Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline.

Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (ß=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (ß=0.006, p < 0.01) and global tau SUVR (ß=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation-glial fibrillary acidic protein-is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.

A deep learning model for generating [18F]FDG PET Images from early-phase [18F]Florbetapir and [18F]Flutemetamol PET images.

INTRODUCTION: Amyloid-ß (Aß) plaques is a significant hallmark of Alzheimer's disease (AD), detectable via amyloid-PET imaging. The Fluorine-18-Fluorodeoxyglucose ([18F]FDG) PET scan tracks cerebral glucose metabolism, correlated with synaptic dysfunction and disease progression and is complementary for AD diagnosis. Dual-scan acquisitions of amyloid PET allows the possibility to use early-phase amyloid-PET as a biomarker for neurodegeneration, proven to have a good correlation to [18F]FDG PET. The aim of this study was to evaluate the added value of synthesizing the later from the former through deep learning (DL), aiming at reducing the number of PET scans, radiation dose, and discomfort to patients. METHODS: A total of 166 subjects including cognitively unimpaired individuals (N = 72), subjects with mild cognitive impairment (N = 73) and dementia (N = 21) were included in this study. All underwent T1-weighted MRI, dual-phase amyloid PET scans using either Fluorine-18 Florbetapir ([18F]FBP) or Fluorine-18 Flutemetamol ([18F]FMM), and an [18F]FDG PET scan. Two transformer-based DL models called SwinUNETR were trained separately to synthesize the [18F]FDG from early phase [18F]FBP and [18F]FMM (eFBP/eFMM). A clinical similarity score (1: no similarity to 3: similar) was assessed to compare the imaging information obtained by synthesized [18F]FDG as well as eFBP/eFMM to actual [18F]FDG. Quantitative evaluations include region wise correlation and single-subject voxel-wise analyses in comparison with a reference [18F]FDG PET healthy control database. Dice coefficients were calculated to quantify the whole-brain spatial overlap between hypometabolic ([18F]FDG PET) and hypoperfused (eFBP/eFMM) binary maps at the single-subject level as well as between [18F]FDG PET and synthetic [18F]FDG PET hypometabolic binary maps. RESULTS: The clinical evaluation showed that, in comparison to eFBP/eFMM (average of clinical similarity score (CSS) = 1.53), the synthetic [18F]FDG images are quite similar to the actual [18F]FDG images (average of CSS = 2.7) in terms of preserving clinically relevant uptake patterns. The single-subject voxel-wise analyses showed that at the group level, the Dice scores improved by around 13% and 5% when using the DL approach for eFBP and eFMM, respectively. The correlation analysis results indicated a relatively strong correlation between eFBP/eFMM and [18F]FDG (eFBP: slope = 0.77, R2 = 0.61, P-value < 0.0001); eFMM: slope = 0.77, R2 = 0.61, P-value < 0.0001). This correlation improved for synthetic [18F]FDG (synthetic [18F]FDG generated from eFBP (slope = 1.00, R2 = 0.68, P-value < 0.0001), eFMM (slope = 0.93, R2 = 0.72, P-value < 0.0001)). CONCLUSION: We proposed a DL model for generating the [18F]FDG from eFBP/eFMM PET images. This method may be used as an alternative for multiple radiotracer scanning in research and clinical settings allowing to adopt the currently validated [18F]FDG PET normal reference databases for data analysis.

Neuroimaging-guided diagnosis of possible FTLD-FUS pathology: a case report.

BACKGROUND: This case report presents a patient with progressive memory loss and choreiform movements. CASE PRESENTATION: Neuropsychological tests indicated multi-domain amnestic mild cognitive impairment (aMCI), and neurological examination revealed asymmetrical involuntary hyperkinetic movements. Imaging studies showed severe left-sided atrophy and hypometabolism in the left frontal and temporoparietal cortex. [18F]Flortaucipir PET exhibited moderately increased tracer uptake in hypometabolic areas. The diagnosis initially considered Alzheimer's disease (AD), frontotemporal degeneration (FTD), and corticobasal degeneration (CBD), cerebral hemiatrophy syndrome, but imaging and cerebrospinal fluid analysis excluded AD and suggested fused-in-sarcoma-associated FTD (FTLD-FUS), a subtype of the behavioural variant of FTD. CONCLUSIONS: Our case highlights that despite the lack of specific FUS biomarkers the combination of clinical features and neuroimaging biomarkers can guide choosing the most likely differential diagnosis in a complex neurological case. Imaging in particular allowed an accurate measure of the topography and severity of neurodegeneration and the exclusion of AD-related pathology.

