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Vulnerability of multiple large‐scale brain networks in dementia with Lewy bodies

Original Article
Arianna Sala, Silvia Paola Caminiti, Leonardo Iaccarino, Luca Beretta, Sandro Iannaccone, Giuseppe Magnani, Alessandro Padovani, Luigi Ferini‐Strambi, Daniela Perani
Human Brain Mapping https://doi.org/10.1002/hbm.24719
Publication year: 2019

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.

Testing the diagnostic accuracy of [18F]FDG-PET in discriminating spinal- and bulbar-onset amyotrophic lateral sclerosis

Original Article
Arianna Sala, Leonardo Iaccarino, Piercarlo Fania, Emilia G Vanoli, Federico Fallanca, Caterina Pagnini, Chiara Cerami, Andrea Calvo, Antonio Canosa, Marco Pagani, Adriano Chiò, Angelina Cistaro, Daniela Perani
Sala, A., Iaccarino, L., Fania, P. et al. Eur J Nucl Med Mol Imaging (2019). https://doi.org/10.1007/s00259-018-4246-2
Publication year: 2019

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.

Tau covariance patterns in Alzheimer's disease patients match intrinsic connectivity networks in the healthy brain

Original Article
Rik Ossenkoppele, Leonardo Iaccarino, Daniel R Schonhaut, Jesse A Brown, Renaud La Joie, James P O'Neil, Mustafa Janabi, Suzanne L Baker, Joel H Kramer, Maria-Luisa Gorno-Tempini, Bruce L Miller, Howard J Rosen, William W Seeley, William J Jagust, Gil D Rabinovici
Neuroimage:Clinical: https://doi.org/10.1016/j.nicl.2019.101848
Publication year: 2019

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-β ([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 ± 8 years) who underwent [18F]flortaucipir, [11C]PIB and [18F]FDG PET, and 1000 young adults (427 male, 21 ± 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-β 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.

Prefrontal Cortical Stimulation in Tourette Disorder: Proof‐of‐concept Clinical and Neuroimaging Study

Original Article
Daniela Perani, Stefania Lalli, Leonardo Iaccarino, Pierpaolo Alongi, Orsola Gambini, Angelo Franzini, Alberto Albanese
Perani, D., Lalli, S., Iaccarino, L., Alongi, P., Gambini, O., Franzini, A., & Albanese, A. (2018). Prefrontal Cortical Stimulation in Tourette Disorder: Proof‐of‐concept Clinical and Neuroimaging Study. Movement disorders clinical practice, 5(5), 499-505.
Publication year: 2019

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.

Predicting long‐term clinical stability in amyloid‐positive subjects by FDG‐PET

Original Article
Leonardo Iaccarino, Arianna Sala, Daniela Perani for the Alzheimer's Disease Neuroimaging Initiative
Annals of Clinical and Translational Neurology, online-first, doi:10.1002/acn3.782
Publication year: 2019

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 (≥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.

Brain glucose metabolism in Lewy body dementia: implications for diagnostic criteria

Original Article
Caminiti SP, Sala A, Iaccarino L, Beretta L, Pilotto A, Gianolli L, Iannaccone S, Magnani G, Padovani A, Ferini-Strambi L, Perani D
Alzheimers Res Ther. 2019 Feb 23;11(1):20. doi: 10.1186/s13195-019-0473-4.
Publication year: 2019

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 < 0.05, FWE-corrected). The hypometabolism patterns were independently classified by expert raters blinded to any clinical information. The final clinical diagnosis at follow-up (2.94 ± 1.39 [0.34-6.04] years) was considered as the diagnostic reference and compared with clinical classification at entry and with [18F]FDG-PET classification alone. In addition, we calculated the diagnostic accuracy of [18F]FDG-PET maps in the differential diagnosis of DLB with Alzheimer’s disease dementia (ADD) (N = 60) and Parkinson’s disease (PD) (N = 36).

