysis with motor symptoms 

 severity, as measured by ALS-FRS-R. RESULTS: Primary motor 

 cortex showed the most frequent hypo-metabolism in both 

 spinal-onset (∼57%) and bulbar-onset (∼64%) ALS; 

 hyper-metabolism was prevalent in the cerebellum in both 

 spinal-onset (∼56.5%) and bulbar-onset (∼55.7%) ALS, and in 

 the occipital cortex in bulbar-onset (∼62.5%) ALS. Regional 

 hypo- and hyper-metabolism yielded a very low accuracy (AUC < 

 0.63) in discriminating spinal- vs. bulbar-onset ALS, as 

 obtained from single-subject SPM-t-maps. Severity of motor 

 symptoms correlated with hypo-metabolism in sensorimotor cortex 

 in spinal-onset ALS, and with cerebellar hyper-metabolism in 

 bulbar-onset ALS. CONCLUSIONS: The high variability in regional 

 hypo- and hyper-metabolism patterns, likely reflecting the 

 heterogeneous pathology and clinical phenotypes, limits the 

 diagnostic potential of [18F]FDG-PET in discriminating spinal 

 and bulbar onset patients.},

keywords = {Amyotrophic lateral sclerosis; Biomarkers; Brain metabolism;   Diagnosis; [18F]FDG-PET},

pubstate = {published},

tppubtype = {article}

}

@article{Caminiti2019-gm,

title = {Brain glucose metabolism in Lewy body dementia: implications for 

 diagnostic criteria},

author = {Silvia Paola Caminiti and Arianna Sala and Leonardo Iaccarino and Luca Beretta and Andrea Pilotto and Luigi Gianolli and Sandro Iannaccone and Giuseppe Magnani and Alessandro Padovani and Luigi Ferini-Strambi and Daniela Perani},

year  = {2019},

date = {2019-02-01},

journal = {Alzheimers. Res. Ther.},

volume = {11},

number = {1},

pages = {20},

publisher = {Springer Science and Business Media LLC},

abstract = {BACKGROUND: [18F]FDG-PET hypometabolism patterns are indicative 

 of different neurodegenerative conditions, even from the 

 earliest disease phase. This makes [18F]FDG-PET a valuable tool 

 in the diagnostic workup of neurodegenerative diseases. The 

 utility of [18F]FDG-PET in dementia with Lewy bodies (DLB) needs 

 further validation by considering large samples of patients and 

 disease comparisons and applying state-of-the-art statistical 

 methods. Here, we aimed to provide an extensive validation of 

 the [18F]FDG-PET metabolic signatures in supporting DLB 

 diagnosis near the first clinical assessment, which is 

 characterized by high diagnostic uncertainty, at the 

 single-subject level. METHODS: In this retrospective study, we included N = 72 patients with heterogeneous clinical 

 classification at entry (mild cognitive impairment, atypical 

 parkinsonisms, possible DLB, probable DLB, and other dementias) 

 and an established diagnosis of DLB at a later follow-up. We 

 generated patterns of [18F]FDG-PET hypometabolism in single 

 cases by using a validated voxel-wise analysis (p 90%. 

 CONCLUSION: The present validation of the diagnostic and 

 prognostic accuracy of the disease-specific brain metabolic 

 signature in DLB at the single-subject level argues for the 

 consideration of [18F]FDG-PET in the early phase of the DLB 

 diagnostic flowchart. The assessment of the [18F]FDG-PET 

 hypometabolism pattern at entry may shorten the diagnostic time, 

 resulting in benefits for treatment options and management of 

 patients.},

keywords = {Biomarker: diagnosis, prognosis; Brain metabolism; Dementia with   Lewy bodies; FDG-PET},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2018-ef,

title = {The brain metabolic signature of visual hallucinations in 

 dementia with Lewy bodies},

author = {Leonardo Iaccarino and Arianna Sala and Silvia Paola Caminiti and Roberto Santangelo and Sandro Iannaccone and Giuseppe Magnani and Daniela Perani},

year  = {2018},

date = {2018-11-01},

journal = {Cortex},

volume = {108},

pages = {13--24},

abstract = {Visual hallucinations (VH) are a core clinical feature of 

 dementia with Lewy bodies (DLB), but their specific neural 

 substrate remains elusive. We used 18F-FDG-PET to study the 

 neural dysfunctional signature of VH in a group of 38 DLB 

 patients (mean age$pm$SD 72.9 $pm$ 7.5) with available 

 anamnestic records, cognitive and neurological examination and 

 NeuroPsychiatric Inventory assessing VH. We tested the voxel-wise 

 correlation between 18F-FDG-PET hypometabolism and VH NPI scores 

 at the whole-group level, then adopting inter-regional 

 correlation analysis to explore the resting-state networks (RSNs) 

