Verbal adynamia in parkinsonian syndromes: behavioral correlates and neuroanatomical substrate.
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ABSTRACT:
SUBMITTER: Magdalinou NK
PROVIDER: S-EPMC6234546 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.
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Project description:Atypical parkinsonism or atypical parkinsonian syndromes (APS) refer to a group of neurodegenerative disorders which mimic typical Parkinson's disease but poorly respond to levodopa treatment and deteriorate faster. APS are very rare and among them, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) are the three relatively better characterized entities. The prevalence estimates of PSP, MSA, or CBD are mostly <10/105, and the incidence estimates are around 1/105 person-year; both estimates remain stable over the past few decades. The age at onset is relatively young for MSA at late 50s, followed by CBD at early 60s, and then PSP at late 60s. The gender difference is not significant in APS, although slight female predominance in CBD has been reported in literature. Little is known about genetic and environmental risk factors for PSP, MSA, and CBD; although the COQ2 mutation has been identified as a genetic risk for MSA, familial cases are extremely rare. Survival after symptom onset is generally within 10 years, but cases with longer disease duration do exist. Respiratory infection remains the major cause of death for APS, but cardiac arrest should be particularly considered in MSA. In addition to disease rarity, the phenotype-pathology discrepancy in APS makes the epidemiological studies even more challenging. Including biomarkers in future diagnostic criteria and establishing disease registry for collecting sufficient number of APS cases may increase the likelihood of finding modifiable risk factors for prevention and intervention.
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Project description:Background/objectiveParkinson's disease (PD) and the atypical parkinsonian syndromes multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are movement disorders associated with degeneration of the central nervous system. Degeneration of the retina has not been systematically compared in these diseases.MethodsThis cross-sectional study used spectral-domain optical coherence tomography with manual segmentation to measure the peripapillar nerve fiber layer, the macular thickness, and the thickness of all retinal layers in foveal scans of 40 patients with PD, 19 with MSA, 10 with CBS, 15 with PSP, and 35 age- and sex-matched controls.ResultsThe mean paramacular thickness and volume were reduced in PSP while the mean RNFL did not differ significantly between groups. In PSP patients, the complex of retinal ganglion cell- and inner plexiform layer and the outer nuclear layer was reduced. In PD, the inner nuclear layer was thicker than in controls, MSA and PSP. Using the ratio between the outer nuclear layer and the outer plexiform layer with a cut-off at 3.1 and the additional constraint that the inner nuclear layer be under 46 µm, we were able to differentiate PSP from PD in our patient sample with a sensitivity of 96% and a specificity of 70%.ConclusionDifferent parkinsonian syndromes are associated with distinct changes in retinal morphology. These findings may serve to facilitate the differential diagnosis of parkinsonian syndromes and give insight into the degenerative processes of patients with atypical parkinsonian syndromes.
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Project description:BackgroundBone health and fracture risk reduction are increasingly recognized as important issues in Parkinson's disease (PD). However, the evidence for fracture risk management in atypical parkinsonism (AP) is less clear. Guidance on management of bone health in PD has recently been published.ObjectivesTo evaluate the outcome of fracture risk assessment in a cohort of patients with AP, compared to a population with idiopathic PD.MethodsWe did a cross-sectional study of patients with PD or AP who had fracture risk assessed at two tertiary movement disorder centres. Data on fracture risk as assessed using QFracture and FRAX were collected. To assess for the effect of age on fracture risk we compared the risks of PD and AP patients aged ≤70 and >70 years.ResultsWe assessed 71 patients with AP and 267 with PD. Age, sex and body mass index were similar between groups; patients with AP were more likely to have fallen in the previous year. Major osteoporotic fracture risk was greater in patients with AP aged ≤70 compared to PD; no differences between groups were seen in those aged >70 years. 76% of those with AP, and 63% with PD, had an estimated fracture risk indicating bone-sparing treatment, but only 33% of patients with AP were receiving this where it was indicated.ConclusionThere is scope for considerable improvement in fracture risk assessment and treatment in atypical parkinsonism, taking into account the worse prognosis of this patient group.
| S-EPMC8015890 | biostudies-literature
Project description:The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non-fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson-plus syndromes in the past, they are now classified as FTD-related disorders, reflecting that they pathologically differ from α-synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.