RESULTS:

The single-subject [18F]FDG-PET hypometabolism pattern, showing temporo-parietal and occipital involvement, was highly consistent across DLB cases. Clinical classification at entry produced several misclassifications with an agreement of only 61.1% with the diagnostic reference. On the contrary, [18F]FDG-PET hypometabolism maps alone accurately predicted diagnosis of DLB at follow-up (88.9%). The high power of the [18F]FDG-PET hypometabolism signature in predicting the final clinical diagnosis allowed a ≈ 50% increase in accuracy compared to the first clinical assessment alone. Finally, [18F]FDG-PET hypometabolism maps yielded extremely high discriminative power, distinguishing DLB from ADD and PD conditions with an accuracy of > 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.

Application of advanced brain positron emission tomography–based molecular imaging for a biological framework in neurodegenerative proteinopathies

Review
Daniela Perani, Leonardo Iaccarino, Andreas H Jacobs, Adriaan A Lammertsma, Agneta Nordberg, Albert D Windhorst, Alexander Gerhard, Alexandra Winkeler, Anthony Gee, Bertrand Kuhnast, Christer Halldin, David Brooks, Elena Rodriguez-Vieitez, Federico E Turkheimer, Francisco López-Picón, Gitte M Knudsen, Johnny Vercouillie, Juha O Rinne, Karl Herholz, Koen Van Laere, Marie Joao Santiago-Ribeiro, Matthias M Herth, Michael A Carroll, Michel Bottlaender, Oskar Hansson, Paul Edison, Rainer Hinz, Ronald Boellaard, Rosa Maria Moresco, Sabina Pappatà
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Volume 11, Pages 327-332
Publication year: 2019

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 imagingtechniques 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.

A new perspective for advanced positron emission tomography–based molecular imaging in neurodegenerative proteinopathies

Perspective
Daniela Perani, Leonardo Iaccarino, Adriaan A Lammertsma, Albert D Windhorst, Paul Edison, Ronald Boellaard, Oskar Hansson, Agneta Nordberg, Andreas H Jacobs, Michel Bottlaender, David Brooks, Michael A Carroll, Sylvie Chalon, Anthony Gee, Alexander Gerhard, Christer Halldin, Karl Herholz, Matthias M Herth, Rainer Hinz, Gitte M Knudsen, Bertrand Kuhnast, Francisco López-Picón, Rosa Maria Moresco, Sabina Pappata, Juha O Rinne, Elena Rodriguez-Vieitez, Marie Joao Santiago-Ribeiro, Federico E Turkheimer, Koen Van Laere, Andrea Varrone, Johnny Vercouillie, Alexandra Winkeler
Alzheimer's & Dementia Volume 15, Issue 8, August 2019, Pages 1081-1103
Publication year: 2019

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.

The brain metabolic signature of visual hallucinations in Dementia with Lewy Bodies

Original Article
Leonardo Iaccarino, Arianna Sala, Silvia Caminiti, Roberto Santangelo, Sandro Iannaccone, Giuseppe Magnani, Daniela Perani
CORTEX 2018, epub ahead of print. https://doi.org/10.1016/j.cortex.2018.06.014
Publication year: 2018

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±sd 72.9±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±sd 71.5±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<0.001 uncorrected, p<0.05 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 attentional 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.

Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia

Original Article
Miguel A. Santos-Santos, MD; Gil D. Rabinovici, MD; Leonardo Iaccarino, MSc; Nagehan Ayakta, MSc; Gautam Tammewar, MSc; Iryna Lobach, PhD; Maya L. Henry, PhD; Isabel Hubbard, PhD; Maria Luisa Mandelli, PhD; Edoardo Spinelli, MD; Zachary A. Miller, MD; Peter S. Pressman, MD; James P. O’Neil, PhD; Pia Ghosh, MSc; Andreas Lazaris, MSc; Marita Meyer, MSc; Christa Watson, PhD; Soo Jin Yoon, MD; Howard J. Rosen, MD; Lea Grinberg, MD, PhD; William W. Seeley, MD; Bruce L. Miller, MD; William J. Jagust, MD; Maria Luisa Gorno-Tempini, MD, PhD
JAMA Neurology. Published online January 8, 2018. doi:10.1001/jamaneurol.2017.4309
Publication year: 2018

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.

