The diagnostic and prognostic value of tau-PET in amnestic MCI with different FDG-PET subtypes.

OBJECTIVES: Mild cognitive impairment presenting with an amnestic syndrome (aMCI) and amyloid positivity is considered due to AD. Many subjects, however, can show an overall very slow progression relevant for differential diagnosis, prognosis, and treatment. This study assessed PET biomarkers, including brain glucose metabolism, tau, and amyloid load, in a series of comparable aMCI at baseline, clinically evaluated at follow-up. METHODS: We included 72 aMCI subjects from Geneva Memory Center (N = 31) and ADNI cohorts (N = 41), selected based on available FDG-PET, tau-PET, amyloid-PET, and clinical follow-up (2.3 years ± 1.2). A data-driven algorithm classified brain metabolic patterns into subtypes that were then compared for clinical and PET biomarker measures and cognitive decline. Voxel-wise comparisons were performed both with FDG-PET and tau-PET data. RESULTS: The algorithm classified three metabolic subtypes, namely "Hippocampal-sparing with cortical hypometabolism" (Type1; N = 27), "Hippocampal and cortical hypometabolism" (Type 2; N = 23), and "Medial temporal hypometabolism" (Type 3; N = 22). Amyloid positivity and tau accumulation in the medial temporal and neocortical regions characterized Type 1 and Type 2, whereas Type 3 showed no significant tau pathology, variable amyloid positivity, and stability at follow-up. All tau-positive patients, independently of the FDG-based subtype, showed faster cognitive decline. INTERPRETATION: aMCI subjects can differ in metabolic patterns, tau and amyloid pathology, and clinical progression. Here, we complemented with PET tau biomarker the specific brain hypometabolic patterns at the individual level in the prodromal phase, contributing to the patient's classification. Tau PET is the most accurate biomarker in supporting or excluding the AD diagnosis in aMCI across metabolic subtypes and also predicting the risk of decline.

Heterogeneity and overlap in the continuum of linguistic profile of logopenic and semantic variants of primary progressive aphasia: a Profile Analysis based on Multidimensional Scaling study.

BACKGROUND: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce. METHODS: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [18F] FDG-PET. Correlations were performed between metabolic and behavioral data. RESULTS: Patients' profiles were distributed across a continuum. All PPA, but two, presented a lexical retrieval impairment, in terms of reduced production of verbs and nouns. svPPA patients occupied a fairly clumped space along the continuum, showing a preponderant semantic deficit, which correlated to fusiform gyrus hypometabolism, while only few presented working memory deficits. Adjacently, lvPPA + presented a semantic impairment combined with phonological deficits, which correlated with metabolism in the anterior fusiform gyrus and posterior middle temporal gyrus. Starting from the shared phonological deficit side, a large portion of the space was occupied by all lvPPA, showing a combination of phonological, lexical, and working memory deficits, with the latter correlating with posterior temporo-parietal hypometabolism. Mixed PPA did not show unique profile, distributing across the space. DISCUSSION: Different clinical PPA entities exist but overlaps are frequent. Identifying shared and unique clinical markers is critical for research and clinical practice. Further research is needed to identify the role of genetic and pathological factors in such distribution, including also higher sample size of less represented groups.

Mapping brain metabolism, connectivity and neurotransmitters topography in early and late onset dementia with lewy bodies.

INTRODUCTION: Early-onset dementia with Lewy bodies (EO-DLB) is associated with rapid cognitive decline and severe neuropsychiatric symptoms at onset. METHODS: Using FDG-PET imaging for 62 patients (21 EO-DLB, 41 LO (late-onset)-DLB), we explored brain hypometabolism, and metabolic connectivity in the whole-brain network and resting-state networks (RSNs). We also evaluated the spatial association between brain hypometabolism and neurotransmitter pathways topography. RESULTS: Direct comparisons between the two clinical subgroups showed that EO-DLB was characterized by a lower metabolism in posterior cingulate/precuneus and occipital cortex. Metabolic connectivity analysis revealed significant alterations in posterior regions in both EO-DLB and LO-DLB. The EO-DLB, however, showed more severe loss of connectivity between occipital and parietal nodes and hyperconnectivity between frontal and cerebellar nodes. Spatial topography association analysis indicated significant correlations between neurotransmitter maps (i.e. acetylcholine, GABA, serotonin, dopamine) and brain hypometabolism in both EO and LO-DLB, with significantly higher metabolic correlation in the presynaptic serotonergic system for EO-DLB, supporting its major dysfunction. CONCLUSIONS: Our study revealed greater brain hypometabolism and loss of connectivity in posterior brain region in EO- than LO-DLB. Serotonergic mapping emerges as a relevant factor for further investigation addressing clinical differences between DLB subtypes.

