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See detailDairy Intake and Parkinson's Disease: A Mendelian Randomization Study
Domenighetti, Cloé; Sugier, Pierre-Emmanuel; Ashok Kumar Sreelatha, Ashwin et al

in Movement Disorders (2022)

Abstract Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained ... [more ▼]

Abstract Background Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR). Methods We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95 confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003; P-difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society [less ▲]

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See detailPINK1 Protects against Staurosporine-Induced Apoptosis by Interacting with Beclin1 and Impairing Its Pro-Apoptotic Cleavage.
Brunelli, Francesco; Torosantucci, Liliana; Gelmetti, Vania et al

in Cells (2022), 11(4),

PINK1 is a causative gene for Parkinson's disease and the corresponding protein has been identified as a master regulator of mitophagy-the autophagic degradation of damaged mitochondria. It interacts with ... [more ▼]

PINK1 is a causative gene for Parkinson's disease and the corresponding protein has been identified as a master regulator of mitophagy-the autophagic degradation of damaged mitochondria. It interacts with Beclin1 to regulate autophagy and initiate autophagosome formation, even outside the context of mitophagy. Several other pro-survival functions of this protein have been described and indicate that it might play a role in other disorders, such as cancer and proliferative diseases. In this study, we investigated a novel anti-apoptotic function of PINK1. To do so, we used SH-SY5Y neuroblastoma cells, a neuronal model used in Parkinson's disease and cancer studies, to characterize the pro-survival functions of PINK1 in response to the apoptosis inducer staurosporine. In this setting, we found that staurosporine induces apoptosis but not mitophagy, and we demonstrated that PINK1 protects against staurosporine-induced apoptosis by impairing the pro-apoptotic cleavage of Beclin1. Our data also show that staurosporine-induced apoptosis is preceded by a phase of enhanced autophagy, and that PINK1 in this context regulates the switch from autophagy to apoptosis. PINK1 protein levels progressively decrease after treatment, inducing this switch. The PINK1-Beclin1 interaction is crucial in exerting this function, as mutants that are unable to interact do not show the anti-apoptotic effect. We characterized a new anti-apoptotic function of PINK1 that could provide options for treatment in proliferative or neurodegenerative diseases. [less ▲]

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See detailImpact of COVID-19 Pandemic on (Health) Care Situation of People with Parkinson’s Disease in Germany (Care4PD)
Fründt, Odette; Hanff, Anne-Marie UL; Mai, Tobias et al

in Brain Sciences (2022), 12(1 62),

The Care4PD study examined the impact of the COVID-19 pandemic on the care situation of people (PwP) with Parkinson’s disease in Germany. A comprehensive, nationwide, anonymous questionnaire for PwP was ... [more ▼]

The Care4PD study examined the impact of the COVID-19 pandemic on the care situation of people (PwP) with Parkinson’s disease in Germany. A comprehensive, nationwide, anonymous questionnaire for PwP was distributed by the members’ journal of the German Parkinson’s Disease Association and in several PD specialized in- and outpatient institutions. PwP subjectively evaluated their general care situation and individual impairments during the pandemic. We analyzed 1269 eligible out of 1437 returned questionnaires (88.3%) and compared PwP with (p-LTC) and without (np-LTC) professional long-term care. Both groups rated the general pandemic-related consequences as being rather mild to moderate (e.g., worsening of symptom or concerns). However, familial/social contact restrictions were indicated as most compromising, whereas access to outpatient professional health care providers was less affected. PwP with professional LTC reported more impairment than those without. COVID-19 vaccination rates and acceptance were generally high (p-LTC: 64.3%, np-LTC: 52.3%) at the time of the study, but realization of sanitary measures—especially wearing masks as a patient during care sessions—still needs to be improved. Technical options for telemedicine were principally available but only rarely used. Altogether, during the COVID-19 pandemic, PwP in Germany seemed to have a relatively stable health care access, at least in outpatient settings, while mainly social isolation compromised them. The p-LTC group was more impaired in everyday live compared with the np-LTC group. [less ▲]

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See detailDeterminants of Self-Stigma in People with Parkinson's Disease: A Mixed Methods Scoping Review
Hanff, Anne-Marie UL; Leist, Anja UL; Fritz, Joëlle UL et al

in Journal of Parkinson's Disease (2021)

Background: Self-stigma in people with Parkinson's disease (PD) can substantially impact quality of life and possibilities for social participation. An integrative analysis of determinants of self-stigma ... [more ▼]

Background: Self-stigma in people with Parkinson's disease (PD) can substantially impact quality of life and possibilities for social participation. An integrative analysis of determinants of self-stigma has been lacking. Objective: We sought to explore which complementary insights from qualitative and quantitative studies, as well as from expert consultation, could be gained. Methods: An established mixed methods study design was employed to first conduct a mixed methods scoping review of published qualitative and quantitative literature, and then consult with experts to arrive at an exhaustive list of determinants of self-stigma after a thematic synthesis. Results: A total of 87 unique determinants of self-stigma were identified. Quantitative studies and expert consultations mainly identified personal determinants of people with self-stigma (e.g., age, anxiety, or apathy). In contrast, qualitative studies identified social situations associated with self-stigma (e.g., joint meals of people with typical PD with others). Notably, self-stigma of people with PD was found to be particularly salient in unfamiliar places, at the working place or in contact with people without PD. Across methods, cognitive impairment, tremor, and abnormal walk and unsteady gait, respectively, were associated with self-stigma. Conclusion: The mixed method study design yielded complementary insights, but also factors commonly associated with self-stigma across methods. Future prioritization exercises may gain further insights into self-stigma of people with PD. Facilitating social encounters by both addressing needs of affected people and raising knowledge and public awareness may improve quality of life in people with PD [less ▲]

