Development of α-Synuclein Real-Time Quaking-Induced Conversion as a Diagnostic Method for α-Synucleinopathies

Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy are characterized by aggregation of abnormal α-synuclein (α-syn) and collectively referred to as α-synucleinopathy. Because these diseases have different prognoses and treatments, it is desirable to diagnose them early and accurately. However, it is difficult to accurately diagnose these diseases by clinical symptoms because symptoms such as muscle rigidity, postural dysreflexia, and dementia sometimes overlap among these diseases. The process of conformational conversion and aggregation of α-syn has been thought similar to that of abnormal prion proteins that cause prion diseases. In recent years, in vitro conversion methods, such as real-time quaking-induced conversion (RT-QuIC), have been developed. This method has succeeded in amplifying and detecting trace amounts of abnormal prion proteins in tissues and central spinal fluid of patients by inducing conversion of recombinant prion proteins via shaking. Additionally, it has been used for antemortem diagnosis of prion diseases. Recently, aggregated α-syn has also been amplified and detected in patients by applying this method and many clinical studies have examined diagnosis using tissues or cerebral spinal fluid from patients. In this review, we discuss the utility and problems of α-syn RT-QuIC for antemortem diagnosis of α-synucleinopathies.

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Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

Human Molecular Genetics ◽

10.1093/hmg/ddab036 ◽

2021 ◽

Author(s):

Maryna Psol ◽

Sofia Guerin Darvas ◽

Kristian Leite ◽

Sameehan U Mahajani ◽

Mathias Bähr ◽

...

Keyword(s):

Neuronal Network ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Sporadic Case ◽

Network Activity ◽

Proteinase K ◽

Neuronal Network Activity ◽

Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

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Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/08919887211023586 ◽

2021 ◽

pp. 089198872110235

Author(s):

Kathryn A. Wyman-Chick ◽

Lauren R. O’Keefe ◽

Daniel Weintraub ◽

Melissa J. Armstrong ◽

Michael Rosenbloom ◽

...

Keyword(s):

Clinical Features ◽

Dementia With Lewy Bodies ◽

Clinical Symptoms ◽

Neuropsychiatric Symptoms ◽

Lewy Bodies ◽

Rem Sleep Behavior Disorder ◽

Data Set ◽

Wide Range ◽

Prodromal Dementia ◽

Dementia Onset

Background: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. Methods: We identified non-demented participants without neurodegenerative disease from the National Alzheimer’s Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. Results: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). Conclusion: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

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Prion Disease Blood Test Using Immunoprecipitation and Improved Quaking-Induced Conversion

mBio ◽

10.1128/mbio.00078-11 ◽

2011 ◽

Vol 2 (3) ◽

Cited By ~ 78

Author(s):

Christina D. Orrú ◽

Jason M. Wilham ◽

Lynne D. Raymond ◽

Franziska Kuhn ◽

Björn Schroeder ◽

...

Keyword(s):

Real Time ◽

Blood Test ◽

Prion Diseases ◽

Proteinase K ◽

Transmissible Spongiform Encephalopathies ◽

Serum Samples ◽

Spongiform Encephalopathies ◽

Jakob Disease

ABSTRACT A key challenge in managing transmissible spongiform encephalopathies (TSEs) or prion diseases in medicine, agriculture, and wildlife biology is the development of practical tests for prions that are at or below infectious levels. Of particular interest are tests capable of detecting prions in blood components such as plasma, but blood typically has extremely low prion concentrations and contains inhibitors of the most sensitive prion tests. One of the latter tests is quaking-induced conversion (QuIC), which can be as sensitive as in vivo bioassays, but much more rapid, higher throughput, and less expensive. Now we have integrated antibody 15B3-based immunoprecipitation with QuIC reactions to increase sensitivity and isolate prions from inhibitors such as those in plasma samples. Coupling of immunoprecipitation and an improved real-time QuIC reaction dramatically enhanced detection of variant Creutzfeldt-Jakob disease (vCJD) brain tissue diluted into human plasma. Dilutions of 1014-fold, containing ~2 attogram (ag) per ml of proteinase K-resistant prion protein, were readily detected, indicating ~10,000-fold greater sensitivity for vCJD brain than has previously been reported. We also discriminated between plasma and serum samples from scrapie-infected and uninfected hamsters, even in early preclinical stages. This combined assay, which we call “enhanced QuIC” (eQuIC), markedly improves prospects for routine detection of low levels of prions in tissues, fluids, or environmental samples. IMPORTANCE Transmissible spongiform encephalopathies (TSEs) are largely untreatable and are difficult to diagnose definitively prior to irreversible clinical decline or death. The transmissibility of TSEs within and between species highlights the need for practical tests for even the smallest amounts of infectivity. A few sufficiently sensitive in vitro methods have been reported, but most have major limitations that would preclude their use in routine diagnostic or screening applications. Our new assay improves the outlook for such critical applications. We focused initially on blood plasma because a practical blood test for prions would be especially valuable for TSE diagnostics and risk reduction. Variant Creutzfeldt-Jakob disease (vCJD) in particular has been transmitted between humans via blood transfusions. Enhanced real-time quaking-induced conversion (eRTQ) provides by far the most sensitive detection of vCJD to date. The 15B3 antibody binds prions of multiple species, suggesting that our assay may be useful for clinical and fundamental studies of a variety of TSEs of humans and animals.

