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Abstract Background and aim Toxic oligomeric α-synuclein (αS; O-αS) has been suggested to play a central role in the pathogenesis of Lewy body diseases such as Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of αS, O-αS, total and phosphorylated tau, and amyloid β 1–42 (Aβ1–42) are thought to reflect the pathophysiology or clinical sympt...
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... correlation coefficients of each CSF protein level with patient background and motor symptoms are shown in Table 1, and those with cognitive assessment scores are given in Table 2. For patient background, CSF levels of total αS, O-αS, Aβ1-42 and total tau were not correlated with age, education, or duration from symptom onset, but P-tau181p was positively correlated with age (p < 0.05). ...Similar publications
Background: Alzheimer’s disease (AD) is characterized by the presence of β-amyloid plaques and neurofibrillary tangles, while Lewy body dementia (LBD) is characterized by α-synuclein (α-syn) inclusions. Some authors examine α-syn protein in the neurodegeneration process of AD and propose to consider cerebrospinal fluid (CSF) α-syn as a possible add...
Coenzyme Q10 (CoQ10) has an important role as an antioxidant. Being that oxidative stress is one of the mechanisms involved in the pathogenesis of Parkinson’s disease (PD) and other neurodegenerative diseases, several studies addressed the concentrations of CoQ10 in the different tissues of patients with PD and other parkinsonian syndromes (PS), tr...
Background
Alzheimer’s disease (AD) and Lewy body dementia (LBD) are two different forms of dementia, but their pathology may involve the same cortical areas with overlapping cognitive manifestation. Dementia cases within the same family share a common genetic background. Nonetheless, the clinical phenotype may be different due to the different und...
Normal brain aging is accompanied by patterns of functional and structural change. Alzheimer's disease (AD), a representative neurodegenerative disease, has been linked to accelerated brain aging at respective age ranges. Here, we developed a deep learning-based brain age prediction model using fluorodeoxyglucose (FDG) PET and structural MRI and te...
Objectives
Impaired olfaction may be a biomarker for early Lewy body disease, but its value in mild cognitive impairment with Lewy bodies (MCI-LB) is unknown. We compared olfaction in MCI-LB with MCI due to Alzheimer’s disease (MCI-AD) and healthy older adults. We hypothesized that olfactory function would be worse in probable MCI-LB than in both M...
Citations
... The concentration of α-synuclein in the CSF of patients with PD is lower than that in healthy individuals [38]. It is positively correlated with the concentration of Aβ 1-42 in the CSF [39]. These reports imply that the concentration of Aβ 1-42 in the blood is lower in patients with PD than in healthy individuals. ...
Measurement of amyloid concentration in blood using time-of-flight mass spectrometry was developed, and the combined normalized score of amyloid precursor proteins (composite biomarker: CM) in plasma was found to be related to the accumulation of β-amyloid (Aβ) in the brain. Therefore, we measured the CM value in healthy subjects aged 30-79 years and investigated the association between the CM value and clinical characteristics using multiple regression and decision tree analyses. The results indicated that the CM value was associated with age, sex, ApoE genotype, blood glucose, and Mg in healthy subjects. Factors affecting CM values differed by age. The CM values of patients with central nervous system disorders were higher than those of the healthy subjects. Moreover, the relationship between CM and Mg concentrations differed between the patients and healthy subjects. These results suggest that the CM value can be used as a biomarker for the onset of dementia, including Alzheimer's disease. The combination of CM values and blood component results may allow for more accurate diagnosis.
... CSF αSyn biomarkers in LBD have been largely investigated. Many studies using ELISA revealed that the CSF total αSyn levels are decreased in LBD compared to other neurodegenerative diseases and controls [21,[48][49][50][51], whereas the CSF oligomeric αSyn levels are increased in patients with PD compared to controls [46,51], suggesting that CSF total and oligomeric αSyn can be used as diagnostic markers for LBD. Murakami et al. asserted that the CSF total αSyn levels decreased with the deterioration of motor symptoms and cognition in patients with PD [21]. ...
