BACKGROUND: Various cerebrospinal fluid (CSF) biomarkers are studied in Parkinson's disease (PD) and atypical parkinsonian syndromes (APS). Several studies found reduced 5-hydroxyindoleacetic acid (5-HIAA), the main serotonin metabolite, in PD. There is little evidence regarding its levels in APS. METHODS: We measured 5-HIAA in the CSF of 90 PD patients, 16 MSA patients, 26 progressive supranuclear palsy (PSP) patients, 11 corticobasal syndrome (CBS) patients, and 31 controls. We also compared the values in depressed and nondepressed patients. RESULTS: There was a statistically significant difference in CSF 5-HIAA in PD and MSA compared to the control group (median in PD 15.8 μg/L, in MSA 13.6 μg/L vs. 24.3 μg/L in controls; p = 0.0008 in PD, p = 0.006 in MSA). There was no statistically significant difference in CSF 5-HIAA in PSP and CBS compared to the control group (median in PSP 22.7 μg/L, in CBS 18.7 μg/L vs. 24.3 μg/L in controls; p = 1 in both PSP and CBS). CSF 5-HIAA levels were lower in PD patients with depression compared to PD patients without depression (median 8.34 vs. 18.48, p < 0.0001). CONCLUSIONS: CSF 5-HIAA is decreased in PD and MSA. The CSF 5-HIAA levels in PSP and CBS did not differ from those of the control group. There was a tendency toward lower CSF 5-HIAA in MSA than in PD; however, the results did not reach statistical significance. These results may be explained by more severe damage of the serotonergic system in synucleinopathies (PD and MSA) than in tauopathies (PSP and CBS).
- Klíčová slova
- 5-Hydroxyindoleacetic acid, Atypical parkinsonian syndromes, Cerebrospinal fluid, Parkinson’s disease,
- MeSH
- diferenciální diagnóza MeSH
- kyselina hydroxyindoloctová MeSH
- lidé MeSH
- multisystémová atrofie * diagnóza MeSH
- Parkinsonova nemoc * diagnóza MeSH
- parkinsonské poruchy * metabolismus MeSH
- progresivní supranukleární obrna * MeSH
- tauopatie * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- kyselina hydroxyindoloctová MeSH
BACKGROUND: Huntington's disease (HD) is a devastating neurodegenerative disorder caused by CAG triplet expansions in the huntingtin gene. Oxidative stress is linked to HD pathology, although it is not clear whether this is an effect or a mediator of disease. The transgenic (TgHD) minipig expresses the N-terminal part of human-mutated huntingtin and represents a unique model to investigate therapeutic strategies towards HD. A more detailed characterization of this model is needed to fully utilize its potential. METHODS: In this study, we focused on the molecular and cellular features of fibroblasts isolated from TgHD minipigs and the wild-type (WT) siblings at different ages, pre-symptomatic at the age of 24-36 months and with the onset of behavioural symptoms at the age of 48 months. We measured oxidative stress, the expression of oxidative stress-related genes, proliferation capacity along with the expression of cyclin B1 and D1 proteins, cellular permeability, and the integrity of the nuclear DNA (nDNA) and mitochondrial DNA in these cells. RESULTS: TgHD fibroblasts isolated from 48-month-old animals showed increased oxidative stress, which correlated with the overexpression of SOD2 encoding mitochondrial superoxide dismutase 2, and the NEIL3 gene encoding DNA glycosylase involved in replication-associated repair of oxidized DNA. TgHD cells displayed an abnormal proliferation capacity and permeability. We further demonstrated increased nDNA damage in pre-symptomatic TgHD fibroblasts (isolated from animals aged 24-36 months). CONCLUSIONS: Our results unravel phenotypic alterations in primary fibroblasts isolated from the TgHD minipig model at the age of 48 months. Importantly, nDNA damage appears to precede these phenotypic alterations. Our results highlight the impact of fibroblasts from TgHD minipigs in studying the molecular mechanisms of HD pathophysiology that gradually occur with age.
