High-oligomeric and low-total-?-synuclein cerebrospinal fluid (CSF) levels have been found in Parkinson's disease (PD), but with inconsistent or limited data, particularly on their clinical and structural correlates in earliest (premotor) or latest (dementia) PD stages. We determined CSF oligomeric- and total-?-synuclein in 77 subjects: 23 with idiopathic REM-sleep behaviour disorder (iRBD, a condition likely to include a remarkable proportion of subjects in the premotor stage of PD) and 41 with PD [21 non-demented (PDND) + 20 demented (PDD)], intended to reflect the premotor-motor-dementia PD continuum, along with 13 healthy controls. The study protocol also included the Unified PD Rating Scale motor-section (UPDRS-III), mini mental state examination (MMSE), neuropsychological cognitive testing, 3T brain MRI for cortical-thickness analyses, CSF ? and CSF A?. CSF oligomeric-?-synuclein was higher in PDND than iRBD and in PDD than iRBD and controls, and correlated with UPDRS-III, MMSE, semantic fluency and visuo-perceptive scores across the proposed premotor-motor-dementia PD continuum (iRBD + PDND + PDD). CSF total-?-synuclein positively correlated with age, CSF A?, and, particularly, CSF ?, tending towards lower levels in PD (but not iRBD) vs. controls only when controlling for CSF ?. Low CSF total-?-synuclein was associated with dysfunction in phonetic-fluency (a frontal-lobe function) in PD and with frontal cortical thinning in iRBD and PDND independently of CSF ?. Conversely, the associations of high (instead of low) CSF total-?-synuclein with posterior-cortical neuropsychological deficits in PD and with posterior cortical thinning in PDD were driven by high CSF ?. These findings suggest that CSF oligomeric- and total-?-synuclein have different clinical, neuropsychological and MRI correlates across the proposed premotor-motor-dementia PD continuum. CSF total-?-synuclein correlations with CSF ? and A? support the hypothesis of an interaction among these proteins in PD, with CSF ? probably influencing the presence of high (instead of low) CSF total-?-synuclein and its correlates mostly in the setting of PD-related dementia.
Nigrostriatal involvement is considered an additional feature in the new consensus criteria for the diagnosis of the cerebellar variant of multiple system atrophy (MSA-C). However, so far, only a few studies, which include a relative small number of patients, give support to this criterion. Our objective was to assess nigrostriatal dopaminergic innervation in patients with MSA-C without parkinsonism by use of dopamine transporter single photon emission computed tomography (DAT SPECT). Thirteen patients that fulfilled criteria for possible or probable MSA-C and presented no parkinsonian signs, and 12 age-matched healthy controls underwent ((123)I-2-?-carbomethoxy-3?-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ([(123)I]FP-CIT) SPECT. Patients were also evaluated through the Unified Multiple System Atrophy Rating Scale (UMSARS) and brain magnetic resonance imaging (MRI). The mean duration of the cerebellar syndrome was 3.8 ± 1.7 years. DAT SPECT showed a significant decrease of striatal [(123)I]FP-CIT uptake ratios in patients (p < 0.001). Radiotracer uptake reduction was 21% in the entire striatum, 19% in putamen, and 24% in caudate nuclei. Striatal binding ratios were within the normal range in 3 patients. We did not find correlation between striatal uptake and disease duration, age of patients, UMSARS-II score, and pontine diameter. [(123)I]FP-CIT SPECT shows that most but not all MSA-C patients without parkinsonism have subclinical nigrostriatal dopaminergic denervation which is not related to disease duration, cerebellar dysfunction, or pontine atrophy.
The present study examined the testicular structure and the seminal pathway in freshwater fish Leporinus macrocephalus (Garavello and Britski, 1988). Twenty-five specimens of this species were studied. Testicular structure was analyzed using light and transmission electron microscopy. The testicular main ducts were examined by means of conventional histology, corrosion-cast technique and scanning electron microscopy. Additional techniques were applied for polysaccharides histochemistry and immunohistochemistry for androgen receptor. The testicular parenchyma was classified as the anastomosing tubular testis type with spermatogonia occurring along the lengths of the seminiferous tubules. The seminiferous tubules emptied directly into the testicular main ducts. The wall of the testicular main ducts in L. macrocephalus consisted of three layers: epithelium, connective tissue and peritoneum. The epithelium changed from simple cuboidal to pseudostratified. The histochemical analysis revealed the presence of granules PAS positive in the epithelial cells. The immunoreactivity to androgen receptor was noted in the testicular main ducts through all cytoplasmic areas of epithelial cells.