FDG-PET markers of heterogeneity and different risk of progression in amnestic MCI.

INTRODUCTION: Amnestic mild cognitive impairment (aMCI) is emerging as a heterogeneous condition. METHODS: We looked at a cohort of N = 207 aMCI subjects, with baseline fluorodeoxyglucose positron emission tomography (FDG-PET), T1 magnetic resonance imaging, cerebrospinal fluid (CSF), apolipoprotein E (APOE), and neuropsychological assessment. An algorithm based on FDG-PET hypometabolism classified each subject into subtypes, then compared biomarker measures and clinical progression. RESULTS: Three subtypes emerged: hippocampal sparing-cortical hypometabolism, associated with younger age and the highest level of Alzheimer's disease (AD)-CSF pathology; hippocampal/cortical hypometabolism, associated with a high percentage of APOE ε3/ε4 or ε4/ε4 carriers; medial-temporal hypometabolism, characterized by older age, the lowest AD-CSF pathology, the most severe hippocampal atrophy, and a benign course. Within the whole cohort, the severity of temporo-parietal hypometabolism, correlated with AD-CSF pathology and marked the rate of progression of cognitive decline. DISCUSSION: FDG-PET can distinguish clinically comparable aMCI at single-subject level with different risk of progression to AD dementia or stability. The obtained results can be useful for the optimization of pharmacological trials and automated-classification models. HIGHLIGHTS: Algorithm based on FDG-PET hypometabolism demonstrates distinct subtypes across aMCI; Three different subtypes show heterogeneous biological profiles and risk of progression; The cortical hypometabolism is associated with AD pathology and cognitive decline; MTL hypometabolism is associated with the lowest conversion rate and CSF-AD pathology.

Atypical brain FDG-PET patterns increase the risk of long-term cognitive and motor progression in Parkinson's disease.

INTRODUCTION: Brain hypometabolism patterns have been previously associated with cognitive decline in Parkinson's disease (PD). Our aim is to evaluate the impact of single-subject fluorodeoxyglucose (FDG)-PET brain hypometabolism on long-term cognitive and motor outcomes in PD. METHODS: Forty-nine non-demented PD patients with baseline brain FDG-PET data underwent an extensive clinical follow-up for 8 years. The ability of FDG-PET to predict long-term cognitive and motor progression was evaluated using Cox regression and mixed ANCOVA models. RESULTS: Participants were classified according to FDG-PET pattern in PD with typical (n = 26) and atypical cortical metabolism (n = 23). Patients with atypical brain hypometabolic patterns showed higher incidence of dementia (60% vs 3%; HR = 18.3), hallucinations (56% vs 7%, HR = 7.3) and faster motor decline compared to typical pattern group. CONCLUSION: This study argues for specific patterns of FDG-PET cortical hypometabolism in PD as a prognostic marker for long term cognitive and motor outcomes at single-subject level.

Sex differences in brain metabolic connectivity architecture in probable dementia with Lewy bodies.

We investigated how sex modulates metabolic connectivity alterations in probable dementia with Lewy bodies (pDLB). We included 131 pDLB patients (males/females: 58/73) and similarly aged healthy controls (HC) (male/female: 59/75) with available (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans. We assessed (1) sex differences in the whole-brain connectivity, identifying pathological hubs, (2) connectivity alterations in functional pathways of the neurotransmitter systems, (3) Resting State Networks (RSNs) integrity. Both pDLBM (males) and pDLBF (females) shared dysfunctional hubs in the insula, Rolandic operculum, and inferior parietal lobule, but the pDLBM group showed more severe and diffuse whole-brain connectivity alterations. Neurotransmitters connectivity analysis revealed common alterations in dopaminergic and noradrenergic pathways. Sex differences emerged particularly in the Ch4-perisylvian division, with pDLBM showing more severe alterations than pDLBF. The RSNs analysis showed no sex differences, with decreased connectivity strength in the primary visual, posterior default mode, and attention networks in both groups. Extensive connectivity changes characterize both males and females in the dementia stage, with a major vulnerability of cholinergic neurotransmitter systems in males, possibly contributing to the observed different clinical phenotypes.

Dopaminergic connectivity reconfiguration in the dementia with Lewy bodies continuum.

INTRODUCTION: The impairment of nigrostriatal dopaminergic network is a core feature of dementia with Lewy bodies (DLB). The involvement and reconfiguration of extranigrostriatal dopaminergic circuitries in the DLB continuum is still theme of debate. We aim to investigate in vivo the dynamic changes of local and long-distance dopaminergic networks across DLB continuum. METHODS: Forty-nine patients (including 29 with dementia and 20 prodromal cases) and fifty-two controls entered the study. Each subject underwent a standardized clinical and neurological examination and performed Brain SPECT to measuring brain dopamine transporter (DAT) density. Spatially normalized images underwent the occipital-adjusted specific binding to obtain parametric data. The ANCOVA was applied to assess 123I-FP-CIT differences between pDLB, overt-DLB and CG, considering age, gender, and motor impairment as variables of no interest. Between-nodes correlation analysis measured molecular connectivity within the ventral and dorsal dopaminergic networks. RESULTS: Prodromal DLB and DLB patients showed comparable nigrostriatal deficits in basal ganglia regions compared with CG. Molecular connectivity analyses revealed extensive connectivity losses, more in ventral than in dorsal dopaminergic network in DLB dementia. Conversely, the prodromal group showed increased connectivity compared to CG, mostly putamen-thalamus-cortical and striatal-cortical connectivity. CONCLUSIONS: This study indicates a comparable basal ganglia deficit in nigrostriatal projections in DLB continuum and supports a different reorganization of extra-striatal dopaminergic connectivity in the prodromal phases of DLB. The shift from an increased to a decreased bilateral putamen-thalamus-cortex connectivity might be a hallmark of transition from prodromal to dementia DLB stages.

Sex differences in dementia with Lewy bodies: an imaging study of neurotransmission pathways.

PURPOSE: Dementia with Lewy bodies (DLB) is characterized by a wide clinical and biological heterogeneity, with sex differences reported in both clinical and pathologically confirmed DLB cohorts. No research evidence is available on sex differences regarding molecular neurotransmission. This study aimed to assess whether sex can influence neurotransmitter systems in patients with probable DLB (pDLB). METHODS: We included 123 pDLB patients (male/female: 77/46) and 78 control subjects (male/female: 34/44) for comparison, who underwent 123I-FP-CIT SPECT imaging. We assessed sex differences in the dopaminergic activity of the nigrostriatal and mesolimbic systems using regional-based and voxel-wise analyses of 123I-FP-CIT binding. We tested whether sex-specific binding alterations would also pertain to the serotoninergic and noradrenergic systems by applying spatial correlation analyses. We applied molecular connectivity analyses to assess potential sex differences in the dopaminergic pathways. RESULTS: We found comparable 123I-FP-CIT binding decreases in the striatum for pDLB males and females compared to controls. However, pDLB females showed lower binding in the extrastriatal projections of the nigrostriatal and mesolimbic dopaminergic systems compared to pDLB males. According to the spatial correlation analysis, sex-specific molecular alterations were also associated with serotonergic and noradrenergic systems. Nigrostriatal and mesolimbic systems' connectivity was impaired in both groups, with males showing local alterations and females presenting long-distance disconnections between subcortical and cortical regions. CONCLUSIONS: Sex-specific differences in 123I-FP-CIT binding were found in our cohort, namely, a trend for lower 123I-FP-CIT binding in females, significant in the presence of a pDLB diagnosis. pDLB females showed also different patterns of connectivity compared to males, mostly involving extrastriatal regions. The results suggest the presence of a sex-related regional vulnerability to alpha-synuclein pathology, possibly complicated also by the higher prevalence of Alzheimer's disease co-pathology in females, as previously reported in pDLB populations.

Brain connectomics: time for a molecular imaging perspective?

In the past two decades brain connectomics has evolved into a major concept in neuroscience. However, the current perspective on brain connectivity and how it underpins brain function relies mainly on the hemodynamic signal of functional magnetic resonance imaging (MRI). Molecular imaging provides unique information inaccessible to MRI-based and electrophysiological techniques. Thus, positron emission tomography (PET) has been successfully applied to measure neural activity, neurotransmission, and proteinopathies in normal and pathological cognition. Here, we position molecular imaging within the brain connectivity framework from the perspective of timeliness, validity, reproducibility, and resolution. We encourage the neuroscientific community to take an integrative approach whereby MRI-based, electrophysiological techniques, and molecular imaging contribute to our understanding of the brain connectome.