... Many studies using ELISA revealed that the CSF total αSyn levels are decreased in LBD compared to other neurodegenerative diseases and controls [21,[48][49][50][51], whereas the CSF oligomeric αSyn levels are increased in patients with PD compared to controls [46,51], suggesting that CSF total and oligomeric αSyn can be used as diagnostic markers for LBD. Murakami et al. asserted that the CSF total αSyn levels decreased with the deterioration of motor symptoms and cognition in patients with PD [21]. Murakami et al. also showed that the CSF total αSyn levels were positively correlated with CSF Aβ 1-42 and CSF phosphorylated tau protein (p-tau: phosphorylated at threonine-181), suggesting that both Aβ 1-42 and p-tau possibly co-aggregated with αSyn in LBD patients [21]. ...
... Murakami et al. asserted that the CSF total αSyn levels decreased with the deterioration of motor symptoms and cognition in patients with PD [21]. Murakami et al. also showed that the CSF total αSyn levels were positively correlated with CSF Aβ 1-42 and CSF phosphorylated tau protein (p-tau: phosphorylated at threonine-181), suggesting that both Aβ 1-42 and p-tau possibly co-aggregated with αSyn in LBD patients [21]. Compta et al. demonstrated that the CSF oligomeric αSyn levels increased in patients with PDD but not in patients with non-demented PD and isolated rapid-eye-movement sleep behavior disorder (iRBD) [52], which was considered prodromal stages of α-synucleinopathies [53]. ...
Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-β (Aβ) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aβ, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aβ and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.
... This finding was further confirmed in subsequent studies by the same group 79,80,132 , suggesting that oligomeric aSyn species could be utilized as prognostic PD biomarkers. On the other hand, Murakami et al. 159 observed no association between oligomeric aSyn levels and disease progression. ...
Parkinson’s disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10–15 years before the clinical diagnostic symptoms of the disease are manifested. Furthermore, several aspects of PD pathology overlap with other neurodegenerative diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need to discover and validate early diagnostic and prognostic markers that reflect disease pathophysiology, progression, severity, and potential differences in disease mechanisms between PD and other NDDs. The close association between aSyn and the development of pathology in synucleinopathies, along with the identification of aSyn species in biological fluids, has led to increasing interest in aSyn species as potential biomarkers for early diagnosis of PD and differentiate it from other synucleinopathies. In this review, we (1) provide an overview of the progress toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological fluids; (2) present comparative and critical analysis of previous studies that measured total aSyn as well as other species such as modified and aggregated forms of aSyn in different biological fluids; and (3) highlight conceptual and technical gaps and challenges that could hinder the development and validation of reliable aSyn biomarkers; and (4) outline a series of recommendations to address these challenges. Finally, we propose a combined biomarker approach based on integrating biochemical, aggregation and structure features of aSyn, in addition to other biomarkers of neurodegeneration. We believe that capturing the diversity of aSyn species is essential to develop robust assays and diagnostics for early detection, patient stratification, monitoring of disease progression, and differentiation between synucleinopathies. This could transform clinical trial design and implementation, accelerate the development of new therapies, and improve clinical decisions and treatment strategies.
... Y.E. Huh et al. the association between the GlcCer/SM ratio and α-synuclein could potentially also partly explain the association between baseline GlcCer/SM ratio and cognitive prognosis as other studies reported that decreased CSF α-synuclein levels were related to cognitive decline in drug-naive early-stage PD patients 27,28 . ...
Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson’s disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson’s Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants ( GBA -PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased ( P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced ( P = 0.0001) in CSF of GBA -PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA -PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P -value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA -PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development.
... LB and amyloid plaque pathologies in cortical and limbic regions are highly associated with the occurrence of dementia in the clinical course of PD 4,5,21 , and the patients with PD dementia were more likely to show lower CSF Aβ 1-42 and higher CSF t-tau and p-tau levels, when compared to those with normal cognition [22][23][24] . Similar to our results, PD patients with low CSF Aβ 1-42 at early stage showed worse cognitive performance 25,26 and faster decline of cognitive performance in memory, executive and visuospatial function than those with high CSF Aβ 1-42 27,28 . NfL is a subunit of neurofilament protein, which is a major component of neuronal cytoskeleton and abundant in myelinated axons with large caliber 29,30 . ...
