Preoperative network activity predicts the response to subthalamic DBS for Parkinson's disease.

Quantitative imaging markers to aid in the selection of Parkinson's disease (PD) patients for surgical interventions such as subthalamic nucleus deep brain stimulation (STN-DBS) are currently lacking. Using metabolic PET and network analysis we identified and validated a treatment-induced topography, termed STN StimNet. Stimulation-mediated changes in network expression correlated with concurrent motor improvement in independent STN-DBS cohorts scanned on and off stimulation.

Longitudinal network changes and phenoconversion risk in isolated REM sleep behavior disorder.

Isolated rapid eye movement sleep behavior disorder is a prodrome of α-synucleinopathies. Using positron emission tomography, we assessed changes in Parkinson's disease-related motor and cognitive metabolic networks and caudate/putamen dopaminergic input in a 4-year longitudinal imaging study of 13 male subjects with this disorder. We also correlated times to phenoconversion with baseline network expression in an independent validation sample.

A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism.

Synaptic dysfunction is recognized as an early step in the pathophysiology of parkinsonism. Several genetic mutations affecting the integrity of synaptic proteins cause or increase the risk of developing disease. We have identified a candidate causative mutation in synaptic "SH3GL2 Interacting Protein 1" (SGIP1), linked to early-onset parkinsonism in a consanguineous Arab family.

Preoperative network activity predicts the response to subthalamic DBS for Parkinson's disease.

Quantitative imaging markers to aid in the selection of Parkinson's disease (PD) patients for surgical interventions such as subthalamic nucleus deep brain stimulation (STN-DBS) are currently lacking. Using metabolic PET and network analysis we identified and validated a treatment-induced topography, termed STN StimNet. Stimulation-mediated changes in network expression correlated with concurrent motor improvement in independent STN-DBS cohorts scanned on and off stimulation.

A Network Imaging Biomarker of X-Linked Dystonia-Parkinsonism.

Objective: The purpose of this study was to characterize a metabolic brain network associated with X-linked dystonia-parkinsonism (XDP).

Methods: Thirty right-handed Filipino men with XDP (age = 44.4 ± 8.

Longitudinal changes in metabolic network activity in early Alzheimer's disease.

Introduction: The progression of Alzheimer's disease (AD) has been linked to two metabolic networks, the AD-related pattern (ADRP) and the default mode network (DMN).

Methods: Converting and clinically stable cognitively normal subjects (n = 47) and individuals with mild cognitive impairment (n = 96) underwent 2-[ F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) three or more times over 6 years (n  = 705). Expression levels for ADRP and DMN were measured in each subject and time point, and the resulting changes were correlated with cognitive performance.

Automated differential diagnosis of dementia syndromes using FDG PET and machine learning.

Background: Metabolic brain imaging with 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive diagnostic and differential diagnostic tool for neurodegenerative dementias. In the clinic, scans are usually visually interpreted. However, computer-aided approaches can improve diagnostic accuracy.

Stereotyped Relationship Between Motor and Cognitive Metabolic Networks in Parkinson's Disease.

Background: Idiopathic Parkinson's disease (iPD) is associated with two distinct brain networks, PD-related pattern (PDRP) and PD-related cognitive pattern (PDCP), which correlate respectively with motor and cognitive symptoms. The relationship between the two networks in individual patients is unclear.

Objective: To determine whether a consistent relationship exists between these networks, we measured the difference between PDRP and PDCP expression, termed delta, on an individual basis in independent populations of patients with iPD (n = 356), patients with idiopathic REM sleep behavioral disorder (iRBD) (n = 21), patients with genotypic PD (gPD) carrying GBA1 variants (n = 12) or the LRRK2-G2019S mutation (n = 14), patients with atypical parkinsonian syndromes (n = 238), and healthy control subjects (n = 95) from the United States, Slovenia, India, and South Korea.

Abnormal metabolic covariance patterns associated with multiple system atrophy and progressive supranuclear palsy.

Purpose: Differentiation between neurodegenerative parkinsonisms, whose early clinical presentation is similar, may be improved with metabolic brain imaging. In this study we applied a specific network analysis to 2-[F]FDG PET brain scans to identify the characteristic metabolic patterns for multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) in a new European cohort. We also developed a new tool to recognize and estimate patients' metabolic brain heterogeneity.

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.

Neuropathological correlation supports automated image-based differential diagnosis in parkinsonism.

Purpose: Up to 25% of patients diagnosed as idiopathic Parkinson's disease (IPD) have an atypical parkinsonian syndrome (APS). We had previously validated an automated image-based algorithm to discriminate between IPD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). While the algorithm was accurate with respect to the final clinical diagnosis after long-term expert follow-up, its relationship to the initial referral diagnosis and to the neuropathological gold standard is not known.

Blood-brain barrier permeability in Parkinson's disease patients with and without dyskinesia.

Objective: Recent studies on a rodent model of Parkinson's disease (PD) have raised the possibility of increased blood-brain barrier (BBB) permeability, demonstrated by histology, autoradiography, and positron emission tomography (PET). However, in human PD patients, in vivo evidence of increased BBB permeability is lacking. We examined the hypothesis that levodopa treatment increases BBB permeability in human subjects with PD, particularly in those with levodopa-induced dyskinesia (LID).

