Humans ; alpha-Synuclein/genetics* ; Parkinson Disease/pathology*

Current evidence from monogenic Parkinson's disease (PD) supports the view that PD is a clinical syndrome, rather than a single disease entity, and that the heterogeneity of PD indeed reflects different pathogenesis. Recent developments in functional imaging have enabled the in vivo assessment of cellular and molecular pathology of PD with respect to temporal and topographical patterns. We propose that this new technology will be useful for linking monogenic and sporadic PD, and thus, for classifying PD based on the pathogenesis. It will be also useful in clinico-genetic studies exploring susceptibility factors and at-risk groups, which are important for neuroprotective treatment when it becomes available.
Parkinson Disease* ; Pathology ; Pathology, Molecular ; Population Characteristics ; Positron-Emission Tomography

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.
Alzheimer Disease ; Biomarkers* ; Cerebrospinal Fluid* ; Humans ; Models, Animal ; Neurodegenerative Diseases ; Parkinson Disease ; Pathology ; Therapeutic Uses

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
Humans ; Prions ; Neurodegenerative Diseases/pathology* ; Amyloid beta-Peptides ; Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; Parkinson Disease

Parkinson's disease (PD), a progressive neurodegenerative disorder, is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of deposits of aggregated α-synuclein in intracellular inclusions known as Lewy bodies (LB). A highly localized inflammatory response mediated by reactive microglia is prominent in PD brains, but the mechanisms underlying the microglial activation are poorly understood. Recently some lines of evidences have shown that monomeric, or aggregated α-synuclein can activate microglia, the toxic factors released from activated microglia may lead to the cell death of dopaminergic neurons. This review is to summarize the recent progress on the role of α-synuclein induced microglia activation on the PD pathogenesis and progression, and to discuss the possible mechanisms involved.
Humans ; Microglia ; pathology ; Parkinson Disease ; etiology ; metabolism ; pathology ; alpha-Synuclein ; chemistry ; metabolism ; physiology

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.
Mice ; Animals ; Epilepsy, Temporal Lobe/pathology* ; Parvalbumins/metabolism* ; Parkinson Disease/pathology* ; Neurons/metabolism* ; Interneurons/physiology* ; Disease Models, Animal ; Brain/pathology*

To study the effects of 6-hydroxydopamine (6-OHDA) and reduced glutathione (GSH) on the nigral dopaminergic neurons in brain slices in vitro, immolunohistochemical technique was used to observe the changes of TH-stained neurons, including cell bodies and the dendrites, in the substantia nigra (SN) of midbrain slices of rats after incubation for 1 h in the presence of GSH 15 min before and during the period of incubation with 6-OHDA. The results showed that cell bodies remained intact but dendrites were fragmented and truncated after treatment with 6-OHDA. The antioxidant GSH alone did not significantly affect the dendrites of SN neurons but prevented 6-O-HDA-induced damage of dendrites. It was concluded that glutathione may prevent 6-OHDA-induced dopaminergic neurodegeneration and play a protective role in dopaminergic neurons.
Glutathione/*therapeutic use ; Neurons/pathology ; Oxidopamine ; Parkinson Disease, Secondary/chemically induced ; Parkinson Disease, Secondary/*drug therapy ; Random Allocation ; Rats, Sprague-Dawley ; Substantia Nigra/pathology ; Tyrosine 3-Monooxygenase/metabolism

Alzheimer Disease ; Diabetic Neuropathies ; pathology ; Glaucoma ; pathology ; Humans ; Multiple Sclerosis ; pathology ; Nerve Fibers ; pathology ; Ophthalmoscopy ; Optic Nerve ; pathology ; Parkinson Disease ; pathology ; Retinal Neurons ; pathology ; Tomography, Optical Coherence

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by loss of dopaminergic (DA) neurons in the dense part of the substantia nigra (SNpc). Postmortem analysis of PD patients and experimental animal studies found that microglial cell activation and increased levels of pro-inflammatory factors were common features of PD brain tissue. At the same time, the invasion and accumulation of peripheric immune cells were detected in the brain of PD patients. In this paper, peripheral inflammation across the blood-brain barrier (BBB), the misfolded α-synuclein (α-syn)-induced microglial cell activation and intracerebral inflammation in PD are summarized, providing potential therapeutic measures for delaying the onset of PD.
Animals ; Blood-Brain Barrier ; Dopaminergic Neurons ; pathology ; Humans ; Inflammation ; pathology ; Microglia ; Parkinson Disease ; pathology ; Substantia Nigra ; pathology ; alpha-Synuclein

In order to explore the role of acetylcholine in the pathogenesis of Parkinson's disease (PD), the changes in the concentration of acetylcholine (Ach) in the striatum, the apoptosis of substantia nigra cells, the ultrastructure and the changes of Nissl cells in rats during the morbidity of PD, and the corresponding behaviors in rats with PD were observed. Rat PD model was established by using the modified Thomas method. Eighty-one rats were randomly divided into normal control, sham operation and PD groups and their behavior features were observed at post-operative day (POD) 7, 14 and 21 as three subgroups (n=9 each). The concentration of Ach in the striatum was determined by using high-performance liquid chromatography. The apoptosis of substantia nigra cells was assayed by using TUNEL method. The ultrastructural changes in the substantia nigra were observed under the electron microscopy, and the survival of neurons in the substantia nigra area was examined by using Nissl staining. In PD group at POD 7 to 21, the damage in the substantia nigra area was gradually aggravated, the concentration of Ach, apoptosis rate and turns of rotation were gradually increased, and the number of Nissl cells was gradually reduced over the time as compared with the normal control and sham operation groups (all P<0.05). It was concluded that there exist dynamic changes in Ach concentration, ethology and apoptosis of the substantia nigra cells during the morbidity of PD, suggesting the contribution of apoptosis to the morbidity of PD, and critical role of Ach in the pathogenesis of PD.
Acetylcholine ; pharmacology ; Animals ; Corpus Striatum ; drug effects ; metabolism ; pathology ; Disease Models, Animal ; Male ; Parkinson Disease ; metabolism ; pathology ; Rats ; Rats, Wistar