... Similarly, α-syn pathology promoted fibrillization and phosphorylation of tau proteins in cellular and transgenic animal models 42,43 . Several studies demonstrated a correlation between CSF α-syn, Aβ 1-42 and p-tau levels 6,25,44,45 . Therefore, amyloid load in central nervous system of PD patients may cause not only neurodegenerative process related with Alzheimer's disease, but accelerated propagation of α-syn pathology. ...
Full dynamics of biofluid biomarkers have been unknown in patients with Parkinson’s disease (PD). Using data from 396 PD patients and 182 controls in the Parkinson's Progression Markers Initiative (PPMI) database, we estimated long-term temporal trajectories of CSF α-synuclein (α-syn), amyloid-β (Aβ), total tau (t-tau), phosphorylated tau (p-tau) and serum neurofilament light chain (NfL) by integrating function between the baseline levels and annual changes. At baseline, PD patients showed lower CSF α-syn, Aβ, t-tau and p-tau levels than those of the controls. In all PD patients, CSF α-syn and Aβ decreased in a negative exponential pattern before the onset of motor symptoms, whereas CSF t-tau and p-tau, and serum NfL increased. Patients with cognitive impairment exhibited faster decline of Aβ and α-syn and faster rise of t-tau, p-tau and NfL, when compared to those without. Similarly, low Aβ group showed earlier decline of α-syn, faster rise of t-tau, p-tau and NfL, and faster decline of cognitive performances, when compared to high Aβ group. Our results suggest that longitudinal changes in biomarkers can be influenced by cognitive impairment and Aβ burden at baseline. PD patients with Aβ pathology may be associated with early appearance of α-synuclein pathology, rapid progression of axonal degeneration and neurodegeneration, and consequently greater cognitive decline.
... Skogseth et al. (2015) showed that low CSF α-synuclein was significantly associated with phonemic fluency and attention, but not with posterior cortical domains, such as memory and visuospatial domains, in PD and PD with mild cognitive impairment (PD-MCI). We have shown that lower CSF α-synuclein is associated with worse performance in a judgement subtest that assesses planning and executive function, but not with subtests assessing other cognitive domains in patients with PD, PD-MCI and PDD (Murakami et al., 2019). In these four studies, CSF α-synuclein levels were also correlated with CSF levels of amyloid-β 1-42 and total tau. ...
... PD often presents with an AD pathology such as senile plaques and neurofibrillary tangles (Apaydin et al., 2002), and several experimental studies have explained the co-pathology of AD and PD. α-synuclein has been shown to co-aggregate with amyloid-β 1-42 (Ono et al., 2012) and tau (Guo et al., 2013), and some of the studies in this review showed that CSF αsynuclein levels were correlated with those of amyloid-β 1-42 (Buddhala et al., 2015;Compta et al., 2015;Skogseth et al., 2015;Hall et al., 2016;Murakami et al., 2019;Wijeyekoon et al., 2020) and tau (Kang et al., 2013;Buddhala et al., 2015;Compta et al., 2015;Hall et al., 2015Hall et al., , 2016Skogseth et al., 2015;Murakami et al., 2019). These reports support an interaction of α-synuclein with amyloid beta and tau in the progressive course of PD and cognitive deterioration. ...
... PD often presents with an AD pathology such as senile plaques and neurofibrillary tangles (Apaydin et al., 2002), and several experimental studies have explained the co-pathology of AD and PD. α-synuclein has been shown to co-aggregate with amyloid-β 1-42 (Ono et al., 2012) and tau (Guo et al., 2013), and some of the studies in this review showed that CSF αsynuclein levels were correlated with those of amyloid-β 1-42 (Buddhala et al., 2015;Compta et al., 2015;Skogseth et al., 2015;Hall et al., 2016;Murakami et al., 2019;Wijeyekoon et al., 2020) and tau (Kang et al., 2013;Buddhala et al., 2015;Compta et al., 2015;Hall et al., 2015Hall et al., , 2016Skogseth et al., 2015;Murakami et al., 2019). These reports support an interaction of α-synuclein with amyloid beta and tau in the progressive course of PD and cognitive deterioration. ...
