Challenges in the diagnosis of Parkinson's disease

Tolosa, Eduardo; Garrido, Alícia; Scholz, Sonja W.; Poewe, Werner

doi:10.1016/s1474-4422(21)00030-2

Cited by 828 publications

(486 citation statements)

References 103 publications

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“…The clinical utility of DaTSCAN was investigated in a recent systematic review and meta-analysis demonstrating that the results of DaT imaging are associated both with a change in diagnosis and management of patients with suspected parkinsonian syndromes, even in individuals with long symptom duration [ 115 ]. However, despite a rigorous clinical assessment, diagnosing de novo untreated PD can be challenging, even for movement disorders specialist [ 116 ]. For example, the clinical presentation of isolated or atypical tremors can be insufficient to allow a precise early-stage diagnosis whereas the detection of abnormal striatal DAT binding in such patients predicts the future development of additional signs and symptoms consistent with clinical criteria for PD [ 117 ].…”

Section: Dat Imaging As Diagnostic Biomarkermentioning

confidence: 99%

“…Nevertheless, although all these MRI techniques provide suitable markers for the nigral structure, they generally may not differentiate PD and other types of degenerative parkinsonism [ 116 ]. Further recent neuroimaging techniques, such as diffusion-tensor imaging and density imaging, might help clinicians to differentiate between these conditions but their unavailability on most scanners and the lack of normative databases challenge their use in clinical practice [ 300 , 301 ].…”

Section: Beyond Dat: Correlation With Other Potential Nigrostriatal Biomarkers In Pdmentioning

confidence: 99%

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Dopamine Transporter Imaging, Current Status of a Potential Biomarker: A Comprehensive Review

Palermo

Giannoni

Bellini

et al. 2021

IJMS

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A major goal of current clinical research in Parkinson’s disease (PD) is the validation and standardization of biomarkers enabling early diagnosis, predicting outcomes, understanding PD pathophysiology, and demonstrating target engagement in clinical trials. Molecular imaging with specific dopamine-related tracers offers a practical indirect imaging biomarker of PD, serving as a powerful tool to assess the status of presynaptic nigrostriatal terminals. In this review we provide an update on the dopamine transporter (DAT) imaging in PD and translate recent findings to potentially valuable clinical practice applications. The role of DAT imaging as diagnostic, preclinical and predictive biomarker is discussed, especially in view of recent evidence questioning the incontrovertible correlation between striatal DAT binding and nigral cell or axon counts.

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Section: Dat Imaging As Diagnostic Biomarkermentioning

confidence: 99%

Section: Beyond Dat: Correlation With Other Potential Nigrostriatal Biomarkers In Pdmentioning

confidence: 99%

Dopamine Transporter Imaging, Current Status of a Potential Biomarker: A Comprehensive Review

Palermo

Giannoni

Bellini

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…14 Generally, the natural history of PD can be divided into three phases including the preclinical phase with no clinical signs and symptoms; the prodromal phase with the presence of non-motor symptoms and with or without slight motor symptoms; and the clinical phase that can be further classified into an early stage with cardinal motor dysfunction and a late stage with the presence of axial motor symptoms, dementia, and psychosis. 15 Accumulating evidence supports a prion-like templating and propagation property of α-syn, 16-18 which is believed to contribute to the distribution of α-syn pathology in patients’ brains associated with the progression of PD. 19-21 However, given the polymorphism of α-syn fibrils, it remains unknown whether the structure of α-syn fibrils changes during spread in different phases of PD.…”

Section: Introductionmentioning

confidence: 99%

Different structures and pathologies of α-synuclein fibrils derived from preclinical and postmortem patients of Parkinson’s disease

Fan

Sun

et al. 2021

Preprint

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Abstractα-Synuclein (α-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinson’s disease (PD). Studies have shown that α-syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro α-syn aggregation, and the amplified fibrils are more potent in inducing endogenous α-syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of α-syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD α-syn aggregation and suggests potential alteration of α-syn fibrils during the progression of PD clinical phases.Significance StatementIncreasing evidence support different conformational α-syn fibrils in patients with different α-synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is unknown. Here, we show that α-syn fibrils amplified from the cerebrospinal fluid (CSF) of the late-stage postmortem PD (post-PD) patient are more potent in inducing endogenous α-syn aggregation in neurons than that amplified from the preclinical (pre-PD) patient. Cryo-EM structures further reveal that the post-PD fibrils contain a novel conformation that is distinct from either the pre-PD fibrils or those previously reported. Our work suggests conformational evolution of α-syn fibrils along with PD progression.

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“…Parkinson’s disease (PD; Paralysis agitans ) is a progressive neurodegenerative disorder. After Alzheimer’s disease (AD), it represents the second most frequent neurodegenerative disease entity with the vast majority of cases being idiopathic [ 1 , 2 ]. On the neuronal level, PD is characterized by the degeneration of dopaminergic substantia nigra (SN) neurons, resulting in dopaminergic striatal under-supply and hypofunction [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Proteolytic α-Synuclein Cleavage in Health and Disease

Bluhm

Schrempel

Hörsten

et al. 2021

IJMS

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In Parkinson’s disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect α-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of α-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and/or pathological properties. In the present review, we summarize the current knowledge on proteolytical α-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer’s disease and report potential cross-disease mechanisms of pathogenic protein aggregation.

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Challenges in the diagnosis of Parkinson's disease

Cited by 828 publications

References 103 publications

Dopamine Transporter Imaging, Current Status of a Potential Biomarker: A Comprehensive Review

Dopamine Transporter Imaging, Current Status of a Potential Biomarker: A Comprehensive Review

Different structures and pathologies of α-synuclein fibrils derived from preclinical and postmortem patients of Parkinson’s disease

Proteolytic α-Synuclein Cleavage in Health and Disease

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