BACKGROUND: Although neuromelanin-sensitive magnetic resonance imaging (NM-MRI) has been used to evaluate early neurodegeneration in Parkinson's disease, studies concentrating on the locus coeruleus (LC) in pre-dementia stages of dementia with Lewy bodies (DLB) are lacking. OBJECTIVES: The aims were to evaluate NM-MRI signal changes in the LC in patients with mild cognitive impairment with Lewy bodies (MCI-LB) compared to healthy controls (HC) and to identify the cognitive correlates of the changes. We also aimed to test the hypothesis of a caudal-rostral α-synuclein pathology spread using NM-MRI of the different LC subparts. METHODS: A total of 38 MCI-LB patients and 59 HCs underwent clinical and cognitive testing and NM-MRI of the LC. We calculated the contrast ratio of NM-MRI signal (LC-CR) in the whole LC as well as in its caudal, middle, and rostral MRI slices, and we compared the LC-CR values between the MCI-LB and HC groups. Linear regression analyses were performed to assess the relationship between the LC-CR and cognitive outcomes. RESULTS: The MCI-LB group exhibited a significant reduction in the right LC-CR compared to HCs (P = 0.021). The right LC-CR decrease was associated with impaired visuospatial memory in the MCI-LB group. Only the caudal part of the LC exhibited significant LC-CR decreases in MCI-LB patients compared to HCs on both sides (P < 0.0001). CONCLUSIONS: This is the first study that focuses on LC-CRs in MCI-LB patients and analyzes the LC subparts, offering new insights into the LC integrity alterations in the initial stages of DLB and their clinical correlates. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• MeSH
• alfa-synuklein metabolismus   MeSH
• demence s Lewyho tělísky * diagnostické zobrazování   patologie   MeSH
• kognitivní dysfunkce * diagnostické zobrazování   patologie   patofyziologie   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• locus coeruleus * diagnostické zobrazování   patologie   MeSH
• magnetická rezonanční tomografie * MeSH
• neuropsychologické testy MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Chitinase-3-like protein 1 (CHI3L1) is a glycoprotein implicated in various neurological conditions. It is associated with neuroinflammation and tissue remodeling. The study aimed to validate the reference interval (RI) of serum (S) CHI3L1 in a control group, to correlate S CHI3L1 values with other biomarkers of neurodegenerative damage, and to estimate the diagnostic accuracy of S CHI3L1. METHODS: Samples from 108 healthy volunteers were used to estimate the S CHI3L1 RI. For the comparison, we used cerebrospinal fluid (CSF) and serum (S) samples from 121 patients with cognitive disorders, and cognitive deterioration was assessed using the Mini-Mental State Examination (MMSE). ELISA assays were used to determine the S CHI3L1, CSF, and S neurofilament light chain (NfL) levels; CSF and plasma β-amyloid peptide42; CSF and plasma β-amyloid peptide40; CSF total tau protein; CSF phosphorylated tau protein; and CSF alpha-synuclein. RESULTS: The estimated RI of S CHI3L1 was 14.44 to 63.11 μg/L. The cut-off value of S CHI3L1 was 34.37 μg/L. ROC analysis showed that S CHI3L1 has 81.4% sensitivity and 76.9% specificity. We found a moderate Spearman's rank correlation coefficient between the S CHI3L1 and age (rS = 0.486; p < 0.001) and between S CHI3L1 and S NfL (rS = 0.489; p < 0.001) in all groups. The Kruskal-Wallis test showed a significant overall difference in S CHI3L1 among diagnostic groups (p = 0.013). S CHI3L1 and CSF NfL had statistically significant effects on MMSE values (multiple R2 was 0.431). CONCLUSIONS: Our results suggest that S CHI3L1 reflects the severity of cognitive deficits assessed by MMSE. It can be used as a supportive biomarker in neurodegenerative diseases.