 metabolic connectivity in DLB patients with and without visual hallucinations, as compared to N = 38 age-matched healthy 

 controls (HCs) (mean age$pm$SD 71.5 $pm$ 6.9). At the 

 whole-group level, we found a negative correlation between VH NPI 

 scores and 18F-FDG-PET hypometabolism in the right 

 occipito-temporal cortex (p < .001 uncorrected, p < .05 

 Family-Wise Error cluster-corrected). Then, splitting the group 

 according to VH presence, we found that DLB non-hallucinators 

 presented a pattern of connectivity seeding from this 

 occipito-temporal cluster and extending to the ventral visual 

 stream. At difference, the DLB hallucinators showed a metabolic 

 connectivity pattern limited to the occipital-dorsal parietal 

 regions. As for RSNs, both the DLB subgroups showed a markedly 

 reduced extent of attention and visual networks compared to HCs, 

 with a variable alteration in the topography. DLB-VH patients 

 showed a more pronounced shrinkage of the primary visual network, 

 which was disconnected from the higher visual hubs, at difference 

 with both HC and DLB non-hallucinators. These findings suggest 

 that an altered brain metabolic connectivity within and beyond 

 visual systems may promote VH in DLB. These results support the 

 most recent neurocognitive models interpreting VH as the result 

 of an inefficient recruitment of the ventral visual stream and of 

 a large-scale multi-network derangement.},

keywords = {18F-FDG-PET; Dementia with Lewy bodies; Metabolic connectivity;   NPI; Visual hallucinations},

pubstate = {published},

tppubtype = {article}

}

@article{Perani2018-lt,

title = {Prefrontal cortical stimulation in tourette disorder: 

 Proof-of-concept clinical and neuroimaging study},

author = {Daniela Perani and Stefania Lalli and Leonardo Iaccarino and Pierpaolo Alongi and Orsola Gambini and Angelo Franzini and Alberto Albanese},

year  = {2018},

date = {2018-09-01},

journal = {Mov. Disord. Clin. Pract.},

volume = {5},

number = {5},

pages = {499--505},

publisher = {Wiley},

abstract = {Background: The benefits of neurosurgery in Tourette Syndrome 

 (TS) are still incompletely understood. Prefrontal cortical 

 electrical stimulation offers a less invasive alternative to 

 deep brain stimulation. Objective: To perform a pilot assessment 

 on safety and efficacy of prefrontal cortical bilateral 

 electrical stimulation in TS using clinical and brain metabolic 

 assessments. Methods: Four adult TS patients underwent tic 

 assessment using the Yale Global Tic Severity Scale and the Rush 

 Video Rating Scale at baseline and 1, 3, 6, and 12-months after 

 implant; whereas FDG-PET scans were acquired at baseline and 

 after 6 and 12 months. Results: Tic clinical scores were 

 improved at 6 months after implant, meanwhile they showed a 

 tendency to re-emerge at the 12-month follow-up. There was a 

 correlation between FDG-PET and tics, mainly consisting in a 

 reduction of baseline brain hypermetabolism, which paralleled 

 tic score reduction. Conclusion: Epidural stimulation in TS is 

 safe and yields a modulation of tics, paralleled by FDG-PET 

 metabolic modulation.},

keywords = {SPM analysis; Tourette's syndrome; cerebral metabolism;   prefrontal cortical stimulation; tics},

pubstate = {published},

tppubtype = {article}

}

@article{Presotto2018-ow,

title = {Low-dose CT for the spatial normalization of PET images: A 

 validation procedure for amyloid-PET semi-quantification},

author = {Luca Presotto and Leonardo Iaccarino and Arianna Sala and Emilia G Vanoli and Cristina Muscio and Anna Nigri and Maria Grazia Bruzzone and Fabrizio Tagliavini and Luigi Gianolli and Daniela Perani and Valentino Bettinardi},

year  = {2018},

date = {2018-07-01},

journal = {NeuroImage Clin.},

volume = {20},

pages = {153--160},

abstract = {The reference standard for spatial normalization of brain 

 positron emission tomography (PET) images involves structural 

 Magnetic Resonance Imaging (MRI) data. However, the lack of such 

 structural information is fairly common in clinical settings. 

 This might lead to lack of proper image quantification and to 

 evaluation based only on visual ratings, which does not allow 

 research studies or clinical trials based on quantification. 

