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Crossed cerebellar diaschisis on 18F-FDG PET: Frequency across neurodegenerative syndromes and association with 11C-PIB and 18F-Flortaucipir

Original Article
Karine Provost, Renaud La Joie, Amelia Strom, Leonardo Iaccarino, Lauren Edwards, Taylor J Mellinger, Julie Pham, Suzanne L Baker, Bruce L Miller, William J Jagust, Gil D Rabinovici
Journal of Cerebral Blood Flow & Metabolism, 2021
Publication year: 2021

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 (β-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 β-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.

Detecting Alzheimer’s disease biomarkers with a brief tablet-based cognitive battery: sensitivity to Aβ and tau PET

Original Article
Elena Tsoy, Amelia Strom, Leonardo Iaccarino, Sabrina J Erlhoff, Collette A Goode, Anne-Marie Rodriguez, Gil D Rabinovici, Bruce L Miller, Joel H Kramer, Katherine P Rankin, Renaud La Joie, Katherine L Possin
Alzheimer's research & therapy 13 (1), 1-10
Publication year: 2021

Background

β-amyloid (Aβ) and tau positron emission tomography (PET) detect the pathological changes that define Alzheimer’s disease (AD) in living people. Cognitive measures sensitive to Aβ 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 Aβ -PET status using logistic regression models in individuals with mild cognitive impairment (MCI) or dementia (N = 140; 43 Aβ-, 97 Aβ+). 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 Aβ+ individuals with MCI or dementia.

Results

Favorites (associative memory), Match (executive functions and speed), and Everyday Cognition Scale scores were significantly associated with Aβ 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 Aβ and regional tau in vivo imaging markers and could be used for the identification of patients with suspected AD pathology in clinical practice.

Diagnostic Accuracy of Amyloid versus 18 F-Fluorodeoxyglucose Positron Emission Tomography in Autopsy-Confirmed Dementia

Original Article
Orit H Lesman-Segev, Renaud La Joie, Leonardo Iaccarino, Iryna Lobach, Howard J Rosen, Sang Won Seo, Mustafa Janabi, Suzanne L Baker, Lauren Edwards, Julie Pham, John Olichney, Adam Boxer, Eric Huang, Marilu Gorno-Tempini, Charles DeCarli, Mackenzie Hepker, Ji-Hye L Hwang, Bruce L Miller, Salvatore Spina, Lea T Grinberg, William W Seeley, William J Jagust, Gil D Rabinovici
Ann Neurol . 2021 Feb;89(2):389-401. doi: 10.1002/ana.25968. Epub 2020 Dec 7.
Publication year: 2021

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%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies.

Interpretation: In our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent.

Association of remote mild traumatic brain injury with cortical amyloid burden in clinically normal older adults

Original Article
Breton M Asken, William G Mantyh, Renaud La Joie, Amelia Strom, Kaitlin B Casaletto, Adam M Staffaroni, Alexandra C Apple, Cutter A Lindbergh, Leonardo Iaccarino, Michelle You, Harli Grant, Corrina Fonseca, Charles Windon, Kyan Younes, Jeremy Tanner, Gil D Rabinovici, Joel H Kramer, Raquel C Gardner
Brain Imaging Behav . 2021 Jan 11. doi: 10.1007/s11682-020-00440-1. Online ahead of print.
Publication year: 2021

We investigated whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aβ burden. Our study included 134 clinically normal older adults (age 74.1 ± 6.8 years, 59.7% female, 85.8% white) who underwent Aβ positron emission tomography (Aβ-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 Aβ-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aβ-PET burden, interactions between remote mTBI and age, sex, and APOE status, longitudinal Aβ accumulation, and the interaction between remote mTBI and Aβ burden on memory and executive functioning. Of 134 participants, 48 (36%) reported remote mTBI (0, N = 86; 1, N = 31, 2+, N = 17; mean 37 ± 23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aβ burden (p = .94, η2 < 0.01), and for all interaction analyses. Longitudinally, we found a non-statistically significant association of those with remote mTBI (N = 11) having a faster rate of Aβ accumulation (B = 0.01, p = .08) than those without (N = 19). There was no significant interaction between remote mTBI and Aβ burden on cognition. In clinically normal older adults, history of mTBI is not associated with greater cortical Aβ burden and does not interact with Aβ burden to impact cognition. Longitudinal analyses suggest remote mTBI may be associated with more rapid cortical Aβ accumulation. This finding warrants further study in larger and more diverse samples with well-characterized lifelong head trauma exposure.

