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Apolipoproteins, lipids, lipid-lowering drugs and risk of amyotrophic lateral sclerosis and frontotemporal dementia: a meta-analysis and Mendelian randomisation study
Abstract Background Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have clinical, pathological and genetic overlapping. Lipid pathways are implicated in ALS. This study examined the effect of blood lipid levels on ALS, FTD risk, and survival in ALS. Methods A systematic review and meta-analysis of high and low-density lipoprotein cholesterol (HDL-c and LDL-c), total cholesterol, triglycerides, apolipoproteins B and A1 levels with ALS was performed. Two-sample Mendelian randomisation (MR) analysis sought the causal effects of these exposures on ALS, FTD, and survival in ALS. The effect of lipid-lowering drugs was also examined using genetic proxies for targets of lipid-lowering medications. Results Three cohort studies met the inclusion criteria for meta-analysis. Meta-analysis indicated an association between higher LDL-c (HRper mmol/L = 1.07, 95%CI:1.02–1.12; $${I}^{2}$$ I 2 =18%) and lower HDL-c (HRper mmol/L = 0.83, 95%CI:0.74–0.94; $${I}^{2}$$ I 2 =0%) with an increased risk of ALS. MR suggested causal effects of higher LDL-c (ORIVW = 1.085, 95%:CI 1.008–1.168, pFDR = 0.0406), total cholesterol (ORIVW = 1.081, 95%:CI 1.013–1.154, pFDR = 0.0458) and apolipoprotein B (ORIVW = 1.104, 95%:CI 1.041–1.171, pFDR = 0.0061) increasing ALS risk, and higher apolipoprotein B level increasing FTD risk (ORIVW = 1.424, 95%CI 1.072–1.829, pFDR = 0.0382). Reducing LDL-c through APOB inhibition was associated with lower ALS (ORIVW = 0.84, 95%CI 0.759–0.929, pFDR = 0.00275) and FTD risk (ORIVW = 0.581, 95%CI 0.387–0.874, pFDR = 0.0362). Conclusion These data support the influence of LDL-c and total cholesterol on ALS risk and apolipoprotein B on the risk of ALS and FTD. Potential APOB inhibition might decrease the risk of sporadic ALS and FTD. Further work in monogenic forms of ALS and FTD is necessary to determine whether blood lipids influence penetrance and phenotype.
Ku70 Corrupts DNA Repair in the Absence of the Fanconi Anemia Pathway
Righting Repair Pathways The genetic disease Fanconi anemia (FA) results from mutations in a series of genes involved in a DNA repair pathway that helps process the damage caused by erroneous chemical cross-links between the two strands of the DNA double helix. The double-stranded breaks in DNA that arise from such cross-links can be repaired in an error-free manner or through an error-prone repair pathway. Pace et al. (p. 219 , published online 10 June) show that the FA pathway can drive repair through the error-free pathway. The FA FANCC gene shows a genetic interaction with a component of the error-prone repair pathway, Ku70, inhibiting its action and thereby promoting the error-free pathway.
Premorbid brain structure influences risk of amyotrophic lateral sclerosis
BackgroundAmyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known.MethodsThis study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis.ResultsIncreased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule.ConclusionsThis study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.
The Dementias Platform UK (DPUK) Data Portal
AbstractThe Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure ‘lab’ using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
Potential Metabolomic Linkage in Blood between Parkinson’s Disease and Traumatic Brain Injury
The etiologic basis for sporadic forms of neurodegenerative diseases has been elusive but likely represents the product of genetic predisposition and various environmental factors. Specific gene-environment interactions have become more salient owing, in part, to the elucidation of epigenetic mechanisms and their impact on health and disease. The linkage between traumatic brain injury (TBI) and Parkinson’s disease (PD) is one such association that currently lacks a mechanistic basis. Herein, we present preliminary blood-based metabolomic evidence in support of potential association between TBI and PD. Using untargeted and targeted high-performance liquid chromatography-mass spectrometry we identified metabolomic biomarker profiles in a cohort of symptomatic mild TBI (mTBI) subjects (n = 75) 3–12 months following injury (subacute) and TBI controls (n = 20), and a PD cohort with known PD (n = 20) or PD dementia (PDD) (n = 20) and PD controls (n = 20). Surprisingly, blood glutamic acid levels in both the subacute mTBI (increased) and PD/PDD (decreased) groups were notably altered from control levels. The observed changes in blood glutamic acid levels in mTBI and PD/PDD are discussed in relation to other metabolite profiling studies. Should our preliminary results be replicated in comparable metabolomic investigations of TBI and PD cohorts, they may contribute to an “excitotoxic” linkage between TBI and PD/PDD.
Evaluation of Cerebrospinal Fluid α-Synuclein Seed Amplification Assay in Progressive Supranuclear Palsy and Corticobasal Syndrome.
BackgroundSeed amplification assay (SAA) testing has been developed as a biomarker for the diagnosis of α-synuclein-related neurodegenerative disorders.ObjectiveThe objective of this study was to assess the rate of α-synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) and to analyze clinical and pathological features of SAA-positive and -negative cases.MethodsA total of 96 cerebrospinal fluid samples from clinically diagnosed PSP (n = 59) and CBS (n = 37) cases were analyzed using α-synuclein SAA.ResultsSix of 59 (10.2%) PSP cases were α-synuclein SAA positive, including one case who was MSA-type positive. An exploratory analysis showed that PSP cases who were Parkinson's disease-type positive were older and had a shorter disease duration compared with SAA-negative cases. In contrast, 11 of 37 (29.7%) CBS cases were α-synuclein SAA positive, including two cases who were MSA-type positive.ConclusionsOur results suggest that α-synuclein seeds can be detected in PSP and CBS using a cerebrospinal fluid α-synuclein SAA, and in PSP this may impact on clinical course.
Predictors of short-term anxiety outcome in subthalamic stimulation for Parkinson's disease.
The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.