 PET/CT systems are widely available and CT normalization 

 procedures need to be explored. Here we describe and validate a 

 procedure for the spatial normalization of PET images based on 

 the low-dose Computed Tomography (CT) images contextually 

 acquired for attenuation correction in PET/CT systems. We included N = 34 subjects, spanning from cognitively normal to 

 mild cognitive impairment and dementia, who underwent 

 amyloid-PET/CT (18F-Florbetaben) and structural MRI scans. The 

 proposed pipeline is based on the SPM12 unified segmentation 

 algorithm applied to low-dose CT images. The validation of the 

 normalization pipeline focused on 1) statistical comparisons 

 between regional and global 18F-Florbetaben-PET/CT standardized 

 uptake value ratios (SUVrs) estimated from both CT-based and 

 MRI-based normalized PET images (SUVrCT, SUVrMRI) and 2) 

 estimation of the degrees of overlap between warped gray matter 

 (GM) segmented maps derived from CT- and MRI-based spatial 

 transformations. We found negligible deviations between regional 

 and global SUVrs in the two CT and MRI-based methods. SUVrCT and 

 SUVrMRI global uptake scores showed negligible differences (mean 

 $pm$ sd 0.01 $pm$ 0.03). Notably, the CT- and MRI-based warped 

 GM maps showed excellent overlap (90% within 1 mm). The proposed 

 analysis pipeline, based on low-dose CT images, allows accurate 

 spatial normalization and subsequent PET image quantification. A 

 CT-based analytical pipeline could benefit both research and 

 clinical practice, allowing the recruitment of larger samples and 

 favoring clinical routine analysis.},

keywords = {Alzheimer's disease; Amyloid burden; Positron emission   tomography/computed tomography; SUVr},

pubstate = {published},

tppubtype = {article}

}

@article{Alongi2018-eo,

title = {PET evaluation of late cerebral effect in advanced radiation 

 therapy techniques for cranial base tumors},

author = {Pierpaolo Alongi and Leonardo Iaccarino and Marco Losa and Antonella Del Vecchio and Simonetta Gerevini and Valentina Plebani and Nadia Di Muzio and Pietro Mortini and Luigi Gianolli and Daniela Perani},

year  = {2018},

date = {2018-05-01},

journal = {Curr. Radiopharm.},

volume = {11},

number = {2},

pages = {86--91},

abstract = {BACKGROUND AND OBJECTIVE: Even though the benefits of radiation 

 therapy are well established, it is important to recognize the 

 broad spectrum of radiation-induced changes, particularly in the 

 central nervous system. The possible damage to the brain 

 parenchyma may have clinical consequences and in particular 

 cognitive impairment might be one of the major complication of 

 radiotherapy. To date, no studies have investigated the effects 

 of focal radiation therapy on brain structure and function 

 together with the assessment of their clinical outcomes at a long 

 follow-up. METHODS: In this prospective study, we evaluated in 

 six patients the possible brain late effects after radiation 

 therapy, using a standardized neuropsychological battery, MRI and 

 18F-FDG PET using SPM and semi-quantitative methods, in patients 

 affected by cranial base tumors who underwent gamma knife or 

 tomotherapy. RESULTS: Neuropsychological examinations showed no 

 cognitive impairment after the treatment. In all patients, both 

 MRI assessment and 18F-FDG-PET did not reveal any local or 

 distant anatomical and metabolic late effects. CONCLUSION: The 

 present study support the safety of advanced radiation therapy 

 techniques. 18F-FDG-PET, using SPM and semi-quantitative methods, 

 might be a valuable tool to evaluate the cerebral radiotoxicity 

 in patients treated for brain neoplasms.},

keywords = {18F-FDG PET ; MRI ; SPM ; gamma knife ; radiotoxicity;   tomotherapy},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2018-zg,

title = {An in vivo 11C-(R)-PK11195 PET and in vitro pathology study 

 of microglia activation in Creutzfeldt-Jakob disease},

author = {Leonardo Iaccarino and Rosa Maria Moresco and Luca Presotto and Orso Bugiani and Sandro Iannaccone and Giorgio Giaccone and Fabrizio Tagliavini and Daniela Perani},

year  = {2018},

date = {2018-04-01},

journal = {Mol. Neurobiol.},

volume = {55},

number = {4},

pages = {2856--2868},

abstract = {Microgliosis is part of the immunobiology of Creutzfeldt-Jakob 

 disease (CJD). This is the first report using 11C-(R)-PK11195 PET 

 imaging in vivo to measure 18 kDa translocator protein (TSPO) 

 expression, indexing microglia activation, in symptomatic CJD 

 patients, followed by a postmortem neuropathology comparison. One 

 genetic CJD (gCJD) patient, two sporadic CJD (sCJD) patients, one 

 variant CJD (vCJD) patient (mean $pm$ SD age, 47.50 $pm$ 15.95 

 years), and nine healthy controls (mean $pm$ SD age, 44.00 $pm$ 

 11.10 years) were included in the study. TSPO binding potentials 

 were estimated using clustering and parametric analyses of 

 reference regions. Statistical comparisons were run at the 

 regional and at the voxel-wise levels. Postmortem evaluation 

 measured scrapie prion protein (PrPSc) immunoreactivity, neuronal 

 loss, spongiosis, astrogliosis, and microgliosis. 

