Abstract
Background
Although aging is the leading risk factor for Alzheimer’s disease (AD), the exact mechanisms through which aging becomes pathogenic and triggers neurodegeneration have not yet ...been identified. Recent evidence suggests that AD is tightly correlated with the appearance of senescent cells and that mitochondrial dysfunction is a pathological feature occurring during senescence and AD. Additionally, studies have suggested that mitochondrial dysfunction and altered mitophagy might lead to Aβ accumulation. Our goal was to explore if a reduced removal of dysfunctional mitochondria during aging is a key contributor to amyloid pathology and neurodegeneration in AD.
Method
Since telomere shortening is a known trigger of cellular senescence, a telomerase‐deficient mouse model was used: Terc
−/−
. The brain proteome of Terc
−/−
mice was evaluated to validate classical and novel markers of senescence and investigate the alteration of key cellular pathways. Primary cultures and brain tissue from Terc
−/−
mice were evaluated for mitochondrial function/content and mitophagy alterations. Then, we explored the relationship between amyloid pathology and mitochondrial dysfunction by crossing the Terc
−/−
mice with an AD‐related amyloid mouse model (5xFAD) and exploring mitophagy alterations and amyloid‐β (Aβ) accumulation in disease‐vulnerable regions.
Result
Proteomic analysis revealed changes in proteins related to autophagy and mitochondrial functions during accelerated senescence. The mitophagy modulator BCL2/adenovirus E1B 19 kDa protein‐interacting protein 3 (BNIP3) was found downregulated in Terc
−/−
mice. We evidenced the presence of mitochondrial dysfunction and accumulation in senescent neurons. Additionally, we observed that senescence induces intraneuronal Aβ accumulation in specific brain regions (e.g., the subiculum) of an AD mouse model and we suggest that mitochondrial dysfunction and altered mitophagy might lead to Aβ accumulation.
Conclusion
Our results indicate that dysfunctional mitochondria accumulate during pathological aging due to a mitophagy impairment, which might contribute to AD neuropathology.
Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3' untranslated regions (3'UTRs). Yet, the post-transcriptional ...mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3' UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3' UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3' UTR-mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.
Multiple system atrophy (MSA) is a rare oligodendroglial synucleinopathy of unknown etiopathogenesis including two major clinical variants with predominant parkinsonism (MSA-P) or cerebellar ...dysfunction (MSA-C).
To identify novel disease mechanisms we performed a blood transcriptomic study investigating differential gene expression changes and biological process alterations in MSA and its clinical subtypes.
We compared the transcriptome from rigorously gender and age-balanced groups of 10 probable MSA-P, 10 probable MSA-C cases, 10 controls from the Catalan MSA Registry (CMSAR), and 10 Parkinson Disease (PD) patients.
Gene set enrichment analyses showed prominent positive enrichment in processes related to immunity and inflammation in all groups, and a negative enrichment in cell differentiation and development of the nervous system in both MSA-P and PD, in contrast to protein translation and processing in MSA-C. Gene set enrichment analysis using expression patterns in different brain regions as a reference also showed distinct results between the different synucleinopathies.
In line with the two major phenotypes described in the clinic, our data suggest that gene expression and biological processes might be differentially affected in MSA-P and MSA-C. Future studies using larger sample sizes are warranted to confirm these results.