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.

Distinctive clinical and imaging trajectories in SWEDD and Parkinson's disease patients.

A proportion of patients clinically diagnosed with Parkinson's disease (PD) can have a 123I-FP-CIT-SPECT scan without evidence of dopaminergic deficit (SWEDD), generating a debate about the underlying biological mechanisms. This study investigated differences in clinical features, 123I-FP-CIT binding, molecular connectivity, as well as clinical and imaging progression between SWEDD and PD patients. We included 36 SWEDD, 49 de novo idiopathic PD, and 49 healthy controls with 123I-FP-CIT-SPECT from the Parkinson's Progression Markers Initiative. Clinical and imaging 2-year follow-ups were available for 27 SWEDD and 40 PD. Regional-based and voxel-wise analysis assessed dopaminergic integrity in dorsal and ventral striatal, as well as extrastriatal regions, at baseline and follow-up. Molecular connectivity analyses evaluated dopaminergic pathways. Spatial correlation analyses tested whether 123I-FP-CIT-binding alterations would also pertain to the serotoninergic system. SWEDD and PD patients showed comparable symptoms at baseline, except for hyposmia, which was more severe for PD. PD showed significantly lower striatal and extrastriatal 123I-FP-CIT-binding compared to SWEDD and controls. SWEDD exhibited lower binding than controls in striatal regions, insula, and olfactory cortex. Both PD and SWEDD showed extensive altered connectivity of dopaminergic pathways, however, with major impairment in the mesocorticolimbic system for SWEDD. Motor symptoms and dopaminergic deficits worsened after 2 years for PD only. The limited dopaminergic impairment and its stability over time observed for SWEDD, as well as the presence of extrastriatal 123I-FP-CIT binding alterations and prevalent mesocorticolimbic connectivity impairment, suggest other mechanisms contributing to SWEDD pathophysiology.

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.

A comparison of visual assessment and semi-quantification for the diagnostic and prognostic use of [18F]flortaucipir PET in a memory clinic cohort.

PURPOSE: [18F]Flortaucipir PET is a powerful diagnostic and prognostic tool for Alzheimer's disease (AD). Tau status definition is mainly based in the literature on semi-quantitative measures while in clinical settings visual assessment is usually preferred. We compared visual assessment with established semi-quantitative measures to classify subjects and predict the risk of cognitive decline in a memory clinic population. METHODS: We included 245 individuals from the Geneva Memory Clinic who underwent [18F]flortaucipir PET. Amyloid status was available for 207 individuals and clinical follow-up for 135. All scans were blindly evaluated by three independent raters who visually classified the scans according to Braak stages. Standardized uptake value ratio (SUVR) values were obtained from a global meta-ROI to define tau positivity, and the Simplified Temporo-Occipital Classification (STOC) was applied to obtain semi-quantitatively tau stages. The agreement between measures was tested using Cohen's kappa (k). ROC analysis and linear mixed-effects models were applied to test the diagnostic and prognostic values of tau status and stages obtained with the visual and semi-quantitative approaches. RESULTS: We found good inter-rater reliability in the visual interpretation of tau Braak stages, independently from the rater's expertise (k>0.68, p<0.01). A good agreement was equally found between visual and SUVR-based classifications for tau status (k=0.67, p<0.01). All tau-assessment modalities significantly discriminated amyloid-positive MCI and demented subjects from others (AUC>0.80) and amyloid-positive from negative subjects (AUC>0.85). Linear mixed-effect models showed that tau-positive individuals presented a significantly faster cognitive decline than the tau-negative group (p<0.01), independently from the classification method. CONCLUSION: Our results show that visual assessment is reliable for defining tau status and stages in a memory clinic population. The high inter-rater reliability, the substantial agreement, and the similar diagnostic and prognostic performance of visual rating and semi-quantitative methods demonstrate that [18F]flortaucipir PET can be robustly assessed visually in clinical practice.

The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive decline.

