Publications by authors named "Sonja Scholz"

Objective: This article provides an overview of the current understanding of the genetic and pathologic features of neurodegenerative dementias, with an emphasis on Alzheimer disease and related dementias.

Latest Developments: In recent years, there has been substantial progress in genetic research, contributing significant knowledge to our understanding of the molecular risk factors involved in neurodegenerative dementia syndromes. Several genes have been linked to monogenic forms of dementia (eg, APP, PSEN1, PSEN2, SNCA, GRN, C9orf72, MAPT) and an even larger number of genetic variants are known to influence susceptibility for developing dementia.

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  • Repeat expansions in the C9orf72 gene are a leading genetic cause of ALS and frontotemporal dementia, but understanding how this mutation causes neuron death is still unclear, complicating the search for effective therapies.
  • Researchers analyzed data from over 41,000 ALS and healthy samples to identify potential treatments, discovering that acamprosate, a drug used for other conditions, might be repurposed for C9orf72-related diseases.
  • Their findings demonstrated that acamprosate has neuroprotective properties in cell models and works similarly well as the current treatment, riluzole, showing the potential of using genomic data to find new drug applications.
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  • The study investigates various methods for whole genome amplification in the analysis of somatic mutations, specifically copy number variants (CNVs), in human brain tissue.
  • Three techniques are compared: PicoPLEX, primary template-directed amplification (PTA), and droplet MDA, revealing distinct characteristics of each method in terms of amplification efficiency and chimeric profiles.
  • The research confirms that a significant portion of brain cells (20.6%) exhibit CNVs, emphasizing the need for careful selection of amplification methods and reference genomes when studying genomic variations in both healthy and diseased brains.
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Background: Commercial genome-wide genotyping arrays have historically neglected coverage of genetic variation across populations.

Objective: We aimed to create a multi-ancestry genome-wide array that would include a wide range of neuro-specific genetic content to facilitate genetic research in neurological disorders across multiple ancestral groups, fostering diversity and inclusivity in research studies.

Methods: We developed the Illumina NeuroBooster Array (NBA), a custom high-throughput and cost-effective platform on a backbone of 1,914,934 variants from the Infinium Global Diversity Array and added custom content comprising 95,273 variants associated with more than 70 neurological conditions or traits, and we further tested its performance on more than 2000 patient samples.

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  • Restless legs syndrome (RLS) is a neurological disorder characterized by uncomfortable leg sensations and an urge to move, especially during rest, but its genetic causes are not fully known.
  • Researchers conducted a large-scale study analyzing the genomes of nearly 10,000 RLS cases and over 38,000 controls, discovering 9 genetic risk loci, including one novel locus (LMX1B).
  • The findings suggest significant genetic overlaps between RLS and other conditions like neuroticism, depression, and even intelligence, advancing the understanding of RLS's genetic determinants.
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  • - Up to 80% of patients with Parkinson's disease experience dementia, but the timing varies widely, and the relationship between Parkinson's disease dementia and dementia with Lewy bodies is still debated.
  • - A study analyzed genetic data from 7804 patients to investigate how genetic factors influence the development of dementia in Lewy body diseases, revealing certain risk and protective alleles.
  • - Key findings include the identification of the risk allele rs429358, which increases the odds of developing dementia, and protective alleles near specific genes that may help prevent it, highlighting the need for further research with confirmed cases.
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  • * A study analyzed 4,685 sporadic FTD cases and found significant genetic variants at the MAPT and APOE loci that increase the risk for the disease, indicating potential genetic overlap with other neurodegenerative diseases.
  • * The genetic risk factors appear to vary by population, with MAPT and APOE associations predominantly found in Central/Nordic and Mediterranean Europeans, suggesting a need for further research into these population-specific features for better understanding of sporadic FTD.
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  • Multiple system atrophy (MSA) is a neurodegenerative disease that leads to symptoms like parkinsonism and ataxia, but its genetic causes are not well understood and treatment options are limited to supportive care.
  • A comprehensive study involving the whole genome sequencing of nearly 900 MSA patients and over 7,000 controls discovered four key genetic risk factors associated with the disease.
  • The research identified potential susceptibility genes and provided insights into how genetic variations influence gene expression in brain cells, offering a valuable resource for further studies on similar diseases.
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  • - The study explores how sex affects Lewy body dementia (LBD) and addresses the lack of attention to sex-specific risk factors in previous research, particularly focusing on the X chromosome.
  • - Researchers conducted an analysis involving 2,591 LBD patients and 4,391 controls, identifying a key genetic risk factor (MAP3K15) associated with increased LBD risk in females.
  • - Additionally, they found evidence of a higher prevalence of certain genetic mutations (missense mutations in TEX13A) in female LBD cases, suggesting genetic factors may influence the disease differently based on sex.
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Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements.