The level of α-synuclein, a component of Lewy bodies, in cerebrospinal fluid (CSF) in Parkinson's disease (PD) has attracted recent attention. Most meta-analyses conclude that CSF levels of α-synuclein are decreased in PD. Patients with PD present with cognitive impairment, including frontal/executive dysfunction in the early phase and later emergence of visuospatial and mnemonic deficits. To examine whether CSF α-synuclein levels reflect the activities of various cognitive domains, we reviewed reports examining the association of these levels with cognitive performance in each domain in PD. Among 13 cross-sectional studies, five showed that a lower CSF α-synuclein level was associated with worse cognitive function. In four of these five reports, frontal/executive function showed this association, suggesting a link of the pathophysiology with Lewy bodies. In three other reports, a higher CSF α-synuclein level was associated with temporal-parieto-occipital cognitive deterioration such as memory. In the other five reports, the CSF α-synuclein level did not correlate with cognitive performance for any domain. In four longitudinal studies, a higher baseline CSF α-synuclein level was associated with a worse cognitive outcome, including cognitive processing speed, visuospatial function and memory in two, but not with any cognitive outcome in the other two. The different associations may reflect the heterogeneous pathophysiology in PD, including different pathogenic proteins, neurotransmitters. Thus, more studies of the association between cognitive domains and CSF levels of pathogenic proteins are warranted.
... Contrary to previous theories that MRI-visible EPVS represent waste accumulation and predict worse clinical outcomes [21], we found that lower BG-EPVS levels are associated with decreased CSF α-synuclein, t-tau, and accelerated H&Y progression. Previous studies have established that there is decreased CSF αsynuclein levels in patients with PD [22,23], and although controversial [24,25], low CSF α-synuclein appears to predict increased disease severity [23,[26][27][28]. In general, t-tau and p-tau levels were closely correlated. ...
Perivascular spaces in the brain have been known to communicate with cerebrospinal fluid and contribute to waste clearance in animal models. In this study, we sought to determine the association between MRI-visible enlarged perivascular spaces (EPVS) and disease markers in Parkinson's disease (PD). We obtained longitudinal data from 245 patients with PD and 98 healthy controls from the Parkinson's Progression Marker Initiative. Two trained neurologists performed visual ratings on T2-weighted images to characterize EPVS in the centrum semiovale (CSO), the basal ganglia (BG) and the midbrain. We found that a greater proportion of patients with PD had low grade BG-EPVS relative to healthy controls. In patients with PD, lower grade of BG-EPVS and CSO-EPVS predicted lower CSF α-synuclein and t-tau. Lower grade of BG-EPVS were also associated with accelerated Hoehn &Yahr stage progression in patients with baseline stage 1. BG-EPVS might be a valuable predictor of disease progression.
Proteomic profiling is an effective way to identify biomarkers for Parkinson’s disease (PD). Cerebrospinal fluid
(CSF) has direct connectivity with the brain and could be a source of finding biomarkers and their clinical implications. Comparative proteomic profiling has shown that a group of differentially displayed proteins exist. The
studies performed using conventional and classical tools also supported the occurrence of these proteins. Many
studies have highlighted the potential of CSF proteomic profiling for biomarker identification and their clinical
applications. Some of these proteins are useful for disease diagnosis and prediction. Proteomic profiling of CSF
also has immense potential to distinguish PD from similar neurodegenerative disorders. A few protein biomarkers
help in fundamental knowledge generation and clinical interpretation. However, the specific biomarker of PD is
not yet known. The use of proteomic approaches in clinical settings is also rare. A large-scale, multi-centric,
multi-population and multi-continental study using multiple proteomic tools is warranted. Such a study can
provide valuable, comprehensive and reliable information for a better understanding of PD and the development
of specific biomarkers. The current article sheds light on the role of CSF proteomic profiling in identifying
biomarkers of PD and their clinical implications. The article also explains the achievements, obstacles and hopes
for future directions of this approach.