Clinical relevance of single-subject brain metabolism patterns in amyotrophic lateral sclerosis mutation carriers.

BACKGROUND AND OBJECTIVES: The ALS diagnosis requires an integrative approach, combining the clinical examination and supporting tests. Nevertheless, in several cases, the diagnosis proves to be suboptimal, and for this reason, new diagnostic methods and novel biomarkers are catching on. The 18F-fluorodeoxyglucose (18F-FDG)-PET could be a helpful method, but it still requires additional research for sensitivity and specificity. We performed an 18F-FDG-PET single-subject analysis in a sample of familial ALS patients carrying different gene mutations, investigating the genotype-phenotype correlations and exploring metabolism correlations with clinical and neuropsychological data. METHODS: We included ten ALS patients with pathogenic gene mutation who underwent a complete clinical and neuropsychological evaluation and an 18F-FDG-PET scan at baseline. Patients were recruited between 2018 and 2022 at the ALS Tertiary Centre in Novara, Italy. Patients were selected based on the presence of ALS gene mutation (C9orf72, SOD1, TBK1, and KIF5A). Following a validated voxel-based Statistical Parametric Mapping (SPM) procedure, we obtained hypometabolism maps at single-subject level. We extracted regional hypometabolism from the SPM maps, grouping significant hypometabolism regions into three meta-ROIs (motor, prefrontal association and limbic). Then, the corresponding 18F-FDG-PET regional hypometabolism was correlated with clinical and neuropsychological features. RESULTS: Classifying the patients with C9orf72-ALS based on the rate of disease progression from symptoms onset to the time of scan, we observed two different patterns of brain hypometabolism: an extensive motor and prefrontal hypometabolism in patients classified as fast progressors, and a more limited brain hypometabolism in patients grouped as slow progressors. Patients with SOD1-ALS showed a hypometabolic pattern involving the motor cortex and prefrontal association regions, with a minor involvement of the limbic regions. The patient with TBK1-ALS showed an extended hypometabolism, in limbic systems, along with typical motor involvement, while the hypometabolism in the patient with KIF5A-ALS involved almost exclusively the motor regions, supporting the predominantly motor impairment linked to this gene mutation. Additionally, we observed strong correlations between the hypometabolism in the motor, prefrontal association and limbic meta-ROI and the specific neuropsychological performances. CONCLUSIONS: To our knowledge, this is the first study investigating brain hypometabolism at the single-subject level in genetic ALS patients carrying different mutations. Our results show high heterogeneity in the hypometabolism maps and some commonalities in groups sharing the same mutation. Specifically, in patients with C9orf72-ALS the brain hypometabolism was larger in patients classified as fast progressors than slow progressors. In addition, in the whole group, the brain metabolism showed specific correlations with clinical and neuropsychological impairment, confirming the ability of 18F-FDG-PET in revealing pattern of neuronal dysfunction, aiding the diagnostic workup in genetic ALS patients.

Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aß Autoantibodies.

BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities suggestive of vasogenic edema or sulcal effusion (ARIA-E) are the most common adverse events complicating Alzheimer disease (AD) immunotherapy with anti-ß-amyloid (Aß) monoclonal antibodies. ARIA-E can also occur spontaneously in cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare autoimmune encephalopathy associated with increased CSF levels of anti-Aß autoantibodies. Although the pathophysiologic mechanisms of ARIA-E remain to be fully elucidated, experimental evidence from ex vivo studies suggests that gantenerumab and aducanumab enable microglial activation. However, the in vivo evidence for a direct association between neuroinflammation and ARIA-E in patients with high CSF anti-Aß (auto)antibody levels has never been demonstrated. METHODS: The spatial distribution and temporal variations of microglial activation associated with levels of anti-Aß autoantibodies at (sub)acute presentation of ARIA-E and after corticosteroid therapy were evaluated in a longitudinal case series of patients with CAA-ri, the spontaneous variant of the iatrogenic ARIA-E reported in Aß-lowering immunotherapy with monoclonal antibodies. Multimodal and multiparametric MRI was used for CAA and ARIA-E severity quantification, according to validated scoring system; CSF testing for anti-Aß autoantibodies and AD biomarkers; 11C-PK11195 PET for activated microglia. RESULTS: At (sub)acute presentation, we found focal peaks of microglial activation having a greater spatial colocalization with ARIA-E compared with chronic age-related white matter change imaging abnormalities. The severity of ARIA-E and the magnitude of the associated microglial activation were greater in patients having AD and severe CAA concomitant disease compared with patients having CAA only. CSF anti-Aß autoantibodies at presentation were high in all patients and markedly decreased at posttreatment follow-up, in parallel with clinical resolution of acute symptoms, reduced ARIA-E severity, and reduced microglial activation. DISCUSSION: Our findings extend the current notion of ARIA-E by providing the first in vivo 11C-PK11195 PET evidence for an association between microglial activation and the magnitude and severity of ARIA-E in patients with increased CSF concentration of anti-Aß autoantibodies and comorbid AD and CAA disease. Our results highlight CSF testing for anti-Aß autoantibodies as a promising diagnostic, prognostic, and therapy response biomarker to help guide future treatment and management decisions in real clinical practice and clinical trials.