Low-dose CT for the spatial normalization of PET images: A validation procedure for amyloid-PET semi-quantification

Original Article
Luca Presotto, Leonardo Iaccarino, Arianna Sala, Emilia G. Vanoli, Cristina Muscio, Anna Nigri, Maria Grazia Bruzzone, Fabrizio Tagliavini, Luigi Gianolli, Daniela Perani, Valentino Bettinardi
Neuroimage:Clinical (20) pp.153-160
Publication year: 2018

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 PETimages 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 ± sd 0.01 ± 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.

18F-VC701-PET and MRI in the in vivo neuroinflammation assessment of a mouse model of multiple sclerosis

Original Article
Belloli S, Zanotti L, Murtaj V, Mazzon C, Di Grigoli G, Monterisi C, Masiello V, Iaccarino L, Cappelli A, Poliani PL, Politi LS, Moresco RM
J Neuroinflammation. 2018 Feb 5;15(1):33. doi: 10.1186/s12974-017-1044-x
Publication year: 2018

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.

The emerging role of PET imaging in dementia

Review
Iaccarino, L., Sala, A., Caminiti SP. & Perani D.
F1000Res. 2017 Oct 12;6:1830. doi: 10.12688/f1000research.11603.1
Publication year: 2017

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.

Targeting neuroinflammation to treat Alzheimer's Disease

Review
A. Ardura-Fabregat, E. W. G. M. Boddeke, A. Boza-Serrano, S. Brioschi, S. Castro-Gomez, K. Ceyzériat, C. Dansokho, T. Dierkes, G. Gelders, Michael T. Heneka, L. Hoeijmakers, A. Hoffmann, L. Iaccarino, S. Jahnert, K. Kuhbandner, G. Landreth, N. Lonnemann, P. A. Löschmann, R. M. McManus, A. Paulus, K. Reemst, J. M. Sanchez-Caro, A. Tiberi, A. Van der Perren, A. Vautheny, C. Venegas, A. Webers, P. Weydt, T. S. Wijasa, X. Xiang, Y. Yang
CNS Drugs, 2017, online-first, https://doi.org/10.1007/s40263-017-0483-3
Publication year: 2017

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.

Molecular Imaging of Neuroinflammation in Neurodegenerative Dementias: The Role of In Vivo PET Imaging

Review
Cerami C., Iaccarino, L., Perani D.
Int. J. Mol. Sci. 2017, 18(5), 993; doi:10.3390/ijms18050993
Publication year: 2017

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

Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease

Original Article
Iaccarino, L., Tammewar, G., Ayakta, N., Baker, S.L., Bejanin, A., Boxer A.L., Gorno-Tempini, M.L., Janabi, M., Kramer J., Lazaris, A., Lockhart, S.N., Miller, B., Miller, Z.A., O’Neil, J.P., Ossenkoppele, R., Rosen H.J., Schonhaut, D., Jagust, W.J., Rabinovici, G.D.
Neuroimage:Clinical, 2017, online-first
Publication year: 2017

The relationships between β-amyloid (Aβ), tau and neurodegeneration within Alzheimer’s Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Aβ PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 Aβ PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB (Aβ) 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 Aβ and neurodegeneration are not region specific and may be mediated by the interaction between Aβ and tau.

An in vivo 11C-PK PET study of microglia activation in Fatal Familial Insomnia

Original Article
Leonardo Iaccarino, Luca Presotto, Valentino Bettinardi, Luigi Gianolli, Ignazio Roiter, Sabina Capellari, Piero Parchi, Pietro Cortelli, Daniela Perani
Annals of Clinical and Translational Neurology, online-first, doi:10.1002/acn3.498
Publication year: 2017

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 ± SD age:44.13 ± 3.83 years) carrying the pathogenic D178N-129met FFI mutation, one symptomatic patient (male, 45 yrs. old), and nine healthy controls (HC) (mean ± SD age: 44.00 ± 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.