 11C-(R)-PK11195-PET showed a significant TSPO overexpression at 

 the cortical level in the two sCJD patients, as well as thalamic 

 and cerebellar involvement; very limited parieto-occipital 

 activation in the gCJD case; and significant increases at the 

 subcortical level in the thalamus, basal ganglia, and midbrain 

 and in the cerebellum in the vCJD brain. Along with misfolded 

 prion deposits, neuropathology in all patients revealed neuronal 

 loss, spongiosis and astrogliosis, and a diffuse cerebral and 

 cerebellar microgliosis which was particularly dense in thalamic 

 and basal ganglia structures in the vCJD brain. These findings 

 confirm significant microgliosis in CJD, which was variably 

 modulated in vivo and more diffuse at postmortem evaluation. 

 Thus, TSPO overexpression in microglia activation, topography, 

 and extent can vary in CJD subtypes, as shown in vivo, possibly 

 related to the response to fast apoptotic processes, but reaches 

 a large amount at the final disease course.},

keywords = {Creutzfeldt-Jakob disease; Microglia activation; PET; Postmortem   examination; Prion disease},

pubstate = {published},

tppubtype = {article}

}

@article{Santos-Santos2018-sc,

title = {Rates of amyloid imaging positivity in patients with primary 

 progressive aphasia},

author = {Miguel A Santos-Santos and Gil D Rabinovici and Leonardo Iaccarino and Nagehan Ayakta and Gautam Tammewar and Iryna Lobach and Maya L Henry and Isabel Hubbard and Maria Luisa Mandelli and Edoardo Spinelli and Zachary A Miller and Peter S Pressman and James P O'Neil and Pia Ghosh and Andreas Lazaris and Marita Meyer and Christa Watson and Soo Jin Yoon and Howard J Rosen and Lea Grinberg and William W Seeley and Bruce L Miller and William J Jagust and Maria Luisa Gorno-Tempini},

year  = {2018},

date = {2018-03-01},

journal = {JAMA Neurol.},

volume = {75},

number = {3},

pages = {342--352},

abstract = {Importance: The ability to predict the pathology underlying 

 different neurodegenerative syndromes is of critical importance 

 owing to the advent of molecule-specific therapies. Objective: To 

 determine the rates of positron emission tomography (PET) amyloid 

 positivity in the main clinical variants of primary progressive 

 aphasia (PPA). Design, Setting, and Participants: This 

 prospective clinical-pathologic case series was conducted at a 

 tertiary research clinic specialized in cognitive disorders. 

 Patients were evaluated as part of a prospective, longitudinal 

 research study between January 2002 and December 2015. Inclusion 

 criteria included clinical diagnosis of PPA; availability of 

 complete speech, language, and cognitive testing; magnetic 

 resonance imaging performed within 6 months of the cognitive 

 evaluation; and PET carbon 11-labeled Pittsburgh Compound-B or 

 florbetapir F 18 brain scan results. Of 109 patients referred for 

 evaluation of language symptoms who underwent amyloid brain 

 imaging, 3 were excluded because of incomplete language 

 evaluations, 5 for absence of significant aphasia, and 12 for 

 presenting with significant initial symptoms outside of the 

 language domain, leaving a cohort of 89 patients with PPA. Main 

 Outcomes and Measures: Clinical, cognitive, neuroimaging, and 

 pathology results. Results: Twenty-eight cases were classified as 

 imaging-supported semantic variant PPA (11 women [39.3%]; mean 

 [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 

 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic 

 variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 

 4 mixed PPA cases. Twenty-four of 28 patients with semantic 

 variant PPA (86%) and 28 of 31 patients with 

 nonfluent/agrammatic variant PPA (90%) had negative amyloid PET 

 scan results, while 25 of 26 patients with logopenic variant PPA 

 (96%) and 3 of 4 mixed PPA cases (75%) had positive scan 

 results. The amyloid positive semantic variant PPA and 

 nonfluent/agrammatic variant PPA cases with available autopsy 

 data (2 of 4 and 2 of 3, respectively) all had a primary 

 frontotemporal lobar degeneration and secondary Alzheimer disease 

 pathologic diagnoses, whereas autopsy of 2 patients with amyloid 

 PET-positive logopenic variant PPA confirmed Alzheimer disease. 