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See detailWhich demographic and socio-economic factors are associated with vaccination willingness and beliefs towards vaccination? Rapid report with first results
Leist, Anja UL; Klee, Matthias UL; Paccoud, Ivana UL et al

Report (2021)

In the framework of the CoVaLux project on vaccination and long COVID in Luxembourg, the project “Socio-economic determinants of long COVID and vaccination, and economic consequences with focus on labour ... [more ▼]

In the framework of the CoVaLux project on vaccination and long COVID in Luxembourg, the project “Socio-economic determinants of long COVID and vaccination, and economic consequences with focus on labour market and health care” aims to triangulate evidence from different data sources such as social security and general population data, the national cohort CON-VINCE as well as national health surveys. We seek to arrive at robust assessments of how socio-economic determinants shape vaccination willingness, occurrence, severity and persistence of long COVID, and economic consequences of long COVID in Luxembourg. [less ▲]

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See detailGene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function
Barbuti, Peter A; Ohnmacht, Jochen UL; Santos, Bruno FR et al

in Scientific Reports (2021), 11

Parkinson’s disease (PD) is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. The p.A30P SNCA mutation generates the pathogenic form of the ... [more ▼]

Parkinson’s disease (PD) is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. The p.A30P SNCA mutation generates the pathogenic form of the alpha-synuclein protein causing an autosomal-dominant form of PD. There are limited studies assessing pathogenic SNCA mutations in patient-derived isogenic cell models. Here we provide a functional assessment of dopaminergic neurons derived from a patient harbouring the p.A30P SNCA mutation. Using two clonal gene-corrected isogenic cell lines we identified image-based phenotypes showing impaired neuritic processes. The pathological neurons displayed impaired neuronal activity, reduced mitochondrial respiration, an energy deficit, vulnerability to rotenone, and transcriptional alterations in lipid metabolism. Our data describes for the first time the mutation-only effect of the p.A30P SNCA mutation on neuronal function, supporting the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease-modifying compound screenings and drug discovery strategies. [less ▲]

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See detailTherapeutic maps for a sensor-based evaluation of deep brain stimulation programming
Bremm, René Peter UL; Berthold; Krüger, Rejko UL et al

in Biomedizinische Technik. Biomedical Engineering (2021)

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See detailGenetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups
Kaivola, Karri; Shah, Zalak; Chia, Ruth et al

in Brain: a Journal of Neurology (2021), awab402

The APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies (DLB). In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein ... [more ▼]

The APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies (DLB). In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2,466 DLB cases versus 2,928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for DLB in patients without APOE ε4 (p = 6.58 x 10−9, OR = 3.41, 95% CI = 2.25–5.17), but not with DLB with APOE ε4 (p = 0.034, OR = 1.87, 95%, 95% CI = 1.05–3.37). We then divided 495 neuropathologically examined DLB cases into three groups based on the extent of concomitant Alzheimer’s disease co-pathology: pure DLB (n = 88), DLB with intermediate Alzheimer’s disease co-pathology (DLB + iAD, n = 66), and DLB with high Alzheimer’s disease co-pathology (DLB + AD, n = 341). In each group, we tested the association of the APOE ε4 against the 2,928 neurologically healthy controls. Our examination found that APOE ε4 was associated with DLB + AD (p = 1.29x10−32, OR = 4.25, 95% CI = 3.35–5.39) and DLB + iAD (p = 0.0011, OR = 2.31, 95% CI = 1.40–3.83), but not with pure DLB (p = 0.31, OR = 0.75, 95% CI = 0.43–1.30). In conclusion, though deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure DLB, but rather implicate GBA as the main risk gene for the pure DLB subgroup. [less ▲]

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See detailMendelian randomization study of smoking, alcohol, and coffee drinking in relation to Parkinso's disease
Domenighetti, Cloe; Sugier, Pierre Emmanuel; Sreelatha, Ashwin Ashok Kumar et al

in Journal of Parkinson's Disease (2021)

Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility ... [more ▼]

Background:Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson’s disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. Objective:To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. Methods:We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). Results:We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60–0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. Conclusion:Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power. [less ▲]

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See detailA new brain organoid model to study Parkinson’s Disease
Bolognin, Silvia UL; Smits, Lisa UL; Nickels, Sarah Louise UL et al

in Biomedical Science and Engineering (2021)

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See detailThe retrograde procedural memory in people with Parkinson’s disease with or without freezing of gait – a cross-sectional study
Pauly, Laure UL; Rauschenberger, Armin UL; Pauly, Claire UL et al

Poster (2021, September 17)

Objective: To investigate the retrograde procedural memory in people with typical Parkinson’s disease (PwP) with or without freezing of gait (FOG). We hypothesized that the retrograde procedural memory is ... [more ▼]

Objective: To investigate the retrograde procedural memory in people with typical Parkinson’s disease (PwP) with or without freezing of gait (FOG). We hypothesized that the retrograde procedural memory is more strongly impaired in patients with FOG (FOG+) than in patients without FOG (FOG-). Background: Given that cognitive functions, like executive control and automaticity, are crucial for mobility, it is of great importance to get a deeper knowledge of the cognitive impairment that may interfere with walking and causing gait disturbances in PwP, i.e. FOG. The integrity of retrograde procