Abstract
Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many ...previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in
PARK2
in the FTD cohort, and in
NOTCH3
in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.
Background. Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a recently recognized genetic disorder comprised of mandibular hypoplasia, deafness, progeroid ...features, and lipodystrophy. It is caused by an autosomal dominant mutation in the POLD1 gene, with <20 genetically confirmed cases to date. Clinical overlap with other progeroid syndromes including Werner syndrome (WS) can present diagnostic challenges. Case. The proband is a 36-year-old male of Sicilian ancestry who was phenotypically normal at birth. Onset of lipodystrophic and progeroid features began at 18 months, with progressive loss of subcutaneous fat, prominent eyes, and pinched nose. Over the next 2 decades, he developed hearing loss, small fingers, joint contractures, hypogonadism, osteoporosis, and hypertriglyceridemia. Three of his 4 siblings had premature hair graying and loss, severe bilateral cataracts, skin changes, and varying degrees of age-related metabolic conditions, raising suspicion for a genetic progeroid syndrome. Genetic Analysis. A targeted sequencing panel identified a heterozygous WRN mutation in the proband’s genomic DNA. Sanger sequencing further revealed his parents and an asymptomatic brother to be carriers of this mutation, and in his 3 brothers affected with classic WS the mutation was identified in the homozygous state. Whole exome sequencing ultimately revealed the proband harbored the causative de novo in-frame deletion in POLD1 (p.Ser605del), which is the most common mutation in MDPL patients. Conclusion. We report the unusual convergence of 2 rare progeroid disorders in the same family: the proband displayed sporadic MDPL syndrome, while 3 brothers had classical autosomal recessive WS. Whole exome sequencing was invaluable in clarifying the molecular diagnoses in this family.
Matrin3: Disorder and ALS Pathogenesis Salem, Ahmed; Wilson, Carter J; Rutledge, Benjamin S ...
Frontiers in molecular biosciences,
01/2022, Letnik:
8
Journal Article
Recenzirano
Odprti dostop
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons in the brain and spinal cord. ALS is associated with ...protein misfolding and inclusion formation involving RNA-binding proteins, including TAR DNA-binding protein (TDP-43) and fused in sarcoma (FUS). The 125-kDa Matrin3 is a highly conserved nuclear DNA/RNA-binding protein that is implicated in many cellular processes, including binding and stabilizing mRNA, regulating mRNA nuclear export, modulating alternative splicing, and managing chromosomal distribution. Mutations in
, the gene encoding Matrin3, have been identified as causal in familial ALS (fALS). Matrin3 lacks a prion-like domain that characterizes many other ALS-associated RNA-binding proteins, including TDP-43 and FUS, however, our bioinformatics analyses and preliminary studies document that Matrin3 contains long intrinsically disordered regions that may facilitate promiscuous interactions with many proteins and may contribute to its misfolding. In addition, these disordered regions in Matrin3 undergo numerous post-translational modifications, including phosphorylation, ubiquitination and acetylation that modulate the function and misfolding of the protein. Here we discuss the disordered nature of Matrin3 and review the factors that may promote its misfolding and aggregation, two elements that might explain its role in ALS pathogenesis.
Background
Cerebral small vessel disease (SVD) frequently co‐occurs with other neurodegenerative pathologies and collectively lead to cognitive deficits. Previously, we found that the ratios of ...soluble epoxide hydrolase (sEH)‐ derived diols to the parent epoxides (generated by CYP2J/2Cs) linoleic acids were associated with greater white matter hyperintensities (WMH) and poorer executive function in patients with transient ischemic attack. However, the associations with the diol and epoxide species derived from arachidonic acid (AA) have not been explored.
Methods
The study cohort is comprised of 159 stroke patients (mean age = 69.2, 32.1% female) from the Ontario Neurodegenerative Degenerative Research Initiative. EpETrEs (AA epoxides) and DiHETrEs (AA diols) were quantified by a targeted ultrahigh pressure liquid chromatography mass spectrometry (UPLC‐MS/MS). Executive function was assessed using a composite score that included Digit Symbol Substitution Test (DSST), Trial‐Making Test Part B, Stroop Color‐Word Interference Test, and FAS Verbal Fluency Test. WMHs were quantified from T2‐Fluid‐Attenuated‐Inversion‐Recovery MRI through Lesion Explorer (https://imaging.brainlab.ca/lesion‐explorer.html).In linear models controlling for age, sex, education or age, sex, glucose, cholesterol, and waist circumferences were used for cognitive and imaging out comes, respectively.
Results
11(12)‐EpETrE was found to be associated with less WHM (ρ = ‐0.175, p = 0.040) and better executive function (ρ = 0.166, p = 0.039). In a sub‐cohort of patients with small vessel stroke (n = 50), the relationship between WMH and 11(12)‐EpETrE became stronger (ρ = ‐0.390, p = 0.014). 14(15)‐EpETrE was also associated with less WMH (ρ = ‐0.416, p = 0.009). Similar relationships were not seen with the diols or diol to epoxide ratios.