- Klíčová slova
- Permeability, DNA damage, Huntington’s disease, Large-animal model, Minipig model, Mutated huntingtin, Oxidative stress, Primary fibroblasts, Proliferation,
- MeSH
- buněčné dělení MeSH
- fenotyp MeSH
- fibroblasty metabolismus MeSH
- geneticky modifikovaná zvířata MeSH
- lidé MeSH
- miniaturní prasata MeSH
- mitochondriální DNA genetika MeSH
- N-glykosylhydrolasy biosyntéza genetika MeSH
- oxidační stres MeSH
- peroxidace lipidů MeSH
- poškození DNA MeSH
- prasata MeSH
- primární buněčná kultura MeSH
- protein huntingtin genetika metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- regulace genové exprese MeSH
- stárnutí metabolismus MeSH
- superoxiddismutasa biosyntéza genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- HTT protein, human MeSH Prohlížeč
- mitochondriální DNA MeSH
- N-glykosylhydrolasy MeSH
- protein huntingtin MeSH
- reaktivní formy kyslíku MeSH
- superoxiddismutasa MeSH
- superoxide dismutase 2 MeSH Prohlížeč
BACKGROUND: Huntington disease (HD) is an incurable neurodegenerative disease caused by the expansion of a polyglutamine sequence in a gene encoding the huntingtin (Htt) protein, which is expressed in almost all cells of the body. In addition to small animal models, new therapeutic approaches (including gene therapy) require large animal models as their large brains are a more realistic model for translational research. OBJECTIVE: In this study, we describe phenotype development in transgenic minipigs (TgHD) expressing the N-terminal part of mutated human Htt at the age of 24 months. METHODS: TgHD and wild-type littermates were compared. Western blot analysis and subcellular fractionation of different tissues was used to determine the fragmentation of Htt. Immunohistochemistry and optical analysis of coronal sections measuring aggregates, Htt expression, neuroinflammation, and myelination was applied. Furthermore, the expression of Golgi protein acyl-CoA binding domain containing 3 (ACBD3) was analyzed. RESULTS: We found age-correlated Htt fragmentation in the brain. Among various tissues studied, the testes displayed the highest fragmentation, with Htt fragments detectable even in cell nuclei. Also, Golgi protein ACBD3 was upregulated in testes, which is in agreement with previously reported testicular degeneration in TgHD minipigs. Nevertheless, the TgHD-specific mutated Htt fragments were also present in the cytoplasm of striatum and cortex cells. Moreover, microglial cells were activated and myelination was slightly decreased, suggesting the development of a premanifest stage of neurodegeneration in TgHD minipigs. CONCLUSIONS: The gradual development of a neurodegenerative phenotype, ac-companied with testicular degeneration, is observed in 24- month-old TgHD minipigs.
- Klíčová slova
- ACBD3, Aggregates, Fragments, Huntington disease, Mutant huntingtin, Pig model,
- MeSH
- fenotyp MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc genetika MeSH
- jaderné proteiny genetika MeSH
- lidé MeSH
- membránové proteiny metabolismus MeSH
- miniaturní prasata MeSH
- modely nemocí na zvířatech MeSH
- mozek metabolismus MeSH
- prasata MeSH
- protein huntingtin genetika MeSH
- proteiny nervové tkáně genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- jaderné proteiny MeSH
- membránové proteiny MeSH
- protein huntingtin MeSH
- proteiny nervové tkáně MeSH
BACKGROUND: Huntington disease (HD) is a fatal neurodegenerative disorder involving reduced muscle coordination, mental and behavioral changes, and testicular degeneration. In order to further clarify the decreased fertility and penetration ability of the spermatozoa of transgenic HD minipig boars (TgHD), we applied a set of mitochondrial metabolism (MM) parameter measurements to this promising biological material, which can be collected noninvasively in longitudinal studies. OBJECTIVE: We aimed to optimize methods for MM measurements in spermatozoa and to establish possible biomarkers of HD in TgHD spermatozoa expressing the N-terminal part of mutated human huntingtin. METHODS: Semen samples from 12 TgHD and wild-type animals, aged 12-65 months, were obtained repeatedly during the study. Respiration was measured by polarography, MM was assessed by the detection of oxidation of radiolabeled substrates (mitochondrial energy-generating system; MEGS), and the content of the oxidative phosphorylation system subunits was detected by Western blot. Three possibly interfering factors were statistically analyzed: the effect of HD, generation and aging. RESULTS: We found 5 MM parameters which were significantly diminished in TgHD spermatozoa and propose 3 specific MEGS incubations and complex I-dependent respiration as potential biomarkers of HD in TgHD spermatozoa. CONCLUSIONS: Our results suggest a link between the gain of toxic function of mutated huntingtin in TgHD spermatozoa and the observed MM and/or glycolytic impairment. We determined 4 biomarkers useful for HD phenotyping and experimental therapy monitoring studies in TgHD minipigs.