• MeSH
• alfa-synuklein mozkomíšní mok   krev   MeSH
• amyloidní beta-protein krev   mozkomíšní mok   MeSH
• biologické markery krev   mozkomíšní mok   MeSH
• dospělí MeSH
• kognitivní dysfunkce * krev   mozkomíšní mok   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neurofilamentové proteiny mozkomíšní mok   krev   MeSH
• pohybové poruchy * krev   mozkomíšní mok   diagnóza   MeSH
• protein CHI3L1 * krev   mozkomíšní mok   MeSH
• proteiny tau mozkomíšní mok   krev   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

In the study, we employ an affordable, tissue-saving, and precise simultaneous multiplex immunofluorescence method with heat-induced antibody stripping to identify and structurally analyse nigral Lewy bodies in dopaminergic neurones. Analysis of different alpha-synuclein epitopes and proteoforms reveals an almost uniform, onion-like morphology of the Lewy bodies. The N-terminal and C-terminal domains are predominantly accessible to antibody binding in the peripheral shell of the bodies.

• MeSH
• alfa-synuklein * metabolismus   analýza   MeSH
• demence s Lewyho tělísky patologie   MeSH
• dopaminergní neurony metabolismus   patologie   MeSH
• fluorescenční protilátková technika metody   MeSH
• Lewyho tělíska * metabolismus   patologie   MeSH
• lidé MeSH
• substantia nigra * metabolismus   patologie   MeSH
• vysoká teplota MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Parkinson's disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation is a characteristic hallmark of PD pathogenesis. These aggregates facilitate the formation of Lewy bodies and degeneration. The epidemiological evidence demonstrates a definitive association of diabetes with PD risk. Considering this, many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors are being explored as alternative PD therapeutics. This study evaluated the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated by the PI3K/AKT and Nrf2 pathways in PD models. In silico studies were conducted to determine the binding affinity, stability, and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin (15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28 days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models. Neurobehavioral assessments were carried out throughout the study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, and immunohistochemistry were carried out at the end of the study. The in silico studies demonstrate better binding, stability, and ADMET profile of sitagliptin with both target proteins. Sitagliptin restored cognitive and motor deficits in both rotenone- and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT, Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB, and alpha-synuclein levels in both models after treatment with sitagliptin. However, GLP1 levels were not significantly restored, indicating a GLP1-independent mechanism. It also restored histopathological alterations and TH+ neuronal loss induced by rotenone and MPTP/P. These findings demonstrate that sitagliptin exhibits neuroprotective action mediated by upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.

• MeSH
• faktor 2 související s NF-E2 * metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• inhibitory dipeptidylpeptidasy 4 * farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neuroprotektivní látky * farmakologie   MeSH
• parkinsonské poruchy * metabolismus   farmakoterapie   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• rotenon MeSH
• signální transdukce účinky léků   MeSH
• sitagliptin fosfát * farmakologie   MeSH
• upregulace účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Accumulation of misfolded α-synuclein (α-Syn) leads to the formation of Lewy bodies and is a major hallmark of Parkinson's disease (PD). The accumulation of α-Syn involves several post-translational modifications. Recently, though, glycation of α-Syn (advanced glycation end products) and activation of the receptor for advanced glycation end products (RAGE) have been linked to neuroinflammation, which leads to oxidative stress and accumulation of α-Syn. The present study aims to detect the effect of glycated α-Syn (gly-α-Syn)-induced synucleinopathy and loss of dopaminergic (DAergic) neurons in the development of PD. We isolated, purified, and prepared glycated recombinant human α-Syn using d-ribose. Gly-α-Syn was characterized by SDS-PAGE, intact mass analysis, and bottom-up peptide sequence through LC-HRMS/MS. The aggregation propensity of gly-α-Syn has been verified by morphological and shape analysis through Bio-AFM. The gly-α-Syn (2 μg/μL) was injected stereotaxically in the substantia nigra (SN) of ICR mice (3-4 months) and compared with the normal α-Syn, d ribose, and Tris-HCl/artificial CSF groups. 56 days postsurgery (DPS), an immunohistochemical examination was conducted to investigate gly-α-Syn-induced α-Syn accumulation, neuroinflammation, and neurodegeneration. The glycation of α-Syn led to the expression of transglutaminase 2 (TGM2), an enzyme that cross-linked with AGEs and may have caused the accumulation of α-Syn. Significant RAGE activation was also observed in gly-α-Syn, which might have induced glial cell activation, resulting in oxidative stress and, ultimately, apoptosis of dopaminergic neurons. It is important to note that TGM2, phosphorylated α-Syn, RAGE expression, and glial cell activation were only found in the gly-α-Syn group and not in the other groups. This suggests that gly-α-Syn plays a major role in synucleinopathy, neuroinflammation, and neurodegeneration. Overall, the present study demonstrated glycation of α-Syn as one of the important age-associated post-translational modifications that are involved in the degeneration of dopaminergic neurons, at least in a subset of the diabetic patients susceptible to developing PD.

• MeSH
• alfa-synuklein * metabolismus   MeSH
• dopaminergní neurony * metabolismus   patologie   účinky léků   MeSH
• glykosylace MeSH
• lidé MeSH
• myši inbrední ICR MeSH
• myši MeSH
• neuroglie * metabolismus   patologie   účinky léků   MeSH
• oxidační stres MeSH
• Parkinsonova nemoc * metabolismus   patologie   MeSH
• produkty pokročilé glykace metabolismus   MeSH
• receptor pro konečné produkty pokročilé glykace metabolismus   MeSH
• substantia nigra metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue. METHODS: We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF). RESULTS: We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels. CONCLUSIONS: Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.

• MeSH
• alfa-synuklein * metabolismus   MeSH
• biologické markery metabolismus   MeSH
• chaperon endoplazmatického retikula BiP * metabolismus   MeSH
• demence s Lewyho tělísky * patologie   metabolismus   MeSH
• eukaryotický iniciační faktor 2 * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozek metabolismus   patologie   MeSH
• neurotrofní faktory metabolismus   MeSH
• proteiny teplotního šoku * metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální dráha UPR * fyziologie   MeSH
• stres endoplazmatického retikula fyziologie   MeSH
• upregulace * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Isolated REM sleep behavior disorder (iRBD) is an early stage of synucleinopathy with most patients progressing to Parkinson's disease (PD) or related conditions. Quantitative susceptibility mapping (QSM) in PD has identified pathological iron accumulation in the substantia nigra (SN) and variably also in basal ganglia and cortex. Analyzing whole-brain QSM across iRBD, PD, and healthy controls (HC) may help to ascertain the extent of neurodegeneration in prodromal synucleinopathy. 70 de novo PD patients, 70 iRBD patients, and 60 HCs underwent 3 T MRI. T1 and susceptibility-weighted images were acquired and processed to space standardized QSM. Voxel-based analyses of grey matter magnetic susceptibility differences comparing all groups were performed on the whole brain and upper brainstem levels with the statistical threshold set at family-wise error-corrected p-values <.05. Whole-brain analysis showed increased susceptibility in the bilateral fronto-parietal cortex of iRBD patients compared to both PD and HC. This was not associated with cortical thinning according to the cortical thickness analysis. Compared to iRBD, PD patients had increased susceptibility in the left amygdala and hippocampal region. Upper brainstem analysis revealed increased susceptibility within the bilateral SN for both PD and iRBD compared to HC; changes were located predominantly in nigrosome 1 in the former and nigrosome 2 in the latter group. In the iRBD group, abnormal dopamine transporter SPECT was associated with increased susceptibility in nigrosome 1. iRBD patients display greater fronto-parietal cortex involvement than incidental early-stage PD cohort indicating more widespread subclinical neuropathology. Dopaminergic degeneration in the substantia nigra is paralleled by susceptibility increase, mainly in nigrosome 1.