Conclusions
Oxylipins derived from sEH activity may be potential biomarkers of vascular cognitive impairment and small vessel disease in stroke patients.
Abstract
Background
Falls are the most common injury faced by older adults and those with neurodegenerative diseases. Falls can result in concussion/mild traumatic brain injury(mTBI). Concussions in ...older adults or those with neurodegenerative disease can have a significant impact on behavior as post‐concussion symptoms include neuropsychiatric issues. We hypothesized that there is a relationship between past fall and neuropsychiatric symptoms and neuropsychiatric symptom severity.
Methods
We used data on falls and Neuropsychiatric Inventory (NPI) from the Ontario Neurodegenerative Disease Research Initiative dataset for 480 individuals with neurodegenerative diseases (Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, frontotemporal dementia and vascular cognitive impairment). We used the Chi‐squared and Mann‐Whitney tests to compare frequency of NPI symptoms (anxiety, depression, irritability, disinhibition, apathy, delusions, hallucinations, agitation, euphoria, motor‐disturbance, night‐time behaviour, appetite), and total NPI severity and distress, respectively, between patients with and without falls in the past 12 months.
Results
Comparing patients with falls (n = 169; mean‐age = 68.3±9; 36% F) to patients without falls (n = 311; mean‐age = 68.7±7; 32% F), there was a significantly higher frequency of anxiety (Chi‐squared test, X
2
(df = 1, N = 480) = 12.859, P‐value = 0.0003); higher median anxiety severity (Mann‐Whitney/Wilcoxon‐test p‐value = 0.0002); and higher median partner anxiety distress (Wilcox test p‐value = 0.0006) in those who had had a previous fall compared to those who had not, even with multiple comparison correction. Depression, apathy, disinhibition, night‐time behaviours, and eating/appetite changes and total NPI severity were significantly worse in those with previous falls but did not survive multiple comparison correction.
Conclusion
We found that anxiety frequency, severity and distress were much higher in patients with neurodegenerative disease who had a fall in the preceding 12 months compared to those without falls. Our study suggests that neuropsychiatric symptoms, especially anxiety are frequent and should be assessed in those with previous falls as they can be a consequence of mild brain injury and may contribute to worsening cognition or behaviors.
Background
Neuroinflammation (NI) has been implicated in both the pathogenesis of and neuroprotection against neurodegenerative diseases (NDs)(Psenicka et al., 2021). Plasma glial fibrillary acidic ...protein (GFAP), and Neurofilament light (NFL) are measures of astrogliosis and neurodegeneration, respectively. Amyloid beta (Aß)42/40 ratio (Aß42 concentration to total Aß concentration) below 0.068 is associated with AD pathology (Baldeiras et al., 2018). Neuroimaging‐based inflammatory biomarkers have been proposed, including free‐water diffusion (FWD)(Pasternak et al., 2009). Here we investigated FWD as a candidate biomarker for NI in AD compared to non‐AD dementia using Aß42/40 ratio in a subset of data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI).
Method
FWD maps were generated in 370 subjects (126 non‐AD and 244 AD). MRI processing included ICVmapp3r for brain extraction and bias field correction, Synb0, Topup and Eddy for dMRI preprocessing and MATLAB for freewater mapping. Plasma Aß42, Aß40, GFAP and NFL were measured using the Simoa Human Neurology 4‐Plex E assay, and cognition was estimated using the Montreal Cognitive Assessment (MoCA). Linear regression was used to estimate the ability for FWD in the left (LcGM) and right (RcGM) cortical grey matter to predict GFAP, NFL and MoCA score in AD and nonAD based on Aß42/40 threshold of 0.068.
Result
FWD correlated with GFAP (LcGM; R = 0.4, p = 0.0013 and RcGM; R = 0.37, p = 0.0069), and MoCA total score (LcGM; R = ‐0.29, p = 0.001 and RcGM; R = ‐0.27, p = 0.001), but not with NFL across the whole group. This relationship was largely driven by the AD group wherein FWD predicted GFAP (LcGM: R = 0.12, p = 0.02, RcGM approaching significance R = 0.1, p = 0.06), and MoCA Total score (LcGM: R = ‐0.33, p<0.0001), RcGM: R = ‐0.25, p<0.0001). The nonAD group did not show this relationship. FWD did not predict NFL in the AD and nonAD group.
Conclusion
In patients with Aß42/40<0.068, suggestive of AD, FWD in cGM was more strongly related to GFAP than NFL, and predicted cognition, a pattern that was not observed in nonAD patients. Our results suggest distinct patterns of NI in AD compared with nonAD that can be detected with FWD and with a multi‐modal approach could further understanding of differences in pathophysiology across NDs.
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