Comparing ATN-T designation by tau PET visual reads, tau PET quantification, and CSF PTau181 across three cohorts

Original Article
Karine Provost, Leonardo Iaccarino, David N Soleimani-Meigooni, Suzanne Baker, Lauren Edwards, Udo Eichenlaub, Oskar Hansson, William Jagust, Mustafa Janabi, Renaud La Joie, Orit Lesman-Segev, Taylor J Mellinger, Bruce L Miller, Rik Ossenkoppele, Julie Pham, Ruben Smith, Ida Sonni, Amelia Strom, Niklas Mattsson-Carlgren, Gil D Rabinovici, Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Eur J Nucl Med Mol Imaging . 2021 Jan 4. doi: 10.1007/s00259-020-05152-8. Online ahead of print.
Publication year: 2021

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 ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 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 Aβ + 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.

Association of APOE4 and clinical variability in Alzheimer disease with the pattern of tau- and amyloid-PET

Original Article
Renaud La Joie, Adrienne V Visani, Orit H Lesman-Segev, Suzanne L Baker, Lauren Edwards, Leonardo Iaccarino, David N Soleimani-Meigooni, Taylor Mellinger, Mustafa Janabi, Zachary A Miller, David C Perry, Julie Pham, Amelia Strom, Maria Luisa Gorno-Tempini, Howard J Rosen, Bruce L Miller, William J Jagust, Gil D Rabinovici
Neurology . 2020 Dec 1;10.1212/WNL.0000000000011270. doi: 10.1212/WNL.0000000000011270. Online ahead of print.
Publication year: 2020

Objective: To assess whether Alzheimer disease (AD) clinical presentation and APOE4 relate to the burden and topography of β-amyloid and tau pathologies using in vivo PET imaging.

Methods: We studied 119 β-amyloid-positive symptomatic patients aged 48-95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with Posterior Cortical Atrophy (PCA). PIB- (β-amyloid) 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 scale 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 temporo-parietal 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 patients with AD. Cortical Flortaucipir-PET binding was higher in younger patients across phenotypes (r = -0.63, 95%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 MTL-predominant pattern of tau pathology.

Association Between Ambient Air Pollution and Amyloid Positron Emission Tomography Positivity in Older Adults With Cognitive Impairment

Original Article
Leonardo Iaccarino, Renaud La Joie, Orit H Lesman-Segev, Eunice Lee, Lucy Hanna, Isabel E Allen, Bruce E Hillner, Barry A Siegel, Rachel A Whitmer, Maria C Carrillo, Constantine Gatsonis, Gil D Rabinovici
JAMA Neurol . 2020 Nov 30. doi: 10.1001/jamaneurol.2020.3962. Online ahead of print.
Publication year: 2020

Importance: Amyloid-β (Aβ) 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 Aβ 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-μg/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-μg/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 β = 1.01 [95% CI, 0.99-1.04; z score = 1.13; FDR-corrected P = .56]; 2015-2016: β = 1.02 [95% CI, 0.98-1.07; z score = 0.91; FDR-corrected P = .56]) or clinical stage (2002-2003: interaction term β = 1.01 [95% CI, 0.99-1.03; z score = 0.77; FDR-corrected P = .58]; 2015-2016: β = 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 Aβ plaques. These findings suggest the need to consider airborne toxic pollutants associated with Aβ pathology in public health policy decisions and to inform individual lifetime risk of developing AD and dementia.

Evaluation of a visual interpretation method for tau-PET with 18 F-flortaucipir

Original Article
Ida Sonni, Orit H Lesman Segev, Suzanne L Baker, Leonardo Iaccarino, Deniz Korman, Gil D Rabinovici, William J Jagust, Susan M Landau, Renaud La Joie, Alzheimer's Disease Neuroimaging Initiative
Alzheimers Dement (Amst) . 2020 Nov 28;12(1):e12133. doi: 10.1002/dad2.12133. eCollection 2020.
Publication year: 2020

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.

The impact of demographic, clinical, genetic, and imaging variables on tau PET status

Original Article
Rik Ossenkoppele, Antoine Leuzy, Hanna Cho, Carole H Sudre, Olof Strandberg, Ruben Smith, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Tomas Olsson, Jonas Jögi, Erik Stormrud, Young Hoon Ryu, Jae Yong Choi, Alzheimer’s Disease Neuroimaging Initiative; PREVENT-AD research group; Adam L Boxer, Maria L Gorno-Tempini, Bruce L Miller, David Soleimani-Meigooni, Leonardo Iaccarino, Renaud La Joie, Edilio Borroni, Gregory Klein, Michael J Pontecorvo, Michael D Devous Sr, Sylvia Villeneuve, Chul Hyoung Lyoo, Gil D Rabinovici, Oskar Hansson
Eur J Nucl Med Mol Imaging . 2020 Nov 19. doi: 10.1007/s00259-020-05099-w. Online ahead of print.
Publication year: 2020

Purpose: A substantial proportion of amyloid-β (Aβ)+ 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 Aβ+ AD dementia, 381 Aβ+ 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, APOEε4, Aβ 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 Aβ+ 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 Aβ 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.

