Added value of FDG-PET for detection of progressive supranuclear palsy.

Background: Diagnostic criteria for progressive supranuclear palsy (PSP) include midbrain atrophy in MRI and hypometabolism in [F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) as supportive features. Due to limited data regarding their relative and sequential value, there is no recommendation for an algorithm to combine both modalities to increase diagnostic accuracy. This study evaluated the added value of sequential imaging using state-of-the-art methods to analyse the images regarding PSP features.

Parkinson's disease progression: Increasing expression of an invariant common core subnetwork.

Notable success has been achieved in the study of neurodegenerative conditions using reduction techniques such as principal component analysis (PCA) and sparse inverse covariance estimation (SICE) in positron emission tomography (PET) data despite their widely differing approach. In a recent study of SICE applied to metabolic scans from Parkinson's disease (PD) patients, we showed that by using PCA to prespecify disease-related partition layers, we were able to optimize maps of functional metabolic connectivity within the relevant networks. Here, we show the potential of SICE, enhanced by disease-specific subnetwork partitions, to identify key regional hubs and their connections, and track their associations in PD patients with increasing disease duration.

Automatic covariance pattern analysis outperforms visual reading of F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in variant progressive supranuclear palsy.

Background: To date, studies on positron emission tomography (PET) with F-fluorodeoxyglucose (FDG) in progressive supranuclear palsy (PSP) usually included PSP cohorts overrepresenting patients with Richardson's syndrome (PSP-RS).

Objectives: To evaluate FDG-PET in a patient sample representing the broad phenotypic PSP spectrum typically encountered in routine clinical practice.

Methods: This retrospective, multicenter study included 41 PSP patients, 21 (51%) with RS and 20 (49%) with non-RS variants of PSP (vPSP), and 46 age-matched healthy controls.

Adaptive and pathological connectivity responses in Parkinson's disease brain networks.

Functional imaging has been used extensively to identify and validate disease-specific networks as biomarkers in neurodegenerative disorders. It is not known, however, whether the connectivity patterns in these networks differ with disease progression compared to the beneficial adaptations that may also occur over time. To distinguish the 2 responses, we focused on assortativity, the tendency for network connections to link nodes with similar properties.

Dynamic F-FPCIT PET: Quantification of Parkinson's disease metabolic networks and nigrostriatal dopaminergic dysfunction in a single imaging session.

Previous multi-center imaging studies with F-FDG PET have established the presence of Parkinson's disease motor- and cognition-related metabolic patterns termed PDRP and PDCP in patients with this disorder. Given that in PD cerebral perfusion and glucose metabolism are typically coupled in the absence of medication, we determined whether subject expression of these disease networks can be quantified in early-phase images from dynamic F-FPCIT PET scans acquired to assess striatal dopamine transporter (DAT) binding. We studied a cohort of early-stage PD patients and age-matched healthy control subjects who underwent F-FPCIT at baseline; scans were repeated 4 years later in a smaller subset of patients.

Spectral guided sparse inverse covariance estimation of metabolic networks in Parkinson's disease.

In neurodegenerative disorders, a clearer understanding of the underlying aberrant networks facilitates the search for effective therapeutic targets and potential cures. [F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging data of brain metabolism reflects the distribution of glucose consumption known to be directly related to neural activity. In FDG PET resting-state metabolic data, characteristic disease-related patterns have been identified in group analysis of various neurodegenerative conditions using principal component analysis of multivariate spatial covariance.

Hemispheric Network Expression in Parkinson's Disease: Relationship to Dopaminergic Asymmetries.

Background: Parkinson's disease (PD) is characterized by brain metabolic networks, specifically associated with motor and cognitive manifestations. Few studies have investigated network changes in cerebral hemispheres ipsilateral and contralateral to the clinically more affected body side.

Objective: We examined hemispheric network abnormalities and their relationship to striatal dopaminergic deficits in PD patients at different stages.

Gene therapy reduces Parkinson's disease symptoms by reorganizing functional brain connectivity.

Gene therapy is emerging as a promising approach for treating neurological disorders, including Parkinson's disease (PD). A phase 2 clinical trial showed that delivering glutamic acid decarboxylase () into the subthalamic nucleus (STN) of patients with PD had therapeutic effects. To determine the mechanism underlying this response, we analyzed metabolic imaging data from patients who received gene therapy and those randomized to sham surgery, all of whom had been scanned preoperatively and at 6 and 12 months after surgery.