INTRODUCTION: Tau and neurodegeneration strongly correlate with cognitive impairment, as compared to amyloid. However, their contribution in explaining cognition and predicting cognitive decline in memory clinics remains unclarified. METHODS: We included 94 participants with Mini-Mental State Examination (MMSE), tau positron emission tomography (PET), amyloid PET, fluorodeoxyglucose (FDG) PET, and MRI scans from Geneva Memory Center. Linear regression and mediation analyses tested the independent and combined association between biomarkers, cognitive performance, and decline. Linear mixed-effects and Cox proportional hazards models assessed biomarkers' prognostic values. RESULTS: Metabolism had the strongest association with cognition (r = 0.712; p < 0.001), followed by tau (r = -0.682; p < 0.001). Neocortical tau showed the strongest association with cognitive decline (r = -0.677; p < 0.001). Metabolism mediated the association between tau and cognition and marginally mediated the one with decline. Tau positivity represented the strongest risk factor for decline (hazard ratio = 32). DISCUSSION: Tau and neurodegeneration synergistically contribute to global cognitive impairment while tau drives decline. The tau PET superior prognostic value supports its implementation in memory clinics. HIGHLIGHTS: Hypometabolism has the strongest association with concurrent cognitive impairment. Neocortical tau pathology is the main determinant of cognitive decline over time. FDG-PET has a superior value compared to MRI as a measure of neurodegeneration. The prognostic value of tau-PET exceeded all other neuroimaging modalities.

Comparing two picture naming tasks in primary progressive aphasia: Insights from behavioural and neural results.

Picture naming tests are widely used to evaluate language impairments in neurodegenerative diseases, especially in Primary Progressive Aphasia (PPA). The available tests differ for many factors affecting the performance, e.g. format of stimuli and their psycholinguistic properties. We aim to identify the most appropriate naming test to be used on PPA according to the clinical and research demands. We investigated the behavioural characteristics, i.e. proportion of correct responses and error type, and their neural correlates in two Italian naming tests, CaGi naming (CaGi) and naming subtest of the Screening for Aphasia in NeuroDegeneration battery (SAND), administered to 52 PPA patients who underwent an FDG-PET scan. We analysed the effectiveness of the tests in distinguishing PPA versus controls and among PPA variants, considering the psycholinguistic variables affecting performance. We explored the brain metabolic correlates of behavioural performance in the tests. SAND, differently from CaGi, has time limits for the response and its items are less frequent and acquired later. SAND and CaGi differed in terms of number of correct responses and error profile, suggesting a higher difficulty to name SAND items compared to CaGi. Semantic errors predominated in CaGi, while anomic and semantic errors were equally frequent in SAND. Both tests distinguished PPA from controls, but SAND outperformed CaGi in discriminating among PPA variants. FDG-PET imaging revealed a shared metabolic involvement of temporal areas associated with lexico-semantic processing, encompassing anterior fusiform, temporal pole, and extending to posterior fusiform in sv-PPA. Concluding, a picture naming test with response time limit and items which are less frequent and acquired later in life, as SAND, may be effective at highlighting subtle distinctions between PPA variants, improving the diagnosis. Conversely, a naming test without time limit for the response, as CaGi, may be useful for a better characterization of the nature of the naming impairment at the behavioural level, eliciting more naming errors than anomia, possibly helping in the development of rehabilitation protocols.

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.

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.

Manual and semi-automated approaches to MIBG myocardial scintigraphy in patients with Parkinson's disease.

Objective: This study investigates the effects of manual and semi-automatic methods for assessing MIBG semi-quantitative indices in a clinical setting. Materials and methods: We included 123I-MIBG scans obtained in 35 patients with idiopathic Parkinson's Disease. Early and late heart-to-mediastinum (H/M) ratios were calculated from 123I-MIBG images using regions of interest (ROIs) placed over the heart and the mediastinum. The ROIs were derived using two approaches: (i) manually drawn and (ii) semi-automatic fixed-size ROIs using anatomical landmarks. Expert, moderate-expert, and not expert raters applied the ROIs procedures and interpreted the 123I-MIBG images. We evaluated the inter and intra-rater agreements in assessing 123I-MIBG H/M ratios. Results: A moderate agreement in the raters' classification of pathological and non-pathological scores emerged regarding early and late H/M ratio values (κ = 0.45 and 0.69 respectively), applying the manual method, while the early and late H/M ratios obtained with the semi-automatic method reached a good agreement among observers (κ = 0.78). Cohen-Kappa values revealed that the semi-automatic method improved the agreement between expert and inexpert raters: the agreement improved from a minimum of 0.29 (fair, for early H/M) and 0.69 (substantial, in late H/M) with the manual method, to 0.90 (perfect, in early H/M) and 0.87 (perfect, in late H/M) with the semi-automatic method. Conclusion: The use of the semi-automatic method improves the agreement among raters in classifying' H/M ratios as pathological or non-pathological, namely for inexpert readers. These results have important implications for semi-quantitative assessment of 123I-MIBG images in clinical routine.