 One mixed PPA patient with a negative amyloid PET scan had Pick 

 disease at autopsy. Conclusions and Relevance: Primary 

 progressive aphasia variant diagnosis according to the current 

 classification scheme is associated with Alzheimer disease 

 biomarker status, with the logopenic variant being associated 

 with carbon 11-labeled Pittsburgh Compound-B positivity in more 

 than 95% of cases. Furthermore, in the presence of a clinical 

 syndrome highly predictive of frontotemporal lobar degeneration 

 pathology, biomarker positivity for Alzheimer disease may be 

 associated more with mixed pathology rather than primary 

 Alzheimer disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Belloli2018-nx,

title = {18F-VC701-PET and MRI in the in vivo neuroinflammation 

 assessment of a mouse model of multiple sclerosis},

author = {Sara Belloli and Lucia Zanotti and Valentina Murtaj and Cristina Mazzon and Giuseppe Di Grigoli and Cristina Monterisi and Valeria Masiello and Leonardo Iaccarino and Andrea Cappelli and Pietro Luigi Poliani and Letterio Salvatore Politi and Rosa Maria Moresco},

year  = {2018},

date = {2018-02-01},

journal = {J. Neuroinflammation},

volume = {15},

number = {1},

pages = {33},

abstract = {BACKGROUND: Positron emission tomography (PET) using translocator 

 protein (TSPO) ligands has been used to detect neuroinflammatory 

 processes in neurological disorders, including multiple sclerosis 

 (MS). The aim of this study was to evaluate neuroinflammation in 

 a mouse MS model (EAE) using TSPO-PET with 18F-VC701, in 

 combination with magnetic resonance imaging (MRI). METHODS: 

 MOG35-55/CFA and pertussis toxin protocol was used to induce EAE 

 in C57BL/6 mice. Disease progression was monitored daily, whereas 

 MRI evaluation was performed at 1, 2, and 4 weeks post-induction. 

 Microglia activation was assessed in vivo by 18F-VC701 PET at the 

 time of maximum disease score and validated by radioligand ex 

 vivo distribution and immunohistochemistry at 2 and 4 weeks 

 post-immunization. RESULTS: In vivo and ex vivo analyses show 

 that 18F-VC701 significantly accumulates within the central 

 nervous system (CNS), particularly in the cortex, striatum, 

 hippocampus, cerebellum, and cervical spinal cord of EAE compared 

 to control mice, at 2 weeks post-immunization. MRI confirmed the 

 presence of focal brain lesions at 2 weeks post-immunization in 

 both T1-weighted and T2 images. Of note, MRI abnormalities 

 attenuated in later post-immunization phase. Neuropathological 

 analysis confirmed the presence of microglial activation in EAE 

 mice, consistent with the in vivo increase of 18F-VC701 uptake. 

 CONCLUSION: Increase of 18F-VC701 uptake in EAE mice is strongly 

 associated with the presence of microglia activation in the acute 

 phase of the disease. The combined use of TSPO-PET and MRI 

 provided complementary evidence on the ongoing disease process, 

 thus representing an attractive new tool to investigate neuronal 

 damage and neuroinflammation at preclinical levels.},

keywords = {EAE monophasic model; MRI; Multiple sclerosis; Neuroinflammation;   TSPO-PET},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2018-br,

title = {An in vivo 11C-PK PET study of microglia activation in Fatal 

 Familial Insomnia},

author = {Leonardo Iaccarino and Luca Presotto and Valentino Bettinardi and Luigi Gianolli and Ignazio Roiter and Sabina Capellari and Piero Parchi and Pietro Cortelli and Daniela Perani},

year  = {2018},

date = {2018-01-01},

journal = {Ann. Clin. Transl. Neurol.},

volume = {5},

number = {1},

pages = {11--18},

abstract = {Objective: Postmortem studies reported significant microglia 

 activation in association with neuronal apoptosis in Fatal 

 Familial Insomnia (FFI), indicating a specific glial response, 

 but negative evidence also exists. An in vivo study of local 

 immune responses over FFI natural course may contribute to the 

 understanding of the underlying pathogenesis. Methods: We 

 included eight presymptomatic subjects (mean $pm$ SD age:44.13 

 $pm$ 3.83 years) carrying the pathogenic D178N-129met FFI 

 mutation, one symptomatic patient (male, 45 yrs. old), and nine 

 healthy controls (HC) (mean $pm$ SD age: 44.00 $pm$ 11.10 

 years.) for comparisons. 11C-(R)-PK11195 PET allowed the 

 measurement of Translocator Protein (TSPO) overexpression, 

 indexing microglia activation. A clustering algorithm was adopted 

 to define subject-specific reference regions. Voxel-wise 

 statistical analyses were performed on 11C-(R)-PK11195 binding 

 potential (BP) images both at the group and individual level. 