A multivariate metabolic imaging marker for behavioral variant frontotemporal dementia.

Introduction: The heterogeneity of behavioral variant frontotemporal dementia (bvFTD) calls for multivariate imaging biomarkers.

Methods: We studied a total of 148 dementia patients from the Feinstein Institute (Center-A: 25 bvFTD and 10 Alzheimer's disease), Technical University of Munich (Center-B: 44 bvFTD and 29 FTD language variants), and Alzheimer's Disease Neuroimaging Initiative (40 Alzheimer's disease subjects). To identify the covariance pattern of bvFTD (behavioral variant frontotemporal dementia-related pattern [bFDRP]), we applied principal component analysis to combined 18F-fluorodeoxyglucose-positron emission tomography scans from bvFTD and healthy subjects.

Network Structure and Function in Parkinson's Disease.

Little is known of the structural and functional properties of abnormal brain networks associated with neurological disorders. We used a social network approach to characterize the properties of the Parkinson's disease (PD) metabolic topography in 4 independent patient samples and in an experimental non-human primate model. The PD network exhibited distinct features.

Metabolic resting-state brain networks in health and disease.

The delineation of resting state networks (RSNs) in the human brain relies on the analysis of temporal fluctuations in functional MRI signal, representing a small fraction of total neuronal activity. Here, we used metabolic PET, which maps nonfluctuating signals related to total activity, to identify and validate reproducible RSN topographies in healthy and disease populations. In healthy subjects, the dominant (first component) metabolic RSN was topographically similar to the default mode network (DMN).

Quantifying significance of topographical similarities of disease-related brain metabolic patterns.

Multivariate analytical routines have become increasingly popular in the study of cerebral function in health and in disease states. Spatial covariance analysis of functional neuroimaging data has been used to identify and validate characteristic topographies associated with specific brain disorders. Voxel-wise correlations can be used to assess similarities and differences that exist between covariance topographies.

Identification of disease-related spatial covariance patterns using neuroimaging data.

The scaled subprofile model (SSM)(1-4) is a multivariate PCA-based algorithm that identifies major sources of variation in patient and control group brain image data while rejecting lesser components (Figure 1). Applied directly to voxel-by-voxel covariance data of steady-state multimodality images, an entire group image set can be reduced to a few significant linearly independent covariance patterns and corresponding subject scores. Each pattern, termed a group invariant subprofile (GIS), is an orthogonal principal component that represents a spatially distributed network of functionally interrelated brain regions.

Characterization of disease-related covariance topographies with SSMPCA toolbox: effects of spatial normalization and PET scanners.

To generate imaging biomarkers from disease-specific brain networks, we have implemented a general toolbox to rapidly perform scaled subprofile modeling (SSM) based on principal component analysis (PCA) on brain images of patients and normals. This SSMPCA toolbox can define spatial covariance patterns whose expression in individual subjects can discriminate patients from controls or predict behavioral measures. The technique may depend on differences in spatial normalization algorithms and brain imaging systems.

Parkinson's disease: increased motor network activity in the absence of movement.

We used a network approach to assess systems-level abnormalities in motor activation in humans with Parkinson's disease (PD). This was done by measuring the expression of the normal movement-related activation pattern (NMRP), a previously validated activation network deployed by healthy subjects during motor performance. In this study, NMRP expression was prospectively quantified in (15)O-water PET scans from a PD patient cohort comprised of a longitudinal early-stage group (n = 12) scanned at baseline and at two or three follow-up visits two years apart, and a moderately advanced group scanned on and off treatment with either subthalamic nucleus deep brain stimulation (n = 14) or intravenous levodopa infusion (n = 14).

Abnormal network topographies and changes in global activity: absence of a causal relationship.

Changes in regional brain activity can be observed following global normalization procedures to reduce variability in the data. In particular, spurious regional differences may appear when scans from patients with low global activity are compared to those from healthy subjects. It has thus been suggested that the consistent increases in subcortical activity that characterize the abnormal Parkinson's disease-related metabolic covariance pattern (PDRP) are artifacts of global normalization, and that similar topographies can be identified in scans from healthy subjects with varying global activity.

