Showing papers by "Daniela Perani published in 2020"

Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias

Abstract: Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and 18F-fluorodeoxyglucose (18F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and 18F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.

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

Abstract: 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. 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. 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. 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.

Brain metabolic signatures across the Alzheimer’s disease spectrum

Abstract: Given the challenges posed by the clinical diagnosis of atypical Alzheimer’s disease (AD) variants and the limited imaging evidence available in the prodromal phases of atypical AD, we assessed brain hypometabolism patterns at the single-subject level in the AD variants spectrum. Specifically, we tested the accuracy of [18F]FDG-PET brain hypometabolism, as a biomarker of neurodegeneration, in supporting the differential diagnosis of atypical AD variants in individuals with dementia and mild cognitive impairment (MCI). We retrospectively collected N = 67 patients with a diagnosis of typical AD and AD variants according to the IWG-2 criteria (22 typical-AD, 15 frontal variant-AD, 14 logopenic variant-AD and 16 posterior variant-AD). Further, we included N = 11 MCI subjects, who subsequently received a clinical diagnosis of atypical AD dementia at follow-up (21 ± 11 months). We assessed brain hypometabolism patterns at group- and single-subject level, using W-score maps, measuring their accuracy in supporting differential diagnosis. In addition, the regional prevalence of cerebral hypometabolism was computed to identify the most vulnerable core regions. W-score maps pointed at distinct, specific patterns of hypometabolism in typical and atypical AD variants, confirmed by the assessment of core hypometabolism regions, showing that each variant was characterized by specific regional vulnerabilities, namely in occipital, left-sided, or frontal brain regions. ROC curves allowed discrimination among AD variants and also non-AD dementia (i.e., dementia with Lewy bodies and behavioral variant of frontotemporal dementia), with high sensitivity and specificity. Notably, we provide preliminary evidence that, even in AD prodromal phases, these specific [18F]FDG-PET patterns are already detectable and predictive of clinical progression to atypical AD variants at follow-up. The AD variant-specific patterns of brain hypometabolism, highly consistent at single-subject level and already evident in the prodromal stages, represent relevant markers of disease neurodegeneration, with highly supportive diagnostic and prognostic role.

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

Abstract: Background Alzheimer's disease (AD) is characterized by an involvement of brain dopamine (DA) circuitry, the presence of which has been associated with emergence of both neuropsychiatric symptoms and cognitive deficits. Objective In order to investigate whether and how the DA pathways are involved in the pathophysiology of AD, we assessed by in vivo neuroimaging the structural and metabolic alterations of subcortical and cortical DA pathways and targets. Methods We included 54 healthy control participants, 53 amyloid-positive subjects with mild cognitive impairment due to AD (MCI-AD), and 60 amyloid-positive patients with probable dementia due to AD (ADD), all with structural 3T MRI and 18F-FDG-PET scans. We assessed MRI-based gray matter reductions in the MCI-AD and ADD groups within an anatomical a priori-defined Nigrostriatal and Mesocorticolimbic DA pathways, followed by 18F-FDG-PET metabolic connectivity analyses to evaluate network-level metabolic connectivity changes. Results We found significant tissue loss in the Mesocorticolimbic over the Nigrostriatal pathway. Atrophy was evident in the ventral striatum, orbitofrontal cortex, and medial temporal lobe structures, and already plateaued in the MCI-AD stage. Degree of atrophy in Mesocorticolimbic regions positively correlated with the severity of depression, anxiety, and apathy in MCI-AD and ADD subgroups. Additionally, we observed significant alterations of metabolic connectivity between the ventral striatum and fronto-cingulate regions in ADD, but not in MCI-AD. There were no metabolic connectivity changes within the Nigrostriatal pathway. Conclusion Our cross-sectional data support a clinically-meaningful, yet stage-dependent, involvement of the Mesocorticolimbic system in AD. Longitudinal and clinical correlation studies are needed to further establish the relevance of DA system involvement in AD.

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

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.

Italian consensus recommendations for a biomarker-based aetiological diagnosis in mild cognitive impairment patients.