Depression and sleep disorders are among the most prevalent nonmotor symptoms of Parkinson disease (PD). Because agomelatine acts as a MT1 and MT2 agonist and as a 5HT2c antagonist, this study was ...designed to assess the efficacy of agomelatine in treating depressive symptoms in PD patients, and the potential changes both in sleep quality and motor symptoms. Depressed patients with PD were treated with agomelatine for 6 months, and they were evaluated with an array of scales. Completed nocturnal video-polysomnography was performed at baseline and week 12. The efficacy analysis population included 24 patients (12 men). The mean (SD) age was 75.2 (8.3) years. The mean (SD) daily dose of agomelatine was 25.00 (10.43) mg at 24 weeks. No changes in dopamine replacement therapy were made. There was a significant decrease in the 17-item Hamilton Depression Scale score over the course of the study (P < 0.0005). The Scales for Outcomes in Parkinson disease Sleep Questionnaire showed a statistically significant improvement over time in each of its subscales: nighttime sleep (P < 0.005), last month nighttime sleep (P < 0.0005), and daytime sleepiness (P < 0.0005). Surprisingly, changes over time in the motor subscale of Unified Parkinson Disease Rating Scale were statistically significant (P < 0.0005). Periodic limb movements and awakenings measured by polysomnography improved significantly (P < 0.005 and P < 0.05, respectively). We concluded that the use of agomelatine in PD depressed patients may have a considerable therapeutic potential because of its dual action for treating both symptoms of depression and disturbed sleep given its secondary beneficial effects regarding the reduction of extrapyramidal symptoms.
Abstract Central nervous system involvement in rheumatoid arthritis is infrequent. Inflammatory lesions described in the literature are limited to rheumatoid nodules and vasculitis. We report on a ...71-year-old woman who presented with a 1-month history of headache and dysarthria, and who had suffered seropositive rheumatoid arthritis without extra-articular complications, for 15 years. Magnetic resonance imaging showed a high-intensity image in FLAIR-weighted sequences in the right cerebral hemisphere, with meningeal gadolinium enhancement. A brain biopsy revealed necrotizing and lymphocytic vasculitis in the meninges as well as cerebral parenchyma. The patient received treatment with high-dose intravenous methylprednisolone with radiological improvement at 6-month follow-up. She remained neurologically asymptomatic in subsequent years. Three years after the onset of neurological symptoms, she was admitted to the hospital with choluria and jaundice. On the fiftieth day of hospitalization, she died from bronchopneumonia. The autopsy showed no signs of vasculitis. Cerebral vasculitis is an infrequent complication in RA. High-doses of intravenous corticosteroids may be an effective treatment.
The MDS-PSP criteria expand the phenotypic spectrum of PSP by adding to Richardson's syndrome (PSP-RS) other presentations such as PSP-parkinsonism (PSP–P), PSP-pure-gait-freezing (PSP-PGF), ...PSP-speech-language (PSP-SL), PSP-frontal (PSP–F), PSP-postural-instability (PSP-PI) and PSP-corticobasal-syndrome (PSP-CBS). Evidence about the prognostic differences between PSP phenotypes is scarce and focused on PSP-RS vs. non-PSP-RS. Using a brain-bank cohort we assessed PSP survival not only in PSP-RS vs. non-PSP-RS, but also in PSP-RS + cortical vs. subcortical phenotypes. Besides, we assessed sensitivity and specificity of the MDS-PSP criteria in of PSP and other degenerative parkinsonisms.
We retrospectively applied the MDS-PSP diagnostic criteria to 32 definite PSP cases and 30 cases with other degenerative parkinsonian syndromes (Parkinson's disease PD; n = 11, multiple system atrophy MSA; n = 11, corticobasal degeneration CBD; n = 8). We conducted survival statistics in neuropathologically confirmed PSP cases considering PSP-RS vs. non-PSP-RS and PSP-RS + PSP-cortical (PSP–F + PSP-SL + PSP-CBS) vs. PSP-subcortical (PSP–P + PSP-PGF) phenotypes. We also adjusted survival analyses for PSP tau scores.
Diagnostic sensitivity was 100% and specificity ranged from 47% to 87% when excluding cases that met the “suggestive of PSP” definition early in their disease course but with other clinical features better matching with a non-PSP pathological diagnosis. Survival was significantly shorter in PSP-RS vs. non-PSP-RS cases, but it was more markedly shorter in PSP-RS + PSP-cortical vs. PSP-subcortical, independently of PSP tau scores, which were not associated with survival.
PSP-subcortical phenotypes appear to have longer survival than PSP-RS and cortical phenotypes. This might be of prognostic relevance when informing patients upon clinical diagnosis.