Abnormal metabolic brain networks in a nonhuman primate model of parkinsonism.

Parkinson's disease (PD) is associated with a characteristic regional metabolic covariance pattern that is modulated by treatment. To determine whether a homologous metabolic pattern is also present in nonhuman primate models of parkinsonism, 11 adult macaque monkeys with parkinsonism secondary to chronic systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 12 age-matched healthy animals were scanned with [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET). A subgroup comprising five parkinsonian and six control animals was used to identify a parkinsonism-related pattern (PRP).

Three-fold cross-validation of parkinsonian brain patterns.

Abnormal physiological networks of brain areas in disease can be identified by applying specialized multivariate computational algorithms based on principal component analysis to functional image data. Here we demonstrate the reproducibility of network patterns derived using positron emission tomography (PET) data in independent populations of parkinsonian patients for a large, clinically validated data set comprised of subjects with idiopathic Parkinson's disease (iPD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Correlation of voxel values of network patterns derived for the same condition in different data sets was high.

Scaled subprofile modeling of resting state imaging data in Parkinson's disease: methodological issues.

Consistent functional brain abnormalities in Parkinson's disease (PD) are difficult to pinpoint because differences from the normal state are often subtle. In this regard, the application of multivariate methods of analysis has been successful but not devoid of misinterpretation and controversy. The Scaled Subprofile Model (SSM), a principal components analysis (PCA)-based spatial covariance method, has yielded critical information regarding the characteristic abnormalities of functional brain organization that underlie PD and other neurodegenerative disorders.

Differential diagnosis of parkinsonian syndromes using PCA-based functional imaging features.

In the current paper, we describe methodologies for single subject differential diagnosis of degenerative brain disorders using multivariate principal component analysis (PCA) of functional imaging scans. An automated routine utilizing these methods is applied to positron emission tomography (PET) brain data to distinguish several discrete parkinsonian movement disorders with similar clinical manifestations. Disease specific expressions of voxel-based spatial covariance patterns are predetermined using the Scaled Subprofile Model (SSM/PCA) and a scalar measure of the manifestation of each pattern in prospective subject images is subsequently derived.

New strategies for automated differential diagnosis of degenerative brain disorders.

New strategies are considered for automated, single-subject differential diagnosis of independent degenerative brain disorders characterized by similar clinical symptoms using functional imaging. The methodology of these strategies is described and its application in parkinsonian movement disorders is illustrated for PET data. Using an automated diagnostic Topographic Profile Rating (TPR) technique based on the Scaled Subprofile Model (SSM-PCA), single-subject score values for different conditions are compared with reference values to predict diagnosis.

Abnormal metabolic network activity in Parkinson's disease: test-retest reproducibility.

Parkinson's disease (PD) is associated with an abnormal pattern of regional brain function. The expression of this PD-related covariance pattern (PDRP) has been used to assess disease progression and the response to treatment. In this study, we validated the PDRP network as a measure of parkinsonism by prospectively computing its expression (PDRP scores) in (15)O-water (H(2)(15)O) and (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans from PD patients and healthy volunteers.

Microstructural white matter changes in carriers of the DYT1 gene mutation.

We tested the hypothesis that the DYT1 genotype is associated with a disorder of anatomical connectivity involving primarily the sensorimotor cortex. We used diffusion tensor magnetic resonance imaging (DTI) to assess the microstructure of white matter pathways in mutation carriers and control subjects. Fractional anisotropy (FA), a measure of axonal integrity and coherence, was reduced (p < 0.

Comparative analysis of striatal FDOPA uptake in Parkinson's disease: ratio method versus graphical approach.

Unlabelled: Striatal-to-occipital ratio (SOR) and influx constant K(i)(occ) are commonly used as analytic parameters in L-3,4-dihydroxy-6-(18)F-fluorophenylalanine (FDOPA) PET studies. Both have been shown to be useful in discriminating Parkinson's disease (PD) patients from healthy subjects. We evaluated the relative performance of SOR and influx constant (K(i)(occ)) in the clinical assessment of nigrostriatal dopaminergic function in PD.