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Project description:Neuropsychiatric symptoms are commonly observed as brain pathology progresses with dementia. Behavioral and affective disturbances underly the distinct neuroanatomical basis of typical symptoms of cognitive impairment; however it remains unclear whether enriched intellectual experience, such as educational attainment, can mitigate the effect of brain structural patterns on neuropsychiatric symptom severity. We utilized the Open Access Series of Imaging Studies (OASIS-3) dataset, which includes brain structural MRI and behavioral symptom evaluation. We included 904 older adults who were mostly cognitively normal, clinically diagnosed with very mild to moderate Alzheimer's disease, or other types of dementia. Canonical correlation analysis was used to identify the patterns of multivariate association between the gray matter structure and neuropsychiatric symptom severity. First, we identified two canonical modes capturing the distinct neuroanatomical basis of common and mood-specific factors of neuropsychiatric symptoms. The first common pattern reflected a smaller volume in the amygdala and adjacent temporal regional thickness. The second mood-specific pattern reflected patterns in lateral and orbital prefrontal regional thickness. In the external correlational analysis, the two canonical correlations reflected global brain volume and white matter lesions; however, the second pattern was not associated with functional impairments or cognitive function. Moreover, older adults with higher education showed an attenuated severity of behavioral symptoms, even with the presence of a brain structural pattern. Our findings suggest that educational attainment, as a proxy of cognitive reserve, can mitigate the severity of behavioral and affective symptoms of dementia.
| S-EPMC7569337 | biostudies-literature
Project description:Parkinsonism might precede, coincide, or follow the behavioral or language-predominant cognitive impairments characteristic of frontotemporal dementia (FTD). In this study, we analyze the hexanucleotide repeat expansions within C9orf72 gene in various parkinsonian syndromes because it is a recently identified important genetic cause of FTD. The expanded hexanucleotide repeat is only identified in our familial FTD patients but not in patients with predominant parkinsonism. The lack of association between abnormal C9orf72 repeat expansion and parkinsonian syndromes might imply pathogenic mechanisms other than tau or Lewy body pathology.
| S-EPMC4022748 | biostudies-literature
Project description:IntroductionNeuroinflammation has been established to be part of the neuropathological changes in Parkinson's disease (PD) and atypical parkinsonism (APD). Activated microglia play a key role in neuroinflammation by release of cytokines. Evidence of the disparity, if any, in the neuroinflammatory response between PD and APD is sparse. In this study, we investigated CSF cytokine profiles in patients with PD, multiple system atrophy (MSA), or progressive supranuclear palsy (PSP).MethodsOn a sensitive electrochemiluminescence-based platform (Quickplex, Meso Scale Discovery®), we examined a panel of C-reactive protein (CRP) and eight selected cytokines, IFN-γ, IL-10, IL-18, IL-1β, IL-4, IL-6, TGF-β1, and TNF-α, among patients with PD (n = 46), MSA (n = 35), and PSP (n = 39) or controls (n = 31). Additionally, CSF total tau protein levels were measured as a marker of nonspecific neurodegeneration for correlation estimates.ResultsCRP and the pro-inflammatory cytokines TNF-α, IL-1β, and Il-6 were statistically significantly elevated in MSA and PSP patients compared to PD patients but not compared to control patients. No analytes differed statistically significantly between MSA and PSP patients. The best diagnostic discrimination, evaluated by ROC curve (AUC 0.77, p = 007, 95% CI 0.660-0.867), between PD and MSA patients was seen for a subset of analytes: CRP, TNF-α, IL-1β, and IFN-γ.ConclusionAmong the investigated cytokines and CRP, we found a statistically significant increase of microglia-derived cytokines in MSA and PSP patients compared to PD patients.
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Project description: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), trying to elucidate their value as a marker of these diseases. Other studies addressed the potential therapeutic role of CoQ10 in PD and PS. We underwent a systematic review and a meta-analysis of studies measuring tissue CoQ10 concentrations which shows that, compared with controls, PD patients have decreased CoQ10 levels in the cerebellar cortex, platelets, and lymphocytes, increased total and oxidized CoQ10 levels in the cerebrospinal fluid and a non-significant trend toward decreased serum/plasma CoQ10 levels. Patients with multiple system atrophy (MSA) showed decreased CoQ10 levels in the cerebellar cortex, serum/plasma, cerebrospinal fluid, and skin fibroblasts. Patients with Lewy body dementia (LBD) showed decreased cerebellar cortex CoQ10, and those with progressive supranuclear palsy (PSP) had decreased CoQ10 levels in the cerebrospinal fluid. A previous meta-analysis of studies addressing the therapeutic effects of CoQ10 in PD showed a lack of improvement in patients with early PD. Results of the treatment with CoQ10 in PSP should be considered preliminary. The potential role of CoQ10 therapy in the MSA and selected groups of PD patients deserves future studies.
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