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Structures of α-synuclein filaments from multiple system atrophy

10.1101/2020.02.05.935619 ◽

2020 ◽

Cited By ~ 6

Author(s):

Manuel Schweighauser ◽

Yang Shi ◽

Airi Tarutani ◽

Fuyuki Kametani ◽

Alexey G. Murzin ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Human Brain ◽

Multiple System Atrophy ◽

Recombinant Proteins ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Two Dimensional ◽

Filamentous Inclusions

Synucleinopathies are human neurodegenerative diseases that include multiple system atrophy (MSA), Parkinson’s disease, Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) (1). Existing treatments are at best symptomatic. These diseases are characterised by the presence in brain cells of filamentous inclusions of α-synuclein, the formation of which is believed to cause disease (2, 3). However, the structures of α-synuclein filaments from human brain are not known. Here we show, using electron cryo-microscopy, that α-synuclein inclusions from MSA are made of two types of filaments, each of which consists of two different protofilaments. Non-proteinaceous molecules are present at the protofilament interfaces. By two-dimensional class averaging, we show that α-synuclein filaments from the brains of patients with MSA and DLB are different, suggesting that distinct conformers (or strains) characterise synucleinopathies. As was the case of tau assemblies (4–9), the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, with implications for understanding the mechanisms of aggregate propagation and neurodegeneration in human brain. These findings have diagnostic and potential therapeutic relevance, especially in view of the unmet clinical need to be able to image filamentous α-synuclein inclusions in human brain.

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Neuropathology

Oxford Textbook of Old Age Psychiatry ◽

10.1093/med/9780198807292.003.0005 ◽

2020 ◽

pp. 77-98

Author(s):

Johannes Attems ◽

Kurt A. Jellinger

Keyword(s):

Frontotemporal Lobar Degeneration ◽

Dementia With Lewy Bodies ◽

Prion Diseases ◽

Hippocampal Sclerosis ◽

Neurofibrillary Tangle ◽

Lewy Bodies ◽

Corticobasal Degeneration ◽

Amyloid Angiopathy ◽

Argyrophilic Grain ◽

Cerebral Amyloid

This chapter describes the main neuropathological features of the most common age-associated neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and dementia with Lewy bodies, as well as other less frequent ones such as multiple system atrophy, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, neurofibrillary tangle-dominant dementia, frontotemporal lobar degeneration with TDP-43 pathology, and Huntington’s disease. Likewise, cerebral amyloid angiopathy, hippocampal sclerosis, vascular dementia, and prion diseases are described. A main aim of this chapter is to assist the reader in interpreting neuropathological reports; hence criteria for the neuropathological classifications of the major diseases are provided. One section covers general considerations on neurodegeneration, and basic pathophysiological mechanisms of tau, amyloid-β‎, α‎-synuclein, TDP-43, and prions are briefly described in the sections on the respective diseases. Finally, one section is dedicated to cerebral multimorbidity, and a view on currently emerging neuropathological methods is given.

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Magnetic Resonance Spectroscopy in the Diagnosis of Dementia with Lewy Bodies

BioMed Research International ◽

10.1155/2014/809503 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Radoslaw Magierski ◽

Tomasz Sobow

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Dementia With Lewy Bodies ◽

Clinical Symptoms ◽

Clinical Signs ◽

Lewy Bodies ◽

Resonance Spectroscopy ◽

Diagnosis Of Dementia

Dementia with Lewy bodies (DLB) is considered to be the second most frequent primary degenerative dementing illness after Alzheimer’s disease (AD). DLB, together with Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) belong toα-synucleinopathies—a group of neurodegenerative diseases associated with pathological accumulation of theα-synuclein protein. Dementia due to PD and DLB shares clinical symptoms and neuropsychological profiles. Moreover, the core features and additional clinical signs and symptoms for these two very similar diseases are largely the same. Neuroimaging seems to be a promising method in differential diagnosis of dementia studies. The development of imaging methods or other objective measures to supplement clinical criteria for DLB is needed and a method which would accurately facilitate diagnosis of DLB prior to death is still being searched. Proton magnetic resonance spectroscopy (1H-MRS) provides a noninvasive method of assessing anin vivobiochemistry of brain tissue. This review summarizes the main results obtained from the application of neuroimaging techniques in DLB cases focusing on1H-MRS.

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Dementia with Lewy bodies and Parkinson’s disease dementia

10.1093/med/9780199644957.003.0035 ◽

2013 ◽

Cited By ~ 1

Author(s):

Arvid Rongve ◽

Dag Aarsland

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dementia With Lewy Bodies ◽

Clinical Symptoms ◽

Imaging Techniques ◽

Lewy Bodies ◽

Epidemiological Data ◽

Parkinson’S Disease Dementia ◽

Esterase Inhibitors ◽

Staging Systems

Dementia with Lewy bodies and Parkinson’s disease dementia belong to the α-synucleinopathies, a family of diseases pathologically characterized by aggregation of α-synuclein in Lewy bodies in the brain. In this chapter we present the epidemiological data for both conditions including new data on MCI. Clinical diagnostic criteria are reviewed and the different neuropathology staging systems for DLB and PDD and the most important genetic findings are considered. Biomarkers in DLB and PDD with particular focus on imaging techniques like CIT-SPECT and MRI are described. Important clinical symptoms in both conditions are presented in detail and the most important clinical differential diagnoses are discussed. Pharmacological and non- pharmacological treatment of different symptoms in both conditions are discussed with particular emphasis on the choline esterase inhibitors and antipsychotic medications.New data on memantine are presented.

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