Replication and reliability of Parkinson's disease clinical subtypes.

Background: We recently identified three distinct Parkinson's disease subtypes: "motor only" (predominant motor deficits with intact cognition and psychiatric function); "psychiatric & motor" (prominent psychiatric symptoms and moderate motor deficits); "cognitive & motor" (cognitive and motor deficits).

Objective: We used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes.

Methods: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function.

Seeding competent TDP-43 persists in human patient and mouse muscle.

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous system of some neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy (IBM). TDP-43 aggregates from ALS and FTD brain lysates may serve as self-templating aggregate seeds and supporting a prion-like spread from cell to cell.

VCP Inhibition Augments NLRP3 Inflammasome Activation.

Lysosomal membrane permeabilization caused either via phagocytosis of particulates or the uptake of protein aggregates can trigger the activation of NLRP3 inflammasome- an intense inflammatory response that drives the release of the pro-inflammatory cytokine IL-1β by regulating the activity of CASPASE 1. The maintenance of lysosomal homeostasis and lysosomal membrane integrity is facilitated by the AAA+ ATPase, VCP/p97 (VCP). However, the relationship between VCP and NLRP3 inflammasome activity remains unexplored.

A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy.

Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy--(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.

Aggregated alpha-synuclein transcriptionally activates pro-inflammatory canonical and non-canonical NF-κB signaling pathways in peripheral monocytic cells.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by chronic neuroinflammation, loss of dopaminergic neurons in the substantia nigra, and in several cases accumulation of alpha-synuclein fibril (α-syn) containing Lewy-bodies (LBs). Peripheral inflammation may play a causal role in inducing and perpetuating neuroinflammation in PD and accumulation of fibrillar α-syn has been reported at several peripheral sites including the gut and liver. Peripheral fibrillar α-syn may induce activation of monocytes via recognition by toll-like receptors (TLRs) and stimulation of downstream NF-κB signaling; however, the specific mechanism by which this occurs is not defined.

Neocortical Lewy Body Pathology Parallels Parkinson's Dementia, but Not Always.

Objective: The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD.

Methods: We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019.

Proteinopathy and Longitudinal Cognitive Decline in Parkinson Disease.

Background And Objectives: People with Parkinson disease (PD) commonly experience cognitive decline, which may relate to increased α-synuclein, tau, and β-amyloid accumulation. This study examines whether the different proteins predict longitudinal cognitive decline in PD.

Methods: All participants (PD n = 152, controls n = 52) were part of a longitudinal study and completed a lumbar puncture for CSF protein analysis (α-synuclein, total tau [tau], and β-amyloid [β-amyloid]), a β-amyloid PET scan, and/or provided a blood sample for genotype (ε4+, ε4-), which is a risk factor for β-amyloid accumulation.

Quantifying regional α -synuclein, amyloid β, and tau accumulation in lewy body dementia.

Objective: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD).

Is Levodopa Response a Valid Indicator of Parkinson's Disease?

Background: The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients.

Methods: We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St.

Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease.

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta, total tau, and phosphorylated tau as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology.

Sleep Deprivation Affects Tau Phosphorylation in Human Cerebrospinal Fluid.

Tau hyperphosphorylation is an early step in tau-mediated neurodegeneration and is associated with intracellular aggregation of tau as neurofibrillary tangles, neuronal and synaptic loss, and eventual cognitive dysfunction in Alzheimer disease. Sleep loss increases the cerebrospinal fluid concentration of amyloid-β and tau. Using mass spectrometry, we measured tau and phosphorylated tau concentrations in serial samples of cerebrospinal fluid collected from participants who were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally.

genotype regulates pathology and disease progression in synucleinopathy.

Apolipoprotein E () ε4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on knockout (A53T/EKO) or human knockin backgrounds (A53T/E2, E3, and E4).

Proteinopathy and longitudinal changes in functional connectivity networks in Parkinson disease.

Objective: To evaluate resting-state functional connectivity as a potential prognostic biomarker of Parkinson disease (PD) progression. The study examined longitudinal changes in cortical resting-state functional connectivity networks in participants with PD compared to controls as well as in relation to baseline protein measures and longitudinal clinical progression.

Methods: Individuals with PD without dementia (n = 64) and control participants (n = 27) completed longitudinal resting-state MRI scans and clinical assessments including full neuropsychological testing after overnight withdrawal of PD medications ("off").

Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation.

Aggregates of the RNA-binding protein TDP-43 (TAR DNA-binding protein) are a hallmark of the overlapping neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The process of TDP-43 aggregation remains poorly understood, and whether it includes formation of intermediate complexes is unknown. Here, we analyzed aggregates derived from purified TDP-43 under semidenaturing conditions, identifying distinct oligomeric complexes at the initial time points before the formation of large aggregates.

Parkinson's disease and multiple system atrophy have distinct α-synuclein seed characteristics.

Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of α-synuclein (α-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of "strains" that link pathological aggregate structure and neuropathology.

Chalcones and Five-Membered Heterocyclic Isosteres Bind to Alpha Synuclein Fibrils in Vitro.

A series of chalcone and heterocyclic isosteres, in which the enone moiety was replaced with an isoxazole and pyrazole ring system, was synthesized and their affinities for alpha synuclein (Asyn), amyloid beta (Aβ), and tau fibrils were measured in vitro. The compounds were found to have a modest affinity and selectivity for Asyn versus Aβ fibrils and low affinity for tau fibrils. Insertion of a double bond to increase the extendable surface area resulted in an increase in affinity and improvement in selectivity for Asyn versus Aβ and tau fibrils.

Alpha Synuclein Fibrils Contain Multiple Binding Sites for Small Molecules.

The fibrillary aggregation of the protein alpha synuclein (Asyn) is a hallmark of Parkinson's disease, and the identification of small molecule binding sites on fibrils is essential to the development of diagnostic imaging probes. A series of molecular modeling, photoaffinity labeling, mass spectrometry, and radioligand binding studies were conducted on Asyn fibrils. The results of these studies revealed the presence of three different binding sites within fibrillar Asyn capable of binding small molecules with moderate to high affinity.

Design, synthesis, and in vitro evaluation of quinolinyl analogues for α-synuclein aggregation.

Here we report the synthesis and in vitro evaluation of 25 new quinolinyl analogues for α-synuclein aggregates. Three lead compounds were subsequently labeled with carbon-11 or fluorine-18 to directly assess their potency in a direct radioactive competitive binding assay ng both α-synuclein fibrils and tissue homogenates from Alzheimer's disease (AD) cases. The modest binding affinities of these three radioligands toward α-synuclein were comparable with results from the Thioflavin T fluorescence assay.

Resonance assignments of an α-synuclein fibril prepared in Tris buffer at moderate ionic strength.

Fibrils of the protein α-synuclein (α-syn) are implicated in the pathogenesis of Parkinson's disease and related neurodegenerative disorders. We have reported a high-resolution structure (PDB 2N0A) of an α-syn fibril form prepared by in vitro incubation of monomeric protein in 50 mM sodium phosphate buffer pH 7.4 with 0.