- Klíčová slova
- Huntington disease, Large-animal model, Mitochondrial metabolism, Mutant huntingtin, Spermatozoa,
- MeSH
- dýchání MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc komplikace genetika patologie MeSH
- kyseliny trikarboxylové metabolismus MeSH
- lidé MeSH
- miniaturní prasata MeSH
- mitochondriální proteiny metabolismus MeSH
- mitochondrie metabolismus MeSH
- mutace genetika MeSH
- oxidativní fosforylace MeSH
- prasata MeSH
- protein huntingtin genetika MeSH
- pyruvátdehydrogenasový komplex metabolismus MeSH
- sperma metabolismus MeSH
- spermie metabolismus patologie MeSH
- trinukleotidové repetice genetika MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- HTT protein, human MeSH Prohlížeč
- kyseliny trikarboxylové MeSH
- mitochondriální proteiny MeSH
- protein huntingtin MeSH
- pyruvátdehydrogenasový komplex MeSH
BACKGROUND: Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. OBJECTIVE: We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. METHODS: In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt. RESULTS: Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome. CONCLUSIONS: The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt.
- MeSH
- genetické vektory MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc metabolismus patologie MeSH
- Lentivirus genetika MeSH
- lidé MeSH
- miniaturní prasata MeSH
- modely nemocí na zvířatech MeSH
- mutace * MeSH
- počet spermií MeSH
- prasata MeSH
- proliferace buněk fyziologie MeSH
- protein huntingtin genetika metabolismus MeSH
- spermie metabolismus patologie MeSH
- stárnutí metabolismus patologie MeSH
- testis metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- HTT protein, human MeSH Prohlížeč
- protein huntingtin MeSH
BACKGROUND: Drug development for Alzheimer disease (AD) is challenged by the success in animal models tested in the Morris water maze (MWM) and the subsequent failures to meet primary outcome measures in phase II or III clinical trials in patients. The human variant of MWM (hMWM) enables us to examine allocentric and egocentric navigation as in the MWM. OBJECTIVE: It was the aim of this study to examine the utility of a computerized hMWM to assess the effects of donepezil in mild AD. METHODS: Donepezil 5 mg/day was started after initial hMWM testing in the treated group (n = 12), and after 28 days, the dose was increased to 10 mg/day. The performance after 3 months was compared to that of a non-treated group (n = 12). RESULTS: Donepezil stabilized or improved the spatial navigation performance after 3 months, especially in the allocentric delayed recall subtask (p = 0.014). CONCLUSIONS: The computerized hMWM has the potential to measure the effects of donepezil in mild AD. It is a sensitive cognitive outcome measure in AD clinical trials.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- cholinesterasové inhibitory terapeutické užití MeSH
- donepezil MeSH
- indany terapeutické užití MeSH
- lidé MeSH
- neuropsychologické testy * MeSH
- pilotní projekty MeSH
- piperidiny terapeutické užití MeSH
- počítače MeSH
- prostorové chování účinky léků MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cholinesterasové inhibitory MeSH
- donepezil MeSH
- indany MeSH
- piperidiny MeSH
While there is good evidence for altered resting-state networks, particularly the default mode network (DMN), in both Alzheimer's disease (AD) and amnestic mild cognitive impairment preceding AD, there are rather conflicting data on changes in the DMN in Parkinson's disease (PD) and PD with cognitive impairment. This paper will focus on DMN study results, particularly in PD, as assessed by functional MRI.
- MeSH
- Alzheimerova nemoc patofyziologie MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek patofyziologie MeSH
- nervové dráhy fyziologie MeSH
- odpočinek fyziologie MeSH
- Parkinsonova nemoc patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: TDP-43 proteinopathies represent a spectrum of neurodegenerative disorders. Variable clinical presentations including frontotemporal dementia, amyotrophic lateral sclerosis (ALS) and mixed forms are associated with the spatial heterogeneity of the TDP-43 pathology. Recent studies have emphasized the role of oligodendrocytes in the pathogenesis of ALS. OBJECTIVE: To evaluate whether TDP-43 proteinopathies are associated with an oligodendroglial response. METHODS: We performed a study on 7 controls and 10 diseased patients with spinal cord involvement. Using the oligodendroglia-specific antibody TPPP/p25, we assessed oligodendrocyte density in the lateral corticospinal tracts (LCSs) along with the presence of perineuronal oligodendrocytes (PNOGs) in the anterior horns. We performed a densitometry of myelin basic protein (MBP) immunoreactivity. The numbers of TDP-43 and p62 immunoreactive inclusions were counted in both the LCSs and the anterior horns. RESULTS: Double immunolabeling confirmed that oligodendrocytes harbor TDP-43 inclusions. In the LCSs, MBP density, but not the number of oligodendrocytes, was decreased in the diseased group. However, oligodendrocyte counts in the LCS correlated positively, and the density of MBP inversely, with the number of neuronal inclusions in the anterior horn, suggestive of a compensatory response of oligodendrocytes. The number of neurons with PNOGs correlated with the amount of inclusions. CONCLUSION: Our study further emphasizes the importance of oligodendroglia in the pathogenesis of TDP-43 proteinopathies with spinal cord involvement.