Clinical and Dopamine Transporter Imaging Trajectories in a Cohort of Parkinson's Disease Patients with GBA Mutations.

BACKGROUND: Glucosylceramidase (GBA) mutations are considered the most common genetic risk factors for developing Parkinson's disease (PD). OBJECTIVES: We aimed to assess, at different time points, the integrity of brain striatal and extra-striatal dopamine pathways and clinical phenotype of a group of PD subjects bearing heterozygous GBA mutations (GBA-PD), compared with a group of idiopathic PD patients (iPD) stratified by age at disease onset. A longitudinal approach was adopted to evaluate the progression over time for clinical and 123 I-FP-CIT SPECT imaging features. METHODS: We considered 46 GBA-PD patients and 339 iPD patients, subdivided into two groups according to age at PD onset (n = 58 < 50 years and n = 281 > 50 years). We measured differences in the occurrence/severity/progression of motor and non-motor features, 123 I-FP-CIT standard uptake value ratios (SUVr) in striatal and extra-striatal regions, and global cognitive deterioration over time in a subset of 168 cases with available follow-up. RESULTS: At baseline, the GBA-PD cohort showed more severe motor and cognitive deficits than the early-iPD cohort. The 123 I-FP-CIT SUVr reduction in the striatal and the extra-striatal regions was more marked in the GBA-PD than the early- and late-iPD cohorts. Both GBA-PD and late-iPD patients had a significant annual deterioration in their global cognitive performance, while the early-iPD group showed global cognitive stability over time. At follow-up, the iPD cohorts became similar to the GBA-PD group in 123 I-FP-CIT SUVr reduction. CONCLUSION: These new findings support the hypothesis of a biological role of GBA mutations in accelerating the early neurodegenerative processes in PD, leading to the malignant clinical phenotype. © 2021 International Parkinson and Movement Disorder Society.

In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer's disease phases.

BACKGROUND: Preclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer's disease (AD). We in vivo investigated if, when, and in which target regions [123I]FP-CIT-SPECT regional binding and molecular connectivity are damaged along the AD course. METHODS: We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D), and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial correlation analysis. Results were deemed significant at p < 0.05, after Bonferroni correction for multiple comparisons. RESULTS: We found significant reductions of [123I]FP-CIT binding in both AD-MCI and AD-D compared to controls. Binding reductions were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced [123I]FP-CIT binding, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient ≤ 0.25) and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). CONCLUSION: Local- and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

Brain Metabolism and Microglia Activation in Mild Cognitive Impairment: A Combined [18F]FDG and [11C]-(R)-PK11195 PET Study.