Cerebrospinal fluid (CSF) tau and phospho-tau levels have been associated with certain tau gene variants and low CSF amyloid-? (A?) levels in Alzheimer disease (AD), constituting potential biomarkers of molecular mechanisms underlying neurodegeneration. We aimed to assess whether such CSF-genetic endophenotypes are also present in Parkinson disease (PD). CSF tau, phospho-tau and A? levels were obtained from 38 PD patients (19 with dementia) using specific ELISA techniques. All cases were genotyped for a series of tau gene polymorphisms (rs1880753, rs1880756, rs1800547, rs1467967, rs242557, rs2471738 and rs7521). The A-allele rs242557 polymorphism was the only tau gene variant significantly associated with higher CSF tau and phospho-tau levels, under both dominant and dose-response model. This association depended on the presence of dementia, and was only observed in individuals with low (<500pg/mL) CSF A? levels. Such genetic-CSF endophenotypes are probably a reflection of the presence of AD-like molecular changes in part of PD patients in the setting of dementia.
Excessive daytime sleepiness is common in Parkinsons disease and has been associated with Parkinsons disease-related dementia. Narcoleptic features have been observed in Parkinsons disease patients with excessive daytime sleepiness and hypocretin cell loss has been found in the hypothalamus of Parkinsons disease patients, in association with advanced disease. However, studies on cerebrospinal fluid levels of hypocretin-1 (orexin A) in Parkinsons disease have been inconclusive. Reports of sleep studies in Parkinsons disease patients with and without excessive daytime sleepiness have also been disparate, pointing towards a variety of causes underlying excessive daytime sleepiness. In this study, we aimed to measure cerebrospinal fluid hypocretin-1 levels in Parkinsons disease patients with and without dementia and to study their relationship to dementia and clinical excessive daytime sleepiness, as well as to describe potentially related sleep architecture changes. Twenty-one Parkinsons disease patients without dementia and 20 Parkinsons disease patients with dementia, along with 22 control subjects without sleep complaints, were included. Both Epworth sleepiness scale, obtained with the help of the caregivers, and mini-mental state examination were recorded. Lumbar cerebrospinal fluid hypocretin-1 levels were measured in all individuals using a radio-immunoassay technique. Additionally, eight Parkinsons disease patients without dementia and seven Parkinsons disease patients with dementia underwent video-polysomnogram and multiple sleep latencies test. Epworth sleepiness scale scores were higher in Parkinsons disease patients without dementia and Parkinsons disease patients with dementia than controls (P < 0.01) and scores >10 were more frequent in Parkinsons disease patients with dementia than in Parkinsons disease patients without dementia (P = 0.04). Cerebrospinal fluid hypocretin-1 levels were similar among groups (controls = 321.15 +/- 47.15 pg/ml; without dementia = 300.99 +/- 58.68 pg/ml; with dementia = 309.94 +/- 65.95 pg/ml; P = 0.67), and unrelated to either epworth sleepiness scale or mini-mental state examination. Dominant occipital frequency awake was slower in Parkinsons disease patients with dementia than Parkinsons disease patients without dementia (P = 0.05). Presence of slow dominant occipital frequency and/or loss of normal non-rapid eye movement sleep architecture was more frequent among Parkinsons disease patients with dementia (P = 0.029). Thus, excessive daytime sleepiness is more frequent in Parkinsons disease patients with dementia than Parkinsons disease patients without dementia, but lumbar cerebrospinal fluid hypocretin-1 levels are normal and unrelated to severity of sleepiness or the cognitive status. Lumbar cerebrospinal fluid does not accurately reflect the hypocretin cell loss known to occur in the hypothalamus of advanced Parkinsons disease. Alternatively, mechanisms other than hypocretin cells dysfunction may be responsible for excessive daytime sleepiness and the sleep architecture alterations seen in these patients.
Alzheimers disease (AD)-pathology may play a role in Parkinsons disease (PD)-related dementia (PDD). The aim of this study was to assess cerebrospinal fluid (CSF) levels of tau, phospho-tau, and beta-amyloid, proposed AD biomarkers, and their relationship with cognitive function in PD. Forty PD patients [20 nondemented (PDND); 20 PDD] and 30 controls underwent CSF tau, phospho-tau, and beta-amyloid analysis using specific ELISA techniques. All PD patients and 15 controls underwent neuropsychological testing of fronto-subcortical (attention, fluency) and neocortical (memory, naming, visuoperceptive) functions. CSF markers levels were compared between groups, and compared and correlated with neuropsychological measures in PDND and PDD separately and as a continuum (PD). CSF tau and phospho-tau were higher in PDD than in PDND and controls (P < 0.05). CSF beta-amyloid ranged from high (controls) to intermediate (PDND) and low (PDD) levels (P < 0.001). In all PD and PDD patients, high CSF tau and phospho-tau were associated with impaired memory and naming. In PDND, CSF beta-amyloid was related with phonetic fluency. These findings suggest underlying AD-pathology in PDD in association with cortical cognitive dysfunction, and that low CSF beta-amyloid in PDND patients with impaired phonetic fluency can constitute an early marker of cognitive dysfunction.