- MeSH
- buněčná inkluze metabolismus patologie MeSH
- buňky předních rohů míšních metabolismus patologie MeSH
- DNA vazebné proteiny metabolismus MeSH
- dospělí MeSH
- encefalitogenní základní proteiny metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mícha metabolismus patologie MeSH
- mladý dospělý MeSH
- motorické neurony metabolismus patologie MeSH
- oligodendroglie metabolismus patologie MeSH
- proteinopatie TDP-43 metabolismus patologie MeSH
- proteiny vázající RNA metabolismus MeSH
- pyramidové dráhy metabolismus patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- DNA vazebné proteiny MeSH
- encefalitogenní základní proteiny MeSH
- MBP protein, human MeSH Prohlížeč
- P62 protein, human MeSH Prohlížeč
- proteiny vázající RNA MeSH
- TARDBP protein, human MeSH Prohlížeč
BACKGROUND: Spatial navigation performance in the Hidden Goal Task (HGT), a real-space human analogue of the Morris Water Maze, can identify amnestic mild cognitive impairment (aMCI) patients with memory impairment of the hippocampal type, a known indicator of incipient Alzheimer's disease (AD). OBJECTIVE: Contrast results from computer versus real-space versions of the HGT. METHODS: A total of 42 aMCI patients were clinically and neuropsychologically classified into: (1) memory impairment of the hippocampal type--the hippocampal aMCI (HaMCI; n = 10) and (2) isolated retrieval impairment--the nonhippocampal aMCI (NHaMCI; n = 32). Results were compared to the control (n = 28) and AD (n = 21) groups. RESULTS: The HaMCI group, although similar to the NHaMCI group with respect to overall cognitive impairment, performed poorer on the computer version of the HGT and yielded parallel results to the real-space version. The two versions were strongly correlated. CONCLUSIONS: Both versions of the HGT can reliably identify aMCI with pronounced memory impairment of the hippocampal type. The computer version of the HGT may be a useful, relatively inexpensive screening tool for early detection of individuals at a high risk of AD.
- MeSH
- Alzheimerova nemoc komplikace diagnóza MeSH
- bludiště - učení fyziologie MeSH
- diagnóza počítačová metody MeSH
- kognitivní poruchy komplikace diagnóza MeSH
- lidé MeSH
- neuropsychologické testy MeSH
- progrese nemoci MeSH
- psychiatrické posuzovací škály MeSH
- regresní analýza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vnímání prostoru fyziologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
AIMS: Using fMRI, we evaluated the default mode network (DMN) and the extrastriate visual resting state network (ESV-RSN) in 14 patients with Parkinson's disease dementia (PDD) as compared with 18 patients with Parkinson's disease (PD) without dementia and 18 healthy controls (HC). METHODS: We analyzed the seed-based functional connectivity of both resting state data and deactivations during a visual complex scene-encoding task. RESULTS: Using the posterior cingulate cortex/precuneus as a seed for the DMN analysis, we observed significant decreases of connectivity in the right inferior frontal gyrus in PDD as compared to PD and HC. Using the caudate nucleus as a seed for the ESV-RSN analysis, we found significant decreases of connectivity in the left and right inferior occipital gyrus in PDD as compared to HC. CONCLUSION: Differences in functional connectivity patterns between PDD and PD/HC were observed in areas known to be engaged in stimulus-driven reorienting of attention and in visual processing.
- MeSH
- demence komplikace patologie MeSH
- dospělí MeSH
- kyslík krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mapování mozku MeSH
- neuropsychologické testy MeSH
- odpočinek * MeSH
- Parkinsonova nemoc komplikace patologie MeSH
- počítačové zpracování obrazu MeSH
- rozpoznávání (psychologie) MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- statistika jako téma MeSH
- světelná stimulace MeSH
- týlní lalok krevní zásobení patofyziologie MeSH
- zrakové dráhy krevní zásobení patofyziologie 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
- práce podpořená grantem MeSH
- Názvy látek
- kyslík MeSH