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Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis.

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  • * It is 11.8 times faster and 29% more accurate than existing SV callers, effectively handling various sequencing technologies and SV types while also generating fully genotyped VCF files for population-level analysis.
  • * The tool successfully identified complex SVs around the MECP2 gene and detected diverse mosaic SVs in brain tissue, revealing significant implications for genes related to neuron function in conditions like multiple system atrophy.
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  • Restless legs syndrome (RLS) is a neurological condition characterized by uncomfortable leg sensations and an urge to move, especially during rest; the causes are not fully understood.
  • A study involving genome sequencing of nearly 10,000 RLS cases and almost 39,000 controls identified nine genetic risk loci, including one new locus, which contributes to understanding the genetics behind RLS.
  • The research also found correlations between RLS and other conditions like neuroticism, depression, and intelligence, suggesting that common genetic variants play a significant role in this widespread disorder.
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Lewy body dementia is the second most common neurodegenerative dementia after Alzheimer's disease. Disease-modifying therapies for this disabling neuropsychiatric condition are critically needed. To identify drugs associated with the risk of developing Lewy body dementia, we performed a population-based case-control study of 148 170 US Medicare participants diagnosed with Lewy body dementia between 1 January 2008 and 31 December 2014 and of 1 253 043 frequency-matched controls.

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The heterogenous aetiology of Parkinson's disease is increasingly recognized; both mitochondrial and lysosomal dysfunction have been implicated. Powerful, clinically applicable tools are required to enable mechanistic stratification for future precision medicine approaches. The aim of this study was to characterize bioenergetic dysfunction in Parkinson's disease by applying a multimodal approach, combining standardized clinical assessment with midbrain and putaminal 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and deep phenotyping of mitochondrial and lysosomal function in peripheral tissue in patients with recent-onset Parkinson's disease and control subjects.

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  • * Research indicates that genetic factors play a role in disease heterogeneity, with specific alleles linked to an increased risk or protection against developing dementia in Lewy body diseases.
  • * A study involving 7,804 patients identified certain genetic variants that increase the likelihood of dementia, suggesting further investigation is needed, especially in autopsy-confirmed cases for validation.
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Genome-wide genotyping platforms have the capacity to capture genetic variation across different populations, but there have been disparities in the representation of population-dependent genetic diversity. The motivation for pursuing this endeavor was to create a comprehensive genome-wide array capable of encompassing a wide range of neuro-specific content for the Global Parkinson's Genetics Program (GP2) and the Center for Alzheimer's and Related Dementias (CARD). CARD aims to increase diversity in genetic studies, using this array as a tool to foster inclusivity.

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Long-read sequencing technologies substantially overcome the limitations of short-reads but have not been considered as a feasible replacement for population-scale projects, being a combination of too expensive, not scalable enough or too error-prone. Here we develop an efficient and scalable wet lab and computational protocol, Napu, for Oxford Nanopore Technologies long-read sequencing that seeks to address those limitations. We applied our protocol to cell lines and brain tissue samples as part of a pilot project for the National Institutes of Health Center for Alzheimer's and Related Dementias.

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The presence of somatic mutations, including copy number variants (CNVs), in the brain is well recognized. Comprehensive study requires single-cell whole genome amplification, with several methods available, prior to sequencing. We compared PicoPLEX with two recent adaptations of multiple displacement amplification (MDA): primary template-directed amplification (PTA) and droplet MDA, across 93 human brain cortical nuclei.

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After Alzheimer's disease, Frontotemporal dementia (FTD) is the most common cause of early-onset dementia. Several genetic mutations have been identified in familial FTD, with mutations in progranulin (GRN) accounting for approximately 20-25% of familial FTD cases and about 10% of total FTD cases. We report the case of a familial FTD patient with atypical parkinsonism who was found to have frontotemporal dementia (-FTD) with a pathogenic splice site mutation (c.

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Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell.

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