OBJECTIVETo evaluate the statistical parametric mapping (SPM) procedure for fluorodeoxyglucose (FDG)-PET imaging as a possible single-subject marker of progression to dementia in Parkinson disease ...(PD).
METHODSFifty-four consecutive patients with PD without dementia (age at onset of 59.9 ± 10.1 years, disease duration of 5.3 ± 3.4 years) entered the study. The patients underwent an extensive motor and cognitive assessment and a single-subject FDG-PET SPM evaluation at baseline. A 4-year follow-up provided disease progression and dementia diagnosis.
RESULTSThe FDG-PET SPM was evaluated by 2 expert raters allowing the identification of a “typical PD pattern” in 29 patients, whereas 25 patients presented with “atypical patterns,” namely, dementia with Lewy bodies (DLB)-like (n = 12), Alzheimer disease (AD)-like (n = 6), corticobasal syndrome (CBS)-like (n = 5), and frontotemporal dementia (FTD)-like (n = 2). At 4-year follow-up, 13 patients, all showing atypical brain metabolic patterns at baseline, progressed to dementia (PD dementia). The DLB- and AD-like SPM patterns were the best predictor for incident dementia (p < 0.005, sensitivity 85%, specificity 88%), independently from demographics or cognitive baseline classification.
CONCLUSIONSThis study suggests that FDG-PET SPM at the single-subject level might help in identifying patients with PD at risk of developing dementia.
Purpose
An appropriate healthy control dataset is mandatory to achieve good performance in voxel-wise analyses. We aimed at evaluating 18FFDG 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.
To explore the effects of PD pathology on brain connectivity, we characterized with an emergent computational approach the brain metabolic connectome using 18FFDG-PET in early idiopathic PD patients. ...We applied whole-brain and pathology-based connectivity analyses, using sparse-inverse covariance estimation in thirty-four cognitively normal PD cases and thirty-four age-matched healthy subjects for comparisons. Further, we assessed high-order resting state networks by interregional correlation analysis. Whole-brain analysis revealed altered metabolic connectivity in PD, with local decreases in frontolateral cortex and cerebellum and increases in the basal ganglia. Widespread long-distance decreases were present within the frontolateral cortex as opposed to connectivity increases in posterior cortical regions, all suggestive of a global-scale connectivity reconfiguration. The pathology-based analyses revealed significant connectivity impairment in the nigrostriatal dopaminergic pathway and in the regions early affected by α-synuclein pathology. Notably, significant connectivity changes were present in several resting state networks especially in frontal regions. These findings expand previous imaging evidence of altered connectivity in cognitively stable PD patients by showing pathology-based connectivity changes and disease-specific metabolic architecture reconfiguration at multiple scale levels, from the earliest PD phases. These alterations go well beyond the known striato-cortical connectivity derangement supporting in vivo an extended neural vulnerability in the PD synucleinopathy.
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
F-FDG PET and
C-(R)-PK11195 PET. Healthy controls databases were used for statistical comparison.
F-FDG PET brain metabolism in single subjects and as a group was assessed by an optimized SPM voxel-wise single-subject method.
C-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
C-PK11195 PET BP increases.
EOAD patients showed a significant and extended microglia activation, as
C-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.
In this multicentre study in clinical settings, we assessed the accuracy of optimized procedures for FDG-PET brain metabolism and CSF classifications in predicting or excluding the conversion to ...Alzheimer's disease (AD) dementia and non-AD dementias.
We included 80 MCI subjects with neurological and neuropsychological assessments, FDG-PET scan and CSF measures at entry, all with clinical follow-up. FDG-PET data were analysed with a validated voxel-based SPM method. Resulting single-subject SPM maps were classified by five imaging experts according to the disease-specific patterns, as “typical-AD”, “atypical-AD” (i.e. posterior cortical atrophy, asymmetric logopenic AD variant, frontal-AD variant), “non-AD” (i.e. behavioural variant FTD, corticobasal degeneration, semantic variant FTD; dementia with Lewy bodies) or “negative” patterns. To perform the statistical analyses, the individual patterns were grouped either as “AD dementia vs. non-AD dementia (all diseases)” or as “FTD vs. non-FTD (all diseases)”. Aβ42, total and phosphorylated Tau CSF-levels were classified dichotomously, and using the Erlangen Score algorithm. Multivariate logistic models tested the prognostic accuracy of FDG-PET-SPM and CSF dichotomous classifications. Accuracy of Erlangen score and Erlangen Score aided by FDG-PET SPM classification was evaluated.
The multivariate logistic model identified FDG-PET “AD” SPM classification (Expβ = 19.35, 95% C.I. 4.8–77.8, p < 0.001) and CSF Aβ42 (Expβ = 6.5, 95% C.I. 1.64–25.43, p < 0.05) as the best predictors of conversion from MCI to AD dementia. The “FTD” SPM pattern significantly predicted conversion to FTD dementias at follow-up (Expβ = 14, 95% C.I. 3.1–63, p < 0.001). Overall, FDG-PET-SPM classification was the most accurate biomarker, able to correctly differentiate either the MCI subjects who converted to AD or FTD dementias, and those who remained stable or reverted to normal cognition (Expβ = 17.9, 95% C.I. 4.55–70.46, p < 0.001).
Our results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers.
•Appropriate biomarkers measures improve early dementia diagnosis in MCI.•FDG-PET-SPM maps and CSF Aβ42 are the best predictors of AD dementia conversion.•FDG-PET-SPM maps accurately predict conversion to different dementia conditions.•A negative FDG-PET-SPM pattern characterizes stable or reverter MCI cases.