• MeSH
• lidé MeSH
• mozek diagnostické zobrazování   patologie   MeSH
• Parkinsonova nemoc * komplikace   MeSH
• porucha chování v REM spánku * diagnostické zobrazování   MeSH
• substantia nigra diagnostické zobrazování   patologie   MeSH
• synukleinopatie * komplikace   patologie   MeSH
• železo MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Léčba Parkinsonovy nemoci je v současnosti stále léčbou symptomatickou a její management je primárně zaměřen na kontrolu motorických projevů. Hlavním pilířem současné terapie zůstávají dopaminergní preparáty nahrazující působení chybějícího dopaminu. Významného pokroku bylo v posledních desetiletích dosaženo v možnostech terapie pokročilého stadia onemocnění pomocí intervenčních metod, jako je léčba pumpovými systémy a hluboká mozková stimulace. Důležitou součástí léčby je ovlivnění non-motorických symptomů, které významně ovlivňují kvalitu života pacientů. Nové léčebné strategie schopné ovlivnit rozvoj a progresi onemocnění, které jsou stále ve fázi preklinického a klinického výzkumu, zahrnují nejrůznější léčebné postupy s cílem ovlivnit tvorbu a agregaci patologických forem alfa-synukleinu a modifikovat šíření patologického procesu v mozku.

Despite intensive research, the current treatment of Parkinson's disease is still symptomatic treatment and its management is primarily aimed at controlling motor symptoms. Dopaminergic agents that replace the action of the missing dopamine remain the mainstay of current therapy. In recent decades, significant progress has been made in the treatment of advanced stage of disease using interventional methods such as treatment with pump systems and deep brain stimulation. An important part of the treatment is the influence of non-motor symptoms, which significantly affect the quality of life of patients. New treatment strategies capable to affect the development and progression of the disease, which are still in the preclinical and clinical research phase, include various treatment procedures with the aim to influence the formation and aggregation of pathological forms of alpha-synuclein and modify the spread of the pathological process in the brain.

• MeSH
• agonisté dopaminu farmakologie   klasifikace   terapeutické užití   MeSH
• amantadin farmakologie   terapeutické užití   MeSH
• cholinergní antagonisté farmakologie   klasifikace   terapeutické užití   MeSH
• hluboká mozková stimulace metody   MeSH
• inhibitory katechol-O-methyltransferasy farmakologie   klasifikace   terapeutické užití   MeSH
• inhibitory MAO farmakologie   klasifikace   terapeutické užití   MeSH
• levodopa farmakologie   terapeutické užití   MeSH
• lidé MeSH
• motorické poruchy diagnóza   farmakoterapie   MeSH
• Parkinsonova nemoc * diagnóza   farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Neurodegenerative disease (ND) incidence has recently increased due to improved life expectancy. Alzheimer's (AD) or Parkinson's disease (PD) are the most prevalent NDs. Both diseases are poly genetic, multifactorial and heterogenous. Preventive medicine, a healthy diet, exercise, and controlling comorbidities may delay the onset. After the diseases are diagnosed, therapy is needed to slow progression. Recent studies show that local, peripheral and age-related inflammation accelerates NDs' onset and progression. Patients with autoimmune disorders like inflammatory bowel disease (IBD) could be at higher risk of developing AD or PD. However, no increase in ND incidence has been reported if the patients are adequately diagnosed and treated. Autoantibodies against abnormal tau, β amyloid and α- synuclein have been encountered in AD and PD and may be protective. This discovery led to the proposal of immune-based therapies for AD and PD involving monoclonal antibodies, immunization/ vaccines, pro-inflammatory cytokine inhibition and anti-inflammatory cytokine addition. All the different approaches have been analysed here. Future perspectives on new therapeutic strategies for both disorders are concisely examined.

• MeSH
• alfa-synuklein MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• autoimunita MeSH
• autoimunitní nemoci * MeSH
• cytokiny MeSH
• lidé MeSH
• neurodegenerativní nemoci * terapie   MeSH
• Parkinsonova nemoc * farmakoterapie   MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• Alzheimerova nemoc krev   mozkomíšní mok   patologie   MeSH
• biologické markery * MeSH
• demence * krev   mozkomíšní mok   patologie   MeSH
• diferenciální diagnóza MeSH
• lidé MeSH
• synukleinopatie diagnóza   klasifikace   krev   mozkomíšní mok   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• úvodní články MeSH