 Results: The D178N-129met/val FFI patient showed significant 

 11C-(R)-PK11195 BP increases in the midbrain, cerebellum, 

 anterior thalamus, anterior cingulate cortex, orbitofrontal 

 cortex, and anterior insula, bilaterally. Similar TSPO increases, 

 but limited to limbic structures, were observed in four out of 

 eight presymptomatic carriers. The only carrier with the codon 

 129met/val polymorphism was the only one showing an additional 

 TSPO increase in the anterior thalamus. Interpretation: In 

 comparison to nonprion neurodegenerative diseases, the observed 

 lack of a diffuse brain TSPO overexpression in preclinical and 

 the clinical FFI cases suggests the presence of a different 

 microglia response. The involvement of limbic structures might 

 indicate a role for microglia activation in these key pathologic 

 regions, known to show the most significant neuronal loss and 

 functional deafferentation in FFI.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2018-fr,

title = {Local and distant relationships between amyloid, tau and 

 neurodegeneration in Alzheimer's Disease},

author = {Leonardo Iaccarino and Gautam Tammewar and Nagehan Ayakta and Suzanne L Baker and Alexandre Bejanin and Adam L Boxer and Maria Luisa Gorno-Tempini and Mustafa Janabi and Joel H Kramer and Andreas Lazaris and Samuel N Lockhart and Bruce L Miller and Zachary A Miller and James P O'Neil and Rik Ossenkoppele and Howard J Rosen and Daniel R Schonhaut and William J Jagust and Gil D Rabinovici},

year  = {2018},

date = {2018-01-01},

journal = {NeuroImage Clin.},

volume = {17},

pages = {452--464},

abstract = {The relationships between $beta$-amyloid (A$beta$), tau and 

 neurodegeneration within Alzheimer's Disease pathogenesis are not 

 fully understood. To explore these associations in vivo, we 

 evaluated 30 A$beta$ PET-positive patients (mean $pm$ sd age 

 62.4 $pm$ 8.3) with mild probable AD and 12 A$beta$ 

 PET-negative healthy controls (HC) (mean $pm$ sd age 77.3 $pm$ 

 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB 

 (A$beta$) PET and 18F-AV1451 (tau) PET. Multimodal correlation 

 analyses were run at both voxel- and region-of-interest levels. 

 11C-PiB retention in AD showed the most diffuse uptake pattern 

 throughout association neocortex, whereas 18F-AV1451 and gray 

 matter volume reduction (GMR) showed a progressive predilection 

 for posterior cortices (p<0.05 Family-Wise 

 Error-[FWE]-corrected). Voxel-level analysis identified negative 

 correlations between 18F-AV1451 and gray matter peaking in medial 

 and infero-occipital regions (p<0.01 False Discovery 

 Rate-[FDR]-corrected). 18F-AV1451 and 11C-PiB were positively 

 correlated in right parietal and medial/inferior occipital 

 regions (p<0.001 uncorrected). 11C-PiB did not correlate with GMR 

 at the voxel-level. Regionally, 18F-AV1451 was largely associated 

 with local/adjacent GMR whereas frontal 11C-PiB correlated with 

 GMR in posterior regions. These findings suggest that, in mild 

 AD, tau aggregation drives local neurodegeneration, whereas the 

 relationships between A$beta$ and neurodegeneration are not 

 region specific and may be mediated by the interaction between 

 A$beta$ and tau.},

keywords = {Alzheimer's Disease; Amyloid imaging; Brain atrophy; Dementia;   Tau imaging},

pubstate = {published},

tppubtype = {article}

}

@article{Ardura-Fabregat2017-uu,

title = {Targeting Neuroinflammation to treat Alzheimer's disease},

author = {A Ardura-Fabregat and E W G M Boddeke and A Boza-Serrano and S Brioschi and S Castro-Gomez and K Ceyzériat and C Dansokho and T Dierkes and G Gelders and Michael T Heneka and L Hoeijmakers and A Hoffmann and L Iaccarino and S Jahnert and K Kuhbandner and G Landreth and N Lonnemann and P A Löschmann and R M McManus and A Paulus and K Reemst and J M Sanchez-Caro and A Tiberi and A Van der Perren and A Vautheny and C Venegas and A Webers and P Weydt and T S Wijasa and X Xiang and Y Yang},

year  = {2017},

date = {2017-12-01},

journal = {CNS Drugs},

volume = {31},

number = {12},

pages = {1057--1082},

abstract = {Over the past few decades, research on Alzheimer's disease (AD) 