The H1 MAPT haplotype in the 17q21 chromosomal region has been associated with several neurodegenerative diseases. Some reports have suggested that there is an association between genetic variants within the H1 haplotype with Parkinsons disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Here we report a genetic association study using seven SNPs located along the 17q21 region, in PD patients and controls. In addition, we compared these results with a dataset of previously published PSP/CBD patients from the same population. Our results show that the H1-rs242557(G) allele sub-haplotype is increased in PD (p=0.005), while the H1-rs242557(A) allele sub-haplotype is increased in PSP/CBD (p=0.0002), comparing to controls. The rs242557 polymorphism could act modulating the phenotypic expressivity of the H1 risk on these parkinsonisms. The location of this polymorphism in the 5 regulatory region of MAPT gene suggests the presence of a functional mechanism involved in the variation of MAPT expression levels.
Paracoccidioidomycosis is a granulomatous systemic mycosis endemic in Brazil and other Latin America countries. A DNA vaccine encoding the immunoprotective peptide 10 (P10) significantly reduced the fungal burden in mice when given prior to or after intratracheal challenge with Paracoccidioides brasiliensis. Presently, the generation/expansion of CD4+ CD44hi memory T cells as well as Foxp3+ Treg cells in mice immunized with the DNA vaccine (pcDNA3-P10) before and after infection with P. brasiliensis was investigated. Memory CD4+ CD44hi T cells simultaneously with Foxp3+ Treg cells increased in the spleens and lungs of pcDNA3-P10 immunized mice on day 0, 30, 60 and 120 postinfection. Histopathology of the lung tissue showed minimal inflammation in immunized mice compared with the unimmunized group, suggesting a role for regulatory T cells in controlling the immunopathology. The DNA vaccine shows that the repeated immunization generates memory cells and regulatory T cells that replace the initially protective pro-inflammatory T cells conferring a long term protection while preserving the integrity of the infected tissue.
Paraneoplastic cerebellar degeneration (PCD) is characterized by a subacute, severe pancerebellar syndrome, which is related to an underlying tumor. The presence of CSF or serum onconeural antibodies confirms the diagnosis and indicates the underlying tumor type. However, the association between PCD and extragonadal germ cell tumors with the absence of an onconeural antibody has rarely been described. We present a 55-year-old man who developed a pancerebellar syndrome, which made him unable to walk alone after 10months. Routine blood analysis, brain MRI and CSF examination were normal. Despite onconeural antibodies were negative, a whole body PET-CT scan showed a hypermetabolic nodule in the thymus, which was removed, and a hypometabolic presacral mass. The pathologic study revealed a germinoma surrounded by a pronounced inflammatory infiltrate. Shortly after, the patient clearly improved his symptoms, before receiving chemotherapy and prednisone. The cerebellar ataxia worsened when steroids were reduced below 30mg/day. Testicular sonography showed a suspicious lesion in one testicle, but no malignancy was found after orchiectomy. The presacral mass was removed after chemotherapy disclosing a mature teratoma. Our patient emphasizes that despite the absence of onconeural antibodies, studies to rule out an underlying tumor are mandatory in patients with subacute cerebellar ataxia.
Regional brain grey matter volume (GMV) reductions and abnormal cerebrospinal fluid (CSF) levels of ? and A?, extensively studied as biomarkers of Alzheimers disease (AD), have also been reported in Parkinsons disease (PD) and related dementia (PDD). However, the relationship between these CSF and MRI biomarkers in PD and PDD remains unexplored. We studied these associations in 33 PD patients (18 with no dementia [PDND]; 15 fulfilling PDD criteria) and 12 neurologically unimpaired controls, with neuropsychological assessment, CSF ELISA studies, and voxel-based morphometry (VBM) analysis of high-field brain MRI. Neuropsychological assessment showed a gradation in cognitive performance from controls to PDND (significantly worse on visuospatial performance) and then to PDD (more impaired on memory, naming, fluency and visuospatial functions). No CSF-VBM correlations were found in controls or PDND patients. In contrast, in the analysis of both the PDD subgroup and the entire PD (PDND + PDD) sample, we found significant negative CSF-GMV correlations for ? and phospho-? and significant positive CSF-GMV correlations for A? in mostly frontal and temporal structures. The correlations in the entire PD sample fitted with a linear model and were thus unlikely to have been driven solely by the PDD subgroup. Additionally, an association between both the CSF markers and the CSF-associated GMV reductions with several neuropsychological functions was found. We interpret that CSF markers of AD pathology are associated with VBM-measures of brain atrophy in PD-related dementia and within the PD cognitive continuum, and deserve further attention as putative biomarkers of cognitive impairment and dementia in PD.
Related JoVE Video
Journal of Visualized Experiments
What is Visualize?
JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.
How does it work?
We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.
Video X seems to be unrelated to Abstract Y...
In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.