Abstract: Background and purpose Biomarkers support the aetiological diagnosis of neurocognitive disorders in vivo. Incomplete evidence is available to drive clinical decisions; available diagnostic algorithms are generic and not very helpful in clinical practice. The aim was to develop a biomarker-based diagnostic algorithm for mild cognitive impairment patients, leveraging on knowledge from recognized national experts. Methods With a Delphi procedure, experienced clinicians making variable use of biomarkers in clinical practice and representing five Italian scientific societies (neurology - Societa Italiana di Neurologia per le Demenze; neuroradiology - Associazione Italiana di Neuroradiologia; biochemistry - Societa Italiana di Biochimica Clinica; psychogeriatrics - Associazione Italiana di Psicogeriatria; nuclear medicine - Associazione Italiana di Medicina Nucleare) defined the theoretical framework, relevant literature, the diagnostic issues to be addressed and the diagnostic algorithm. An N-1 majority defined consensus achievement. Results The panellists chose the 2011 National Institute on Aging and Alzheimer's Association diagnostic criteria as the reference theoretical framework and defined the algorithm in seven Delphi rounds. The algorithm includes baseline clinical and cognitive assessment, blood examination, and magnetic resonance imaging with exclusionary and inclusionary roles; dopamine transporter single-photon emission computed tomography (if no/unclear parkinsonism) or metaiodobenzylguanidine cardiac scintigraphy for suspected dementia with Lewy bodies with clear parkinsonism (round VII, votes (yes-no-abstained): 3-1-1); 18 F-fluorodeoxyglucose positron emission tomography for suspected frontotemporal lobar degeneration and low diagnostic confidence of Alzheimer's disease (round VII, 4-0-1); cerebrospinal fluid for suspected Alzheimer's disease (round IV, 4-1-0); and amyloid positron emission tomography if cerebrospinal fluid was not possible/accepted (round V, 4-1-0) or inconclusive (round VI, 5-0-0). Conclusions These consensus recommendations can guide clinicians in the biomarker-based aetiological diagnosis of mild cognitive impairment, whilst guidelines cannot be defined with evidence-to-decision procedures due to incomplete evidence.

CSF p-tau/Aβ42 ratio and brain FDG-PET may reliably detect MCI “imminent” converters to AD

Abstract: To know whether mild cognitive impairment (MCI) patients will develop Alzheimer’s disease (AD) dementia in very short time or remain stable is of crucial importance, also considering new experimental drugs usually tested within very short time frames. Here we combined cerebrospinal fluid (CSF) AD biomarkers and a neurodegeneration marker such as brain FDG-PET to define an objective algorithm, suitable not only to reliably detect MCI converters to AD dementia but also to predict timing of conversion. We included 77 consecutive MCI patients with neurological/neuropsychological assessment, brain 18F-FDG-PET and CSF analysis available at diagnosis and a neuropsychological/neurological evaluation every 6 months for a medium- to a long-term follow-up (at least 2 and up to 8 years). Binomial logistic regression models and Kaplan-Meier survival analyses were performed to determine the best biomarker (or combination of biomarkers) in detecting MCI converters to AD dementia and then, among the converters, those who converted in short time frames. Thirty-five out of 77 MCI patients (45%) converted to AD dementia, with an average conversion time since MCI diagnosis of 26.07 months. CSF p-tau/Aβ42 was the most accurate predictor of conversion from MCI to AD dementia (82.9% sensitivity; 90% specificity). CSF p-tau/Aβ42 and FDG-PET-positive MCIs converted to AD dementia significantly earlier than the CSF-positive-only MCIs (median conversion time, 17.1 vs 31.3 months). CSF p-tau/Aβ42 ratio and brain FDG-PET may predict both occurrence and timing of MCI conversion to full-blown AD dementia. MCI patients with both biomarkers suggestive for AD will likely develop an AD dementia shortly, thus representing the ideal target for any new experimental drug requiring short periods to be tested for.

In-vivo signatures of neurodegeneration in isolated rapid eye movement sleep behaviour disorder.

Abstract: BACKGROUND AND PURPOSE Isolated rapid eye movement sleep behaviour disorder (iRBD) is a parasomnia, recently recognized as a risk factor for progression to Parkinson's disease, dementia with Lewy body and multiple system atrophy. Biomarker studies in iRBD are relevant due to lack of evidence in this condition. The identification of biomarkers able to predict progression to synucleinopathy diseases is critical for iRBD. Fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging might provide information about ongoing neurodegenerative processes. In the present study, we tested for presence of brain hypometabolism patterns as biomarkers of neurodegeneration in single iRBD individuals. METHODS We recruited 37 subjects with polysomnography-confirmed iRBD, with neuropsychological assessment and available FDG-PET scan. Images were analysed with a validated statistical parametric mapping procedure, providing individual hypometabolism maps. RESULTS According to the neuropsychological evaluation, 22 subjects with iRBD had normal cognition and 15 subjects showed impairments, particularly in visuoperceptive/visuospatial and memory domains. One-fifth of the cases were impaired on the Qualitative Scoring of Pentagon Test. In 32 iRBD cases, FDG-PET statistical parametric maps revealed significant cerebral hypometabolism, namely in the occipital lobes (n = 5), occipital and cerebellar regions (n = 13), occipitoparietal regions (n = 13) and a selective cerebellar hypometabolism (n = 1). Five cases had normal FDG-PET scans. CONCLUSIONS These imaging findings indicate that brain neurodegenerative processes are present and already detectable in iRBD. The different hypometabolism patterns in the single individuals may reflect specific early pathophysiological events due to the underlying synucleinopathy, with a specific neural vulnerability for the occipital cortex that might pre-date a risk of progression towards dementia with Lewy body.

Neural correlates of naming errors across different neurodegenerative diseases: An FDG-PET study

Abstract: Objective To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates. Methods The same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [18F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network. Results Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital–posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors. Conclusions Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias.