Comprehensive qualitative characterization of linguistic performance profiles in primary progressive aphasia: a multivariate study with FDG-PET.

Primary progressive aphasia (PPA) classification relies on profile characterization of quantitatively impaired/spared performance in language tasks. In this study, we coextracted 8 qualitative types of errors in 67 PPA patients submitted to a comprehensive language assessment. Canonical correlation analysis was applied to simultaneously correlate qualitative errors and brain metabolism, collected with FDG-PET. Results showed the contribution of semantic, syntactic and working memory errors associated with specific correlates of regional metabolic changes. Reduced metabolism in the left fusiform gyrus, anterior-middle and inferior-temporal gyri and middle-temporal pole correlated with an increase of semantic errors. Hypometabolism in the left inferior, middle, and superior frontal gyri, insula and right middle-occipital gyrus was related to syntactic errors. Higher metabolism in the bilateral pallidum, putamen, and left thalamus, as well as hypometabolism in the left angular and supramarginal gyri, inferior-parietal lobule, posterior-middle and inferior-temporal gyri and posterior cingulum predicted the increase of working memory errors. A relevant role of working memory subcomponents was associated with distinct neural systems. Patients' profiles are easily represented in a qualitative multidimensional space, in which mixed PPA overlapped with different phenotypes.

Metabolic connectivity of resting-state networks in alpha synucleinopathies, from prodromal to dementia phase.

Previous evidence suggests that the derangement of large-scale brain networks reflects structural, molecular, and functional mechanisms underlying neurodegenerative diseases. Although the alterations of multiple large-scale brain networks in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are reported, a comprehensive study on connectivity reconfiguration starting from the preclinical phase is still lacking. We aimed to investigate shared and disease-specific changes in the large-scale networks across the Lewy Bodies (LB) disorders spectrum using a brain metabolic connectivity approach. We included 30 patients with isolated REM sleep behavior disorder (iRBD), 28 with stable PD, 30 with DLB, and 30 healthy controls for comparison. We applied seed-based interregional correlation analyses (IRCA) to evaluate the metabolic connectivity in the large-scale resting-state networks, as assessed by [18F]FDG-PET, in each clinical group compared to controls. We assessed metabolic connectivity changes by applying the IRCA and specific connectivity metrics, such as the weighted and unweighted Dice similarity coefficients (DC), for the topographical similarities. All the investigated large-scale brain resting-state networks showed metabolic connectivity alterations, supporting the widespread involvement of brain connectivity within the alpha-synuclein spectrum. Connectivity alterations were already evident in iRBD, severely affecting the posterior default mode, attentive and limbic networks. Strong similarities emerged in iRBD and DLB that showed comparable connectivity alterations in most large-scale networks, particularly in the posterior default mode and attentive networks. Contrarily, PD showed the main connectivity alterations limited to motor and somatosensory networks. The present findings reveal that metabolic connectivity alterations in the large-scale networks are already present in the early iRBD phase, resembling the DLB metabolic connectivity changes. This suggests and confirms iRBD as a risk condition for progression to the severe LB disease phenotype. Of note, the neurobiology of stable PD supports its more benign phenotype.

Early-phase 18F-Florbetapir and 18F-Flutemetamol images as proxies of brain metabolism in a memory clinic setting.