BACKGROUND: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. [18F]FDG-PET reveals brain hypometabolism patterns reflecting neuronal/synaptic dysfunction, already in the prodromal MCI phase. Activated microglia is part of the pathogenetic processes leading to neurodegeneration. OBJECTIVE: Using [11C]-(R)-PK11195 and [18F]FDG-PET, we aimed to in vivo investigate the presence of microglial activation, and the relationship with brain glucose metabolism, in single MCI subjects. METHODS: Eight MCI subjects underwent both [18F]FDG-PET and [11C]-(R)-PK11195 PET. We used validated quantification methods to obtain brain hypometabolism maps and microglia activation peaks in single subjects. We investigated both the spatial overlap and the relationship between brain glucose hypometabolism and microglia activation, by means of Dice similarity coefficient and using Pearson's correlation at single subject level. RESULTS: Each MCI showed a specific brain hypometabolism pattern indicative of different possible etiologies, as expected in MCI population (i.e., Alzheimer's disease-like, frontotemporal dementia-like, hippocampal-type, normal aging type). [11C]-(R)-PK11195 PET analysis revealed a spatial concordance with regional hypometabolism in all subjects with several clusters of significant microglia activation showing an inverse correlation with the regional metabolism. This was proportional to the strength of between-signals correlation coefficient (ß â€Š=  -0.804; p = 0.016). CONCLUSION: Microglia activation is present in the prodromal MCI phase of different underlying etiologies, showing spatial concordance and inverse correlation with brain glucose metabolism at single-subject level. These findings suggest a possible contribution of activated microglia to neurodegeneration, showing important implications for local immune activity in the early neurodegenerative processes.

Validation of FDG-PET datasets of normal controls for the extraction of SPM-based brain metabolism maps.

PURPOSE: An appropriate healthy control dataset is mandatory to achieve good performance in voxel-wise analyses. We aimed at evaluating [18F]FDG PET brain datasets of healthy controls (HC), based on publicly available data, for the extraction of voxel-based brain metabolism maps at the single-subject level. METHODS: Selection of HC images was based on visual rating, after Cook's distance and jack-knife analyses, to exclude artefacts and/or outliers. The performance of these HC datasets (ADNI-HC and AIMN-HC) to extract hypometabolism patterns in single patients was tested in comparison with the standard reference HC dataset (HSR-HC) by means of Dice score analysis. We evaluated the performance and comparability of the different HC datasets in the assessment of single-subject SPM-based hypometabolism in three independent cohorts of patients, namely, ADD, bvFTD and DLB. RESULTS: Two-step Cook's distance analysis and the subsequent jack-knife analysis resulted in the selection of n = 125 subjects from the AIMN-HC dataset and n = 75 subjects from the ADNI-HC dataset. The average concordance between SPM hypometabolism t-maps in the three patient cohorts, as obtained with the new datasets and compared to the HSR-HC standard reference dataset, was 0.87 for the AIMN-HC dataset and 0.83 for the ADNI-HC dataset. Pattern expression analysis revealed high overall accuracy (> 80%) of the SPM t-map classification according to different statistical thresholds and sample sizes. CONCLUSIONS: The applied procedures ensure validity of these HC datasets for the single-subject estimation of brain metabolism using voxel-wise comparisons. These well-selected HC datasets are ready-to-use in research and clinical settings.

Impaired metabolic brain networks associated with neurotransmission systems in the α-synuclein spectrum.

INTRODUCTION: While the involvement of multiple neurotransmitter systems in α-synucleinopathies is reported, a comprehensive study on their metabolic connectivity reconfiguration in the preclinical and clinical disease-spectrum is lacking. We aimed to investigate shared and disease-specific neural vulnerabilities of the nigro-striato-cortical dopaminergic, noradrenergic and cholinergic networks within the α-synuclein-spectrum, by means of metabolic connectivity approach. METHODS: We collected 34 polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD) subjects, 29 idiopathic Parkinson's disease (PD) patients without dementia, 30 patients with probable dementia with Lewy bodies (DLB), and 50 healthy controls for comparisons. Neurotransmission networks' analyses were performed through multivariate partial correlations based on FDG-PET brain metabolic data. RESULTS: We found: a) the nigro-striato-cortical dopaminergic network with a limited reconfiguration in individuals with iRBD, but moderate-to-severe alterations in patients with DLB and PD; b) an extended connectivity alteration of the noradrenergic network in all groups; c) changes within the cholinergic networks connectivity in the whole disease-spectrum, with some differences: PD with only moderate connectivity reconfiguration and DLB with the most severe alterations, some of these shared with iRBD. CONCLUSIONS: Synucleinopathies can be considered multisystem disorders, with common and disease-specific neurotransmission networks reconfigurations. The present findings indicate dopaminergic connectivity alterations only when associated with parkinsonism, a very early involvement of noradrenergic networks, occurring in both the iRBD and in symptomatic PD/DLB patients and cholinergic alterations with disease-specific vulnerabilities shared by iRBD and DLB. The latter finding may represent an early biomarker of disease progression to dementia.

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

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.

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

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.