Individual Brain Metabolic Signatures in Corticobasal Syndrome.

Abstract: Background Corticobasal syndrome (CBS) is the usual clinical presentation of patients with corticobasal degeneration pathology. Nevertheless, there are CBS individuals with postmortem neuropathology typical of Alzheimer's disease (AD). Objective In this study, we aim to detect FDG-PET metabolic signatures at the single-subject level in a CBS sample, also evaluated with cerebrospinal fluid (CSF) markers for AD pathology. Methods 21 patients (68.9±6.4 years; MMSE score = 21.7±6.3) fulfilling current criteria for CBS were enrolled. All underwent a clinical-neuropsychological assessment and an instrumental evaluation for biomarkers of neurodegeneration, amyloid and tau pathology (i.e., FDG-PET imaging and CSF Aβ42 and tau levels) at close intervals. CBS subjects were classified according to the presence or absence of CSF markers of AD pathology (i.e., low Aβ42 and high phosphorylated tau levels). Optimized voxel-based SPM procedures provided FDG-PET metabolic patterns at the single-subject and group levels. Results Eight CBS had an AD-like CSF profile (CBS-AD), while thirteen were negative (CBS-noAD). The two subgroups did not differ in demographic characteristics or global cognitive impairment. FDG-PET SPM t-maps identified different metabolic signatures. Namely, all CBS-AD patients showed the typical AD-like hypometabolic pattern involving posterior cingulate cortex, precuneus and temporo-parietal cortex, whereas CBS-noAD cases showed bilateral hypometabolism in fronto-insular cortex and basal ganglia that is typical of the frontotemporal lobar degeneration spectrum. Discussion These results strongly suggest the inclusion of FDG-PET imaging in the diagnostic algorithm of individuals with CBS clinical phenotype in order to early identify functional metabolic signatures due to different neuropathological substrates, thus improving the diagnostic accuracy.

An fMRI Study on Self-Perception of Patients after Aesthetic Implant-Prosthetic Rehabilitation.

Abstract: Objectives: In this functional magnetic resonance (fMRI) study, we investigated the activation of cerebral pathways involved in the elaboration of self-retracting photos (SELF) and the same pictures of others (OTHER). Each of the photographs showed one of the participants during different stages of the rehabilitation: pre-treatment (PRE), virtual planning using “Smile-Lynx” smile design software (VIR), and post-rehabilitation (POST). Methods: We selected eighteen volunteers, both male and female, between 22 and 67 years of age, who previously underwent prosthetic rehabilitation. Each of them was subjected to an fMRI acquisition. Various stimuli were then shown to the subjects in the form of self-retracting photographs and photographs of other participants, all in pseudo-randomized order. We then carried out a two- stage mixed-effects group data analysis with statistical contrast targeting two main effects: one regarding the main effect of Identity (SELF vs. OTHER) and the other regarding the effect of the prosthetic rehabilitation phase (PRE vs. VIR vs. POS). All the effects mentioned above survived a peak-level of p < 0.05. Results: For the effect of identity, results reported the involvement of dorsolateral frontoparietal areas bilaterally. For the phase by identity effect, results reported activation in the supplementary motor area (SMA) in the right hemisphere. A stronger activation in observing self-retracting photos (SELF) post-treatment (POST) was reported compared to the other phases considered in the experiment. Conclusions: All the collected data showed differences regarding the main effect of Identity (SELF vs. OTHER). Most importantly, the present study provides some trend-wise evidence that the pictures portraying the subject in their actual physiognomy (POST) have a somewhat special status in eliciting selectively greater brain activation in the SMA. This effect was interpreted as a plausible correlate of an empathic response for beautiful and neutral faces. The present research suggests a possible way to measure self-perception of the subject after an appearance-altering procedure such an implant-prosthetic rehabilitation. However, future clinical studies are needed to investigate this matter further.

Robust MR-free Grey Matter Extraction in Amyloid PET/CT Studies with Deep Learning

Abstract: Quantification of amyloid PET studies is most accurate if regions of interest (ROIs) are not affected by the presence of cerebrospinal fluid. Patients with high amyloid load often have great atrophy, therefore, the use of atlas-based ROIs, instead of patient specific anatomy, can underestimate amyloid load, leading to a bias. Traditionally, this can be overcome only using MR anatomical sequences, which are burdensome and might not be ideal to be performed for each patient in the clinical routine. In this work, we propose to overcome this issue by using a method based on deep learning. As CT scans provide anatomical information, even at the very low doses used for PET attenuation correction, we propose the use of such a scan, together with the PET one, for a U-NET based segmentation. The approach achieves a median DICE score of 77% on a validation cohort of N=20 patients, even when using only N=14 patients in the training dataset. A dedicated data augmentation strategy is used, and the individual contribution of each modality is analyzed. We find that the joint effect of PET and CT is beneficial (median DICE: PET only 73.0%, CT only 74%). A near perfect correlation with MR-based quantification was also found.