Purpose
The aim of this study was to evaluate the supportive role of molecular and structural biomarkers (CSF protein levels, FDG PET and MRI) in the early differential diagnosis of dementia in a ...large sample of patients with neurodegenerative dementia, and in determining the risk of disease progression in subjects with mild cognitive impairment (MCI).
Methods
We evaluated the supportive role of CSF Aβ
42
, t-Tau, p-Tau levels, conventional brain MRI and visual assessment of FDG PET SPM t-maps in the early diagnosis of dementia and the evaluation of MCI progression.
Results
Diagnosis based on molecular biomarkers showed the best fit with the final diagnosis at a long follow-up. FDG PET SPM t-maps had the highest diagnostic accuracy in Alzheimer’s disease and in the differential diagnosis of non-Alzheimer’s disease dementias. The p-tau/Aβ
42
ratio was the only CSF biomarker providing a significant classification rate for Alzheimer’s disease. An Alzheimer’s disease-positive metabolic pattern as shown by FDG PET SPM in MCI was the best predictor of conversion to Alzheimer’s disease.
Conclusion
In this clinical setting, FDG PET SPM t-maps and the p-tau/Aβ
42
ratio improved clinical diagnostic accuracy, supporting the importance of these biomarkers in the emerging diagnostic criteria for Alzheimer’s disease dementia. FDG PET using SPM t-maps had the highest predictive value by identifying hypometabolic patterns in different neurodegenerative dementias and normal brain metabolism in MCI, confirming its additional crucial exclusionary role.
18FFDG-PET hypometabolism patterns are indicative of different neurodegenerative conditions, even from the earliest disease phase. This makes 18FFDG-PET a valuable tool in the diagnostic workup of ...neurodegenerative diseases. The utility of 18FFDG-PET in dementia with Lewy bodies (DLB) needs further validation by considering large samples of patients and disease comparisons and applying state-of-the-art statistical methods. Here, we aimed to provide an extensive validation of the 18FFDG-PET metabolic signatures in supporting DLB diagnosis near the first clinical assessment, which is characterized by high diagnostic uncertainty, at the single-subject level.
In this retrospective study, we included N = 72 patients with heterogeneous clinical classification at entry (mild cognitive impairment, atypical parkinsonisms, possible DLB, probable DLB, and other dementias) and an established diagnosis of DLB at a later follow-up. We generated patterns of 18FFDG-PET hypometabolism in single cases by using a validated voxel-wise analysis (p < 0.05, FWE-corrected). The hypometabolism patterns were independently classified by expert raters blinded to any clinical information. The final clinical diagnosis at follow-up (2.94 ± 1.39 0.34-6.04 years) was considered as the diagnostic reference and compared with clinical classification at entry and with 18FFDG-PET classification alone. In addition, we calculated the diagnostic accuracy of 18FFDG-PET maps in the differential diagnosis of DLB with Alzheimer's disease dementia (ADD) (N = 60) and Parkinson's disease (PD) (N = 36).
The single-subject 18FFDG-PET hypometabolism pattern, showing temporo-parietal and occipital involvement, was highly consistent across DLB cases. Clinical classification at entry produced several misclassifications with an agreement of only 61.1% with the diagnostic reference. On the contrary, 18FFDG-PET hypometabolism maps alone accurately predicted diagnosis of DLB at follow-up (88.9%). The high power of the 18FFDG-PET hypometabolism signature in predicting the final clinical diagnosis allowed a ≈ 50% increase in accuracy compared to the first clinical assessment alone. Finally, 18FFDG-PET hypometabolism maps yielded extremely high discriminative power, distinguishing DLB from ADD and PD conditions with an accuracy of > 90%.
The present validation of the diagnostic and prognostic accuracy of the disease-specific brain metabolic signature in DLB at the single-subject level argues for the consideration of 18FFDG-PET in the early phase of the DLB diagnostic flowchart. The assessment of the 18FFDG-PET hypometabolism pattern at entry may shorten the diagnostic time, resulting in benefits for treatment options and management of patients.
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 ...123IFP-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 123IFP-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 123IFP-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 123IFP-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 less than or equai to 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. Keywords: Biomarker, Dopamine, Molecular connectivity, Substantia nigra, Ventral tegmental area
A progressive loss of dopamine neurons in the substantia nigra (SN) is considered the main feature of idiopathic Parkinson's disease (PD). Recent neuropathological evidence however suggests that the ...axons of the nigrostriatal dopaminergic system are the earliest target of α-synuclein accumulation in PD, thus the principal site for vulnerability. Whether this applies to
PD, and also to the mesolimbic system has not been investigated yet. We used
CFeCIT PET to measure presynaptic dopamine transporter (DAT) activity in both nigrostriatal and mesolimbic systems, in 36 early PD patients (mean disease duration in months ± SD 21.8 ± 10.7) and 14 healthy controls similar for age. We also performed anatomically-driven partial correlation analysis to evaluate possible changes in the connectivity within both the dopamine networks at an early clinical phase. In the nigrostriatal system, we found a severe DAT reduction in the afferents to the dorsal putamen (DPU) (η
= 0.84), whereas the SN was the less affected region (η
= 0.31). DAT activity in the ventral tegmental area (VTA) and the ventral striatum (VST) were also reduced in the patient group, but to a lesser degree (VST η
= 0.71 and VTA η
= 0.31). In the PD patients compared to the controls, there was a marked decrease in dopamine network connectivity between SN and DPU nodes, supporting the significant derangement in the nigrostriatal pathway. These results suggest that neurodegeneration in the dopamine pathways is initially more prominent in the afferent axons and more severe in the nigrostriatal system. Considering PD as a disconnection syndrome starting from the axons, it would justify neuroprotective interventions even if patients have already manifested clinical symptoms.
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