Background: Alzheimer's disease (AD) neuropathologic changes are ß-amyloid (Aß) deposition, pathologic tau, and neurodegeneration. Dual-phase amyloid-PET might be able to evaluate Aß deposition and neurodegeneration with a single tracer injection. Early-phase amyloid-PET scans provide a proxy for cerebral perfusion, which has shown good correlations with neural dysfunction measured through metabolic consumption, while the late frames depict amyloid distribution. Our study aims to assess the comparability between early-phase amyloid-PET scans and 18F-fluorodeoxyglucose (18F-FDG)-PET brain topography at the individual level, and their ability to discriminate patients. Methods: 166 subjects evaluated at the Geneva Memory Center, ranging from cognitively unimpaired to Mild Cognitive Impairment (MCI) and dementia, underwent early-phase amyloid-PET - using either 18F-florbetapir (eFBP) (n = 94) or 18F-flutemetamol (eFMM) (n = 72) - and 18F-FDG-PET. Aß status was assessed. Standardized uptake value ratios (SUVR) were extracted to evaluate the correlation of eFBP/eFMM and their respective 18F-FDG-PET scans. The single-subject procedure was applied to investigate hypometabolism and hypoperfusion maps and their spatial overlap by Dice coefficient. Receiver operating characteristic analyses were performed to compare the discriminative power of eFBP/eFMM, and 18F-FDG-PET SUVR in AD-related metaROI between Aß-negative healthy controls and cases in the AD continuum. Results: Positive correlations were found between eFBP/eFMM and 18F-FDG-PET SUVR independently of Aß status and Aß radiotracer (R>0.72, p<0.001). eFBP/eFMM single-subject analysis revealed clusters of significant hypoperfusion with good correspondence to hypometabolism topographies, independently of the underlying neurodegenerative patterns. Both eFBP/eFMM and 18F-FDG-PET SUVR significantly discriminated AD patients from controls in the AD-related metaROIs (AUCFBP = 0.888; AUCFMM=0.801), with 18F-FDG-PET performing slightly better, however not significantly (all p-value higher than 0.05), than others (AUCFDG=0.915 and 0.832 for subjects evaluated with 18F-FBP and 18F-FMM, respectively). Conclusion: The distribution of perfusion was comparable to that of metabolism at the single-subject level by parametric analysis, particularly in the presence of a high neurodegeneration burden. Our findings indicate that eFBP/eFMM imaging can replace 18F-FDG-PET imaging, as they reveal typical neurodegenerative patterns, or allow to exclude the presence of neurodegeneration. The finding shows cost-saving capacities of amyloid-PET and supports the routine use of the modality for individual classification in clinical practice.

Brain metabolic connectivity reconfiguration in the semantic variant of primary progressive aphasia.

Functional network-level alterations in the semantic variant of Primary Progressive Aphasia (sv-PPA) are relevant to understanding the clinical features and the neural spreading of the pathology. We assessed the effect of neurodegeneration on brain systems reorganization in early sv-PPA, using advanced brain metabolic connectivity approaches. Forty-four subjects with sv-PPA and forty-four age-matched healthy controls (HC) were included. We applied two multivariate approaches to [18F]FDG-PET data - i.e., sparse inverse covariance estimation and seed-based interregional correlation analysis - to assess the integrity of (i) the whole-brain metabolic connectivity and (ii) the connectivity of brain regions relevant for cognitive and behavioral functions. Whole-brain analysis revealed a global-scale connectivity reconfiguration in sv-PPA, with widespread changes in metabolic connections of frontal, temporal, and parietal regions. In comparison to HC, the seed-based analysis revealed a) functional isolation of the left anterior temporal lobe (ATL), b) decreases in temporo-occipital connections and contralateral homologous regions, c) connectivity increases to the dorsal parietal cortex from the spared posterior temporal cortex, d) a disruption of the large-scale limbic brain networks. In sv-PPA, the severe functional derangement of the left ATL may lead to an extensive connectivity reconfiguration, encompassing several brain regions, including those not yet affected by neurodegeneration. These findings support the hypothesis that in sv-PPA the focal vulnerability of the core region (i.e., ATL) can potentially drive the widespread cerebral connectivity changes, already present in the early phase.