Diagnostic Assessment in Primary Progressive Aphasia: An Illustrative Case Example.

Original Article
Eduardo Europa, Leonardo Iaccarino, David C Perry, Elizabeth Weis, Ariane E Welch, Gil D Rabinovici, Bruce L Miller, Maria Luisa Gorno-Tempini, Maya L Henry
Am J Speech Lang Pathol . 2020 Nov 12;29(4):1833-1849. doi: 10.1044/2020_AJSLP-20-00007. Epub 2020 Sep 10.
Publication year: 2020

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

Sex-related differences in the relationship between β-amyloid and cognitive trajectories in older adults

Original Article
Cutter A Lindbergh, Kaitlin B Casaletto, Adam M Staffaroni, Renaud La Joie, Leonardo Iaccarino, Lauren Edwards, Elena Tsoy, Fanny Elahi, Samantha M Walters, Devyn Cotter, Michelle You, Alexandra C Apple, Breton Asken, John Neuhaus, Jessica E Rexach, Kevin J Wojta, Gil Rabinovici, Joel H Kramer, Hillblom Aging Network
Neuropsychology . 2020 Nov;34(8):835-850. doi: 10.1037/neu0000696. Epub 2020 Oct 8.
Publication year: 2020

Objective: We aimed to test the hypothesis that elevated neocortical β-amyloid (Aβ), 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 Aβ positron emission tomography (PET) was acquired in 149 clinically normal older adults (52% female, Mage = 74). Participants underwent cognitive testing at baseline and during annual follow-up visits over a timespan of up to 5.14 years. Mixed-effects regression models evaluated whether relations between baseline neocortical Standardized Uptake Value Ratio (SUVR) and composite scores of episodic memory, executive functioning, and processing speed were moderated by sex (male/female) and apolipoprotein E (APOE) status (ε4 carrier/noncarrier). Results: Higher baseline SUVR was associated with longitudinal decline in episodic memory in women (b = -1.32, p < .001) but not men (b = -0.30, p = .28). Female APOE ε4 carriers with elevated SUVR showed particularly precipitous declines in episodic memory (b = -4.33, p < .001) whereas other cognitive domains were spared. SUVR did not predict changes in executive functioning or processing speed, regardless of sex (ps >.63), though there was a main effect of SUVR on processing speed (b = 2.50, p = .003). Conclusions: Clinically normal women with elevated Aβ are more vulnerable to episodic memory decline than men. Understanding sex-related differences in AD, particularly in preclinical stages, is crucial for guiding precision medicine approaches to early detection and intervention. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases

Original Article
David N Soleimani-Meigooni, Leonardo Iaccarino, Renaud La Joie, Suzanne Baker, Viktoriya Bourakova, Adam L Boxer, Lauren Edwards, Rana Eser, Maria-Luisa Gorno-Tempini, William J Jagust, Mustafa Janabi, Joel H Kramer, Orit H Lesman-Segev, Taylor Mellinger, Bruce L Miller, Julie Pham, Howard J Rosen, Salvatore Spina, William W Seeley, Amelia Strom, Lea T Grinberg, Gil D Rabinovici
Brain, awaa276, https://doi.org/10.1093/brain/awaa276
Publication year: 2020

Few studies have evaluated the relationship between in vivo  18F-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.

Spatial Relationships between Molecular Pathology and Neurodegeneration in the Alzheimer’s Disease Continuum

Original Article
Leonardo Iaccarino, Renaud La Joie, Lauren Edwards, Amelia Strom, Daniel R Schonhaut, Rik Ossenkoppele, Julie Pham, Taylor Mellinger, Mustafa Janabi, Suzanne L Baker, David Soleimani-Meigooni, Howard J Rosen, Bruce L Miller, William J Jagust, Gil D Rabinovici
Cerebral Cortex, https://doi.org/10.1093/cercor/bhaa184
Publication year: 2020

A deeper understanding of the spatial relationships of β-amyloid (Aβ), 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 ± 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 ± 6.5, no FDG-PET). W-score voxel-wise deviation maps were created and binarized for each imaging-modality (W > 1.64, P < 0.05) adjusting for age, sex, and total intracranial volume (sMRI-only) using amyloid-negative cognitively normal adults. For symptomatic patients, FDG-PET and atrophy W-maps were combined into neurodegeneration maps (ND). Aβ-pathology showed the greatest proportion of cortical gray matter suprathreshold voxels (spatial extent) for both symptomatic and asymptomatic participants (median 94–55%, respectively), followed by tau (79–11%) and neurodegeneration (41–3%). Amyloid > 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.