•The MDS PSP diagnostic criteria have 100% sensitivity and 87% specificity when excluding s.o.PSP with non-PSP features.•Survival is significantly shorter in PSP-RS than in the other phenotypes considered together.•This difference is more remarkable when comparing PSP-RS and PSP cortical phenotypes to the subcortical PSP phenotypes.•This information can be relevant for prognosis upon clinical diagnosis.
A good response to levodopa is a key factor to indicate device-aided therapies in people with Parkinson's disease (PwPD). The aim of the present study was to analyze the response to levodopa in PwPD ...with motor fluctuations followed for 4 years.
PwPD with motor fluctuations recruited from January 2016 to November 2017 from the COPPADIS cohort and assessed annually (from baseline to 4-year follow-up) during the OFF and ON states were included in this analysis. At each visit, the Unified Parkinson's Disease Rating Scale – part III (UPDRS-III) was applied during the OFF state (without medication during the last 12 h) and during the ON state. General linear model repeated measures were used to test for changes in the mean UPDRS–III–OFF, UPDRS–III–ON, and ΔUPDRS-III (UPDRS–III–OFF – UPDRS–III–ON) between visits. Levodopa equivalent daily dose (LEDD) was included as covariate.
Sixty-three patients (63.94 ± 8.42 years old; 68.3% males) were included. Mean disease duration was 7.81 ± 3.64 years. From baseline to 4-year follow-up visit, a significant increase in both the UPDRS–III–OFF (from 27.98 ± 9.58 to 31.75 ± 12.39; p = 0.003) and the UPDRS–III–ON (from 15.92 ± 7.93 to 18.84 ± 8.17; p = 0.006) was observed despite the significant increase in the LEDD (from 896.35 ± 355.65 to 1085.51 ± 488.29; p = 0.003). However, no significant differences were detected between visits in the ΔUPDRS-III.
In this cohort of PwPD with motor fluctuations, the response to levodopa did not weaken after a 4-year follow-up.
•A good response to levodopa is a key factor to indicate device-aided or on-demand therapies in Parkinson's disease.•Response to levodopa did not weaken after a 4-year follow-up in 63 fluctuators PD patients.•On and off scores worsen at the expense of axial symptoms and in parallel with conservation of the levodopa response.•There were no differences by motor phenotype.
Background
Leucine‐rich kinase 2 (LRRK2)‐linked Parkinson's disease (PD) is clinically indistinguishable from idiopathic PD (IPD). A pleiotropic neuropathology has been recognized but the majority of ...studies in LRRK2 p.G2019S patients reveal Lewy‐type synucleinopathy as its principal histological substrate. To date no in vivo biomarkers of synucleinopathy have been found in LRRK2 mutation carriers.
Objectives
We used real‐time quaking‐induced conversion (RT‐QuIC) technique to assess the presence of alpha‐synuclein (a‐syn) aggregates in cerebrospinal fluid (CSF) of LRRK2 p.G2019S carriers.
Methods
CSF samples of 51 subjects were analyzed: 15 LRRK2 p.G2019S PD, 10 IPD, 16 LRRK2 p.G2019S nonmanifesting carriers (NMC) and 10 healthy controls. The presence of parkinsonism and prodromal symptoms was assessed in all study subjects.
Results
Forty percent (n = 6) LRRK2‐PD, and 18.8% (n = 3) LRRK2‐NMC had a positive a‐syn RT‐QuIC response. RT‐QuIC detected IPD with 90% sensitivity and 80% specificity. No clinical differences were detected between LRRK2‐PD patients with positive and negative RT‐QuIC. A positive RT‐QuIC result in LRRK2‐NMC occurred in a higher proportion of subjects meeting the Movement Disorder Society research criteria for prodromal PD.
Interpretation
RT‐QuIC detects a‐syn aggregation in CSF in a significant number of patients with LRRK2‐PD, but less frequently than in IPD. A small percentage of LRRK2‐NMC tested also positive. If appropriately validated in long‐term studies with large number of mutation carriers, and hopefully, postmortem or in vivo confirmation of histopathology, RT‐QuIC could contribute to the selection of candidates to receive disease modifying drugs, in particular treatments targeting a‐syn deposition.
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