An In Vivo 11C-(R)-PK11195 PET and In Vitro Pathology Study of Microglia Activation in Creutzfeldt-Jakob Disease

Original Article
Iaccarino, L., Moresco, RM., Presotto, L., Bugiani, O., Iannaccone, S., Giaccone, G., Tagliavini, F. and Perani, D.
Mol Neurobiol (2017). doi:10.1007/s12035-017-0522-6
Publication year: 2017

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 ± SD age, 47.50 ± 15.95 years), and nine healthy controls (mean ± SD age, 44.00 ± 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.

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.

Original Article
Iaccarino L, Chiotis K, Alongi P, Almkvist O, Wall A, Cerami C, Bettinardi V, Gianolli L, Nordberg A, Perani D
J Alzheimers Dis. 2017 Jun 24. doi: 10.3233/JAD-170158. [Epub ahead of print]
Publication year: 2017

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±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.

Severe Brain Metabolic Decreases Associated with REM Sleep Behavior Disorder in Dementia with Lewy Bodies

Original Article
Iaccarino, L., Marelli S., Iannaccone S., Magnani G., Ferini-Strambi, L. and Perani D.
Journal of Alzheimer’s Disease. 52 (3), 989-997
Publication year: 2016

Qualitative patterns at Raven’s colored progressive matrices in mild cognitive impairment and Alzheimer’s disease

Original Article
Ambra, FI., Iavarone, A., Ronga, B., Chieffi, S., Carnevale, G., Iaccarino, L., Cimminella, F., Chiavazzo, A., Garofalo, E
Aging Clin Exp Res 28: 561.
Publication year: 2016

Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer’s disease

Original Article
Ballarini, T., Iaccarino, L., Magnani, G., Ayakta, N., Miller, BL., Jagust, WJ., Gorno-Tempini, ML., Rabinovici, GD., Perani, D.
Human Brain Mapping. 37.12 (2016): 4234-4247.
Publication year: 2016

The semantic variant of Primary Progressive Aphasia: Clinical and neuroimaging evidence in single subjects

Original Article
Iaccarino, L., Crespi, C., Della Rosa., PA, Catricalà, E., Guidi, L., Marcone, A., Tagliavini, F., Magnani, G., Cappa, S.F. and Perani, D.
PLoS ONE 10(3): e0120197.
Publication year: 2015

Neuroimaging

Chapter
Iaccarino, L., Perani D.
Treccani, Enciclopedia Italiana di Scienze, Lettere ed Arti. Appendice IX
Publication year: 2015

Encyclopedia Article/Entry

Utilization Behavior: What is Known and what has to be known?

Review
Iaccarino, L., Chieffi, S., Iavarone, A
Behavioural Neurology, 2014, doi: 10.1155/2014/297128
Publication year: 2014

The need for “objective measurements” in Amyloid and FDG-PET neuroimaging

Review
Perani, D., Iaccarino, L., Bettinardi, V
Clinical and Translation Imaging, 2(4):331-342
Publication year: 2014

PET neuroimaging: insights on dystonia and Tourette syndrome and potential applications

Review
Alongi, P., Iaccarino, L. and Perani, D.
Frontiers in Neurology, 5, 2014.
Publication year: 2014

Age-related differences in distractor interference on line bisection

Original Article
Chieffi, S., Iavarone, A., Iaccarino, L., La Marra, M., Messina, G., Monda, M
Experimental Brain Research, 232(11): 3659-3664
Publication year: 2014

Schiavi dell’ambiente. Lobi Frontali e Sindrome da Dipendenza Ambientale

Book
Iaccarino, L., Iavarone, A., Ronga B.
Milano:Franco Angeli Editore ISBN:8820402394
Publication year: 2012