11 C-PK11195 PET-based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Original Article
Tondo G, Iaccarino L, Cerami C, Vanoli GE, Presotto L, Masiello V, Coliva A, Salvi F, Bartolomei I, Mosca L, Lunetta C, Perani D
Annals of Clinical and Translational Neurology. 2020 Aug 6. doi: 10.1002/acn3.51112. Online ahead of print.
Publication year: 2020

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.

Longitudinal structural and metabolic changes in frontotemporal dementia

Original Article
Alexandre Bejanin, Gautam Tammewar, Gabe Marx, Yann Cobigo, Leonardo Iaccarino, John Kornak, Adam M Staffaroni, Bradford C Dickerson, Bradley F Boeve, David S Knopman, Marilu Gorno-Tempini, Bruce L Miller, William J Jagust, Adam L Boxer, Howard J Rosen, Gil D Rabinovici
Neurology Jul 2020, 95 (2) e140-e154; DOI: 10.1212/WNL.0000000000009760
Publication year: 2020

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.

In vivo MRI Structural and PET Metabolic Connectivity Study of Dopamine Pathways in Alzheimer’s Disease

Original Article
Leonardo Iaccarino, Arianna Sala, Silvia Paola Caminiti, Luca Presotto, Daniela Perani, Alzheimer’s Disease Neuroimaging Initiative
Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020
Publication year: 2020

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) 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.

The combined effects of microglia activation and brain glucose hypometabolism in early-onset Alzheimer’s disease

Original Article
Giacomo Tondo, Leonardo Iaccarino, Silvia Paola Caminiti, Luca Presotto, Roberto Santangelo, Sandro Iannaccone, Giuseppe Magnani & Daniela Perani
Alz Res Therapy 12, 50 (2020). https://doi.org/10.1186/s13195-020-00619-0
Publication year: 2020

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.

Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

Original Article
Kamalini G. Ranasinghe,, Jungho Cha, Leonardo Iaccarino, Leighton B. Hinkley, Alexander J. Beagle, Julie Pham, William J. Jagust, Bruce L. Miller, Katherine P. Rankin, Gil D. Rabinovici, Keith A. Vossel and Srikantan S. Nagarajan
Science Translational Medicine 11 Mar 2020: Vol. 12, Issue 534, eaaz4069 DOI: 10.1126/scitranslmed.aaz4069
Publication year: 2020

Patients with Alzheimer’s disease (AD) present encephalographic alterations involving multiple brain oscillation frequencies. Whether and how these abnormalities correlate with AD neuropathology and cognitive abilities remained to be investigated. Now, Ranashinghe et al. used magnetoencephalographic imaging (MEGI), positron emission tomography with amyloid-beta (Aβ) and TAU tracers, and cognitive evaluation to show the existence of specific MEGI signatures that correlated with neuropathological abnormalities. Alpha and delta regional brain oscillation differentially correlated with TAU, Ab, and cognitive dysfunctions. The results suggest that MEGI could help the identification of therapeutic approaches for modulating AD neuropathology.

Tau Positron Emission Tomographic Findings in a Former US Football Player With Pathologically Confirmed Chronic Traumatic Encephalopathy

Original Article
William G Mantyh, Salvatore Spina, Alex Lee, Leonardo Iaccarino, David Soleimani-Meigooni, Elena Tsoy, Taylor J Mellinger, Harli Grant, Lawren Vandevrede, Renaud La Joie, Orit Lesman-Segev, Stephanie Gaus, Katherine L Possin, Lea T Grinberg, Bruce L Miller, William W Seeley, Gil D Rabinovici
JAMA Neurol. Published online January 6, 2020. doi:10.1001/jamaneurol.2019.4509
Publication year: 2020

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 (ρ = 0.35, P = .17), was found between FTP standardized uptake value ratio and tau area fraction at the regional level.

Conclusions and Relevance  In this patient, FTP PET findings during life showed a modest correspondence with postmortem pathology in CTE. These findings suggest that FTP may have limited utility as a tau biomarker in CTE.

Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET

Original Article
Renaud La Joie, Adrienne V Visani, Suzanne L Baker, Jesse A Brown, Viktoriya Bourakova, Jungho Cha, Kiran Chaudhary, Lauren Edwards, Leonardo Iaccarino, Mustafa Janabi, Orit H Lesman-Segev, Zachary A Miller, David C Perry, James P O’Neil, Julie Pham, Julio C Rojas, Howard J Rosen, William W Seeley, Richard M Tsai, Bruce L Miller, William J Jagust, Gil D Rabinovici
Science Translational Medicine 01 Jan 2020: Vol. 12, Issue 524, eaau5732 DOI: 10.1126/scitranslmed.aau5732
Publication year: 2020

β-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 β-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 β-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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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

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

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