 has focused on pathomechanisms linked to two of the major 

 pathological hallmarks of extracellular deposition of 

 beta-amyloid peptides and intra-neuronal formation of 

 neurofibrils. Recently, a third disease component, the 

 neuroinflammatory reaction mediated by cerebral innate immune 

 cells, has entered the spotlight, prompted by findings from 

 genetic, pre-clinical, and clinical studies. Various proteins 

 that arise during neurodegeneration, including beta-amyloid, tau, 

 heat shock proteins, and chromogranin, among others, act as 

 danger-associated molecular patterns, that-upon engagement of 

 pattern recognition receptors-induce inflammatory signaling 

 pathways and ultimately lead to the production and release of 

 immune mediators. These may have beneficial effects but 

 ultimately compromise neuronal function and cause cell death. The 

 current review, assembled by participants of the Chiclana Summer 

 School on Neuroinflammation 2016, provides an overview of our 

 current understanding of AD-related immune processes. We describe 

 the principal cellular and molecular players in inflammation as 

 they pertain to AD, examine modifying factors, and discuss 

 potential future therapeutic targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2017-zf,

title = {The emerging role of PET imaging in dementia},

author = {Leonardo Iaccarino and Arianna Sala and Silvia Paola Caminiti and Daniela Perani},

year  = {2017},

date = {2017-10-01},

journal = {F1000Res.},

volume = {6},

pages = {1830},

abstract = {A compelling need in the field of neurodegenerative diseases is 

 the development and validation of biomarkers for early 

 identification and differential diagnosis. The availability of 

 positron emission tomography (PET) neuroimaging tools for the 

 assessment of molecular biology and neuropathology has opened new 

 venues in the diagnostic design and the conduction of new 

 clinical trials. PET techniques, allowing the in vivo assessment 

 of brain function and pathology changes, are increasingly showing 

 great potential in supporting clinical diagnosis also in the 

 early and even preclinical phases of dementia. This review will 

 summarize the most recent evidence on fluorine-18 

 fluorodeoxyglucose-, amyloid -, tau -, and neuroinflammation - 

 PET tools, highlighting strengths and limitations and possible 

 new perspectives in research and clinical applications. 

 Appropriate use of PET tools is crucial for a prompt diagnosis 

 and target evaluation of new developed drugs aimed at slowing or 

 preventing dementia.},

keywords = {PET; amyloid; biomarker; dementia; diagnosis; fluorodeoxyglucose;   molecular imaging; neuroinflammation; prognosis; tau},

pubstate = {published},

tppubtype = {article}

}

@article{Cerami2017-sq,

title = {Molecular imaging of neuroinflammation in neurodegenerative 

 dementias: The role of in vivo PET imaging},

author = {Chiara Cerami and Leonardo Iaccarino and Daniela Perani},

year  = {2017},

date = {2017-05-01},

journal = {Int. J. Mol. Sci.},

volume = {18},

number = {5},

abstract = {Neurodegeneration elicits neuroinflammatory responses to kill 

 pathogens, clear debris and support tissue repair. 

 Neuroinflammation is a dynamic biological response characterized 

 by the recruitment of innate and adaptive immune system cells in 

 the site of tissue damage. Resident microglia and infiltrating 

 immune cells partake in the restoration of central nervous system 

 homeostasis. Nevertheless, their activation may shift to chronic 

 and aggressive responses, which jeopardize neuron survival and 

 may contribute to the disease process itself. Positron Emission 

 Tomography (PET) molecular imaging represents a unique tool 

 contributing to in vivo investigating of neuroinflammatory 

 processes in patients. In the present review, we first provide an 

 overview on the molecular basis of neuroinflammation in 

 neurodegenerative diseases with emphasis on microglia activation, 

 astrocytosis and the molecular targets for PET imaging. Then, we 

 review the state-of-the-art of in vivo PET imaging for 

 neuroinflammation in dementia conditions associated with 

 different proteinopathies, such as Alzheimer's disease, 

 frontotemporal lobar degeneration and Parkinsonian spectrum.},

keywords = {11C-PK11195; Alzheimer's disease; TSPO-PET Imaging; astrocytosis;   microglia activation; molecular imaging; neurodegenerative   disorders; neuroinflammation},

pubstate = {published},

tppubtype = {article}

}

@article{Iaccarino2017-ik,

title = {A cross-validation of FDG- and amyloid-PET biomarkers in mild 

 cognitive impairment for the risk prediction to dementia due to 

 Alzheimer's disease in a clinical setting},

author = {Leonardo Iaccarino and Konstantinos Chiotis and Pierpaolo Alongi and Ove Almkvist and Anders Wall and Chiara Cerami and Valentino Bettinardi and Luigi Gianolli and Agneta Nordberg and Daniela Perani},