The recent validation of the alpha synuclein seed amplification assay as a biomarker with high sensitivity and specificity for the diagnosis of Parkinson’s disease has formed the backbone for a proposed staging system for incorporation in Parkinson’s disease clinical studies and trials. The routine use of this biomarker should greatly aid in the accuracy of diagnosis during recruitment of Parkinson’s disease patients into trials (as distinct from patients with non- Parkinson’s disease parkinsonism or non- Parkinson’s disease tremors). There remain however further challenges in the pursuit of biomarkers for clinical trials of disease modifying agents in Parkinson’s disease, namely: optimising the distinction between different alpha synucleinopathies; the selection of subgroups most likely to benefit from a candidate disease modifying agent; as sensitive means of confirming target engagement; and in the early prediction of longer-term clinical benefit. For example; levels of cerebrospinal fluid proteins such as the lysosomal enzyme ß-glucocerebrosidase may assist in prognostication or allow enrichment of appropriate patients into disease modifying trials of agents with this enzyme as the target; the presence of coexisting Alzheimer disease like pathology (detectable through cerebrospinal fluid levels of Amyloid Beta-42 and tau) can predict subsequent cognitive decline; imaging techniques such as free-water or neuromelanin MRI may objectively track decline of Parkinson’s disease even in its later stages. The exploitation of additional biomarkers to the alpha synuclein seed amplification assay will therefore greatly add to our ability to plan trials and assess disease modifying properties of interventions. The choice of which biomarker(s) to use in the context of disease modifying clinical trials will depend on the intervention, the stage (at risk, premotor, motor, complex) of the population recruited and the aims of the trial. The progress already made lends hope that panels of fluid biomarkers in tandem with structural or functional imaging may provide sensitive and objective methods of confirming that an intervention is modifying a key pathophysiological process of Parkinson’s disease. However, correlation with clinical progression does not necessarily equate to causation and the ongoing validation of quantitative biomarkers will depend on insightful clinical-genetic-pathophysiological comparisons incorporating longitudinal biomarker changes from those at genetic risk with evidence of onset of the pathophysiology and those at each stage of manifest clinical Parkinson’s disease.
Background:
Neuroinflammation is one of the pathophysiologies of Parkinson's disease (PD). Lewy bodies, the pathological hallmark of PD, emerge as a consequence of α-synuclein aggregation, and neuroinflammation is induced concurrently with this aggregation. Imaging and cerebrospinal fluid (CSF) biomarkers that reflect PD pathophysiology have been developed or are under investigation. The IgG index of CSF is a marker of inflammation, and may also reflect the pathophysiology of PD.
Aim:
We examined if the IgG index reflects the pathophysiology of PD in drug-naïve PD patients.
Method:
The subjects were 20 consecutive PD patients who underwent 123I-MIBG scintigraphy for assessment of the heart to mediastinum (H/M) ratio and wash out rate, 123I-Ioflupane SPECT for examination of the specific binding ratio in the striatum, and lumbar puncture before treatment. The CSF IgG index and levels of pathogenic proteins (total α-synuclein, oligomeric α-synuclein, total tau, phosphorylated tau and amyloid Aβ1-42) were determined. The IgG index was compared with the other parameters using Spearman correlation analysis.
Results:
The IgG index showed a significant correlation with the H/M ratio in early (r = -0.563, p = 0.010) and delayed (r = -0.466, p = 0.038) images in 123I-MIBG scintigraphy and with the CSF total tau level (r = -0.513, p = 0.021).
Conclusion:
Neuroinflammation is involved in PD pathophysiology in some patients, and a higher IgG index indicates the presence of neuroinflammation accompanied by emergence of Lewy bodies.