Brain Metabolism and Amyloid Load in Individuals With Subjective Cognitive Decline or Pre-Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVE: Multicenter study aiming at investigating the characteristics of cognitive decline, neuropsychiatric symptoms, and brain imaging in individuals with subjective cognitive decline (SCD) and subtle cognitive decline (pre-Mild Cognitive Impairment, pre-MCI). METHODS: Data were obtained from the Network-AD project (NET-2011-02346784). The included subjects underwent baseline cognitive and neurobehavioral evaluation, FDG-PET, and, amyloid-PET. We used Principal Component Analysis (PCA) to identify independent neuropsychological and neuropsychiatric dimensions and their association with brain metabolism. RESULTS: A total of 105 subjects (SCD=49, pre-MCI=56) were included. FDG-PET was normal in 45% of subjects and revealed brain hypometabolism in 55%, with a frontal-like pattern as the most frequent finding (28%). Neuropsychiatric symptoms emerging from the Neuropsychiatric Inventory and the Starkstein Apathy Scale were highly prevalent in the whole sample (78%). An abnormal amyloid load was detected in the 18% of the subjects that underwent amyloid-PET (n=60). PCA resulted in three neuropsychological factors: 1) executive/visuo-motor, correlating with hypometabolism in frontal, occipital cortices and basal ganglia; 2) memory, correlating with hypometabolism in temporo-parietal regions; 3) visuo-spatial/constructional, correlating with hypometabolism in fronto-parietal cortices. Two factors emerged from the neuropsychiatric PCA: 1) affective, correlating with hypometabolism in orbito-frontal, cingulate cortex, insula; 2) hyperactive/psychotic, correlating with hypometabolism in frontal, temporal and parietal regions. DISCUSSION: FDG-PET evidence suggests either normal brain function or different patterns of brain hypometabolism in SCD and pre-MCI subjects. These results indicate that SCD and pre-MCI represent heterogeneous populations. Consistently, different neuropsychological and neuropsychiatric profiles emerged, which correlated with neuronal dysfunction in specific brain regions. Long-term follow-up studies are needed to assess the risk of progression to dementia in these conditions.

Gender differences in dopaminergic system dysfunction in de novo Parkinson's disease clinical subtypes.

Parkinson's disease (PD) is characterized by heterogeneity in clinical syndromes, prognosis, and pathophysiology mechanisms. Gender differences in neural anatomy and function are emerging as fundamental determinants of phenotypic variability. Different clinical subtypes, defined as mild motor predominant, intermediate, and diffuse-malignant, have been recently proposed in PD. This study investigated gender influence on clinical features, dopaminergic dysfunction, and connectivity in patients with de novo idiopathic PD stratified according to the clinical criteria for subtypes (i.e., mild motor, intermediate, and diffuse-malignant). We included 286 drug-naïve patients (Males/Females: 189/97, age [mean ± standard deviation]: 61.99 ± 9.67; disease duration: 2.08 ± 2.21) with available [123I]FP-CIT-SPECT and high-resolution T1-weighted MRI from the Parkinson's Progression Markers Initiative. We assessed gender differences for clinical and cognitive features, and dopaminergic presynaptic dysfunction in striatal or extra-striatal regions using molecular analysis of [123I]FP-CIT-bindings. We applied an advanced multivariate analytical approach - partial correlations molecular connectivity analyses - to assess potential gender differences in the vulnerability of the nigrostriatal and mesolimbic dopaminergic pathways. In the mild motor and intermediate subtypes, male patients with idiopathic PD showed poorer cognitive performances than females, who - in contrast - presented more severe anxiety symptoms. The male vulnerability emerged also in the motor system in the same subtypes with motor impairment associated with a lower dopamine binding in the putamen and more severe widespread connectivity alterations in the nigrostriatal dopaminergic pathway in males than in females. In the diffuse-malignant subtype, males showed more severe motor impairments, consistent with a lower dopamine uptake in the putamen than females. On the other hand, a severe dopaminergic depletion in several dopaminergic targets of the mesolimbic pathway, together with extensive altered connectivity in the same system, characterized females with idiopathic PD in all the subtypes. The anxiety level was associated with a lower dopaminergic binding in the amygdala only in females. This study provides evidence on gender differences in idiopathic PD across clinical subtypes, and, remarkably, since the early phase. The clinical correlations with the nigrostriatal or mesolimbic systems in males and females support different vulnerabilities and related disease expressions. Gender differences must be considered in a precision medicine approach to preventing, diagnosing, and treating idiopathic PD.

Brain Molecular Connectivity in Neurodegenerative Conditions.

Positron emission tomography (PET) allows for the in vivo assessment of early brain functional and molecular changes in neurodegenerative conditions, representing a unique tool in the diagnostic workup. The increased use of multivariate PET imaging analysis approaches has provided the chance to investigate regional molecular processes and long-distance brain circuit functional interactions in the last decade. PET metabolic and neurotransmission connectome can reveal brain region interactions. This review is an overview of concepts and methods for PET molecular and metabolic covariance assessment with evidence in neurodegenerative conditions, including Alzheimer's disease and Lewy bodies disease spectrum. We highlight the effects of environmental and biological factors on brain network organization. All of the above might contribute to innovative diagnostic tools and potential disease-modifying interventions.