year  = {2017},

date = {2017-01-01},

journal = {J. Alzheimers. Dis.},

volume = {59},

number = {2},

pages = {603--614},

abstract = {Assessments of brain glucose metabolism (18F-FDG-PET) and 

 cerebral amyloid burden (11C-PiB-PET) in mild cognitive 

 impairment (MCI) have shown highly variable performances when 

 adopted to predict progression to dementia due to Alzheimer's 

 disease (ADD). This study investigates, in a clinical setting, 

 the separate and combined values of 18F-FDG-PET and 11C-PiB-PET 

 in ADD conversion prediction with optimized data analysis 

 procedures. Respectively, we investigate the accuracy of an 

 optimized SPM analysis for 18F-FDG-PET and of standardized uptake 

 value ratio semiquantification for 11C-PiB-PET in predicting ADD 

 conversion in 30 MCI subjects (age 63.57$pm$7.78 years). 

 Fourteen subjects converted to ADD during the follow-up (median 

 26.5 months, inter-quartile range 30 months). Receiver operating 

 characteristic analyses showed an area under the curve (AUC) of 

 0.89 and of 0.81 for, respectively, 18F-FDG-PET and 11C-PiB-PET. 

 18F-FDG-PET, compared to 11C-PiB-PET, showed higher specificity 

 (1.00 versus 0.62, respectively), but lower sensitivity (0.79 

 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI 

 subjects positive for both PET biomarkers converted to ADD, 

 whereas all the subjects negative for both remained stable. The 

 difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in 

 predicting MCI to ADD conversion of both 18F-FDG-PET and 

 11C-PiB-PET imaging, the former showing optimal performance based 

 on the SPM optimized parametric assessment. Measures of brain 

 glucose metabolism and amyloid load represent extremely powerful 

 diagnostic and prognostic biomarkers with complementary roles in 

 prodromal dementia phase, particularly when tailored to 

 individual cases in clinical settings.},

keywords = {11C-PiB-PET; 18F-FDG-PET; Alzheimer's disease; conversion   prediction; dementia; early diagnosis; mild cognitive impairment;   prognosis},

pubstate = {published},

tppubtype = {article}

}

@article{Ballarini2016-ta,

title = {Neuropsychiatric subsyndromes and brain metabolic network 

 dysfunctions in early onset Alzheimer's disease},

author = {Tommaso Ballarini and Leonardo Iaccarino and Giuseppe Magnani and Nagehan Ayakta and Bruce L Miller and William J Jagust and Maria Luisa Gorno-Tempini and Gil D Rabinovici and Daniela Perani},

year  = {2016},

date = {2016-12-01},

journal = {Hum. Brain Mapp.},

volume = {37},

number = {12},

pages = {4234--4247},

abstract = {Neuropsychiatric symptoms (NPSs) often occur in 

 early-age-of-onset Alzheimer's disease (EOAD) and cluster into 

 sub-syndromes (SSy). The aim of this study was to investigate the 

 association between 18 F-FDG-PET regional and connectivity-based 

 brain metabolic dysfunctions and neuropsychiatric SSy. NPSs were 

 assessed in 27 EOAD using the Neuropsychiatric Inventory and 

 further clustered into four SSy (apathetic, hyperactivity, 

 affective, and psychotic SSy). Eighty-five percent of EOAD showed 

 at least one NPS. Voxel-wise correlations between SSy scores and 

 brain glucose metabolism (assessed with 18 F-FDG positron 

 emission tomography) were studied. Interregional correlation 

 analysis was used to explore metabolic connectivity in the 

 salience (aSN) and default mode networks (DMN) in a larger sample of EOAD (N = 51) and Healthy Controls (N = 57). The apathetic, 

 hyperactivity, and affective SSy were highly prevalent (>60%) as 

 compared to the psychotic SSy (33%). The hyperactivity SSy 

 scores were associated with increase of glucose metabolism in 

 frontal and limbic structures, implicated in behavioral control. 

 A comparable positive correlation with part of the same network 

 was found for the affective SSy scores. On the other hand, the 

 apathetic SSy scores were negatively correlated with metabolism 

 in the bilateral orbitofrontal and dorsolateral frontal cortex 

 known to be involved in motivation and decision-making processes. 

 Consistent with these SSy regional correlations with brain 

 metabolic dysfunction, the connectivity analysis showed increases 

 in the aSN and decreases in the DMN. Behavioral abnormalities in 

 EOAD are associated with specific dysfunctional changes in brain 

 metabolic activity, in particular in the aSN that seems to play a 

 crucial role in NPSs in EOAD. Hum Brain Mapp 37:4234-4247, 2016. 

 copyright 2016 Wiley Periodicals, Inc.},

keywords = {early onset Alzheimer's Disease; frontal lobe; functional   networks; metabolic connectivity; neuropsychiatric subsyndromes;   positron-emission tomography},

pubstate = {published},

tppubtype = {article}

}