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.

Atypical clinical presentation of pathologically proven Parkinson's disease: The role of Parkinson's disease related metabolic pattern.

Regional changes in brain metabolism upgraded with measurements of specific metabolic brain patterns and automated diagnostic algorithms can help to differentiate among neurodegenerative parkinsonisms, but with few reports on pathological confirmation. Here we describe a parkinsonian patient with atypical presentation and F-FDG-PET imaging consistent with idiopathic Parkinson's disease. The latter was confirmed at the pathohistological examination.

Advanced neuroimaging in neuropsychiatric systemic lupus erythematosus.

Purpose Of Review: Neuropsychiatric lupus (NPSLE) comprises a disparate collection of syndromes affecting the central and peripheral nervous systems. Progress in the attribution of neuropsychiatric syndromes to SLE-related mechanisms and development of targeted treatment strategies has been impeded by a lack of objective imaging biomarkers that reflect specific neuropsychiatric syndromes and/or pathologic mechanisms. The present review addresses recent publications of neuroimaging techniques in NPSLE.

Metabolic Network Abnormalities in Drug-Naïve Parkinson's Disease.

Background: An ideal imaging biomarker for a neurodegenerative disorder should be able to measure abnormalities in the earliest stages of the disease.

Objective: We investigated metabolic network changes in two independent cohorts of drug-naïve Parkinson's disease (PD) patients who have not been exposed to dopaminergic medication.

Methods: We scanned 85 de novo, drug-naïve PD patients and 85 age-matched healthy control subjects from Italy (n = 96) and the United States (n = 74) with [ F]-fluorodeoxyglucose PET.

LRRK2 and GBA Variants Exert Distinct Influences on Parkinson's Disease-Specific Metabolic Networks.

The natural history of idiopathic Parkinson's disease (PD) varies considerably across patients. While PD is generally sporadic, there are known genetic influences: the two most common, mutations in the LRRK2 or GBA1 gene, are associated with slower and more aggressive progression, respectively. Here, we applied graph theory to metabolic brain imaging to understand the effects of genotype on the organization of previously established PD-specific networks.

Metabolic and microstructural alterations in the SLE brain correlate with cognitive impairment.

To address challenges in the diagnosis of cognitive dysfunction (CD) related to systemic lupus erythematosus-associated (SLE-associated) autoimmune mechanisms rather than confounding factors, we employed an integrated approach, using resting-state functional (FDG-PET) and structural (diffusion tensor imaging [DTI]) neuroimaging techniques and cognitive testing, in adult SLE patients with quiescent disease and no history of neuropsychiatric illness. We identified resting hypermetabolism in the sensorimotor cortex, occipital lobe, and temporal lobe of SLE subjects, in addition to validation of previously published resting hypermetabolism in the hippocampus, orbitofrontal cortex, and putamen/GP/thalamus. Regional hypermetabolism demonstrated abnormal interregional metabolic correlations, associated with impaired cognitive performance, and was stable over 15 months.

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.

Levodopa-induced abnormal involuntary movements correlate with altered permeability of the blood-brain-barrier in the basal ganglia.

Chronic levodopa treatment leads to the appearance of dyskinesia in the majority of Parkinson's disease patients. Neurovascular dysregulation in putaminal and pallidal regions is thought to be an underlying feature of this complication of treatment. We used microPET to study unilaterally lesioned 6-hydroxydopamine rats that developed levodopa-induced abnormal involuntary movements (AIMs) after three weeks of drug treatment.

Increased putamen hypercapnic vasoreactivity in levodopa-induced dyskinesia.

In a rodent model of Parkinson's disease (PD), levodopa-induced involuntary movements have been linked to striatal angiogenesis - a process that is difficult to document in living human subjects. Angiogenesis can be accompanied by localized increases in cerebral blood flow (CBF) responses to hypercapnia. We therefore explored the possibility that, in the absence of levodopa, local hypercapnic CBF responses are abnormally increased in PD patients with levodopa-induced dyskinesias (LID) but not in their nondyskinetic (NLID) counterparts.

Long-term follow-up of a randomized AAV2- gene therapy trial for Parkinson's disease.

We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2- delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and F-fluorodeoxyglucose (FDG) PET imaging.

Distinct brain networks underlie cognitive dysfunction in Parkinson and Alzheimer diseases.

Objective: To determine whether cognitive impairment in Parkinson disease (PD) and Alzheimer disease (AD) derives from the same network pathology.

Methods: We analyzed F-fluorodeoxyglucose PET scans from 40 patients with AD and 40 age-matched healthy controls from the Alzheimer's Disease Neuroimaging Initiative and scanned an additional 10 patients with AD and 10 healthy controls at The Feinstein Institute for Medical Research to derive an AD-related metabolic pattern (ADRP) analogous to our previously established PD cognition-related pattern (PDCP) and PD motor-related pattern (PDRP). We computed individual subject expression values for ADRP and PDCP in 89 patients with PD and correlated summary scores for cognitive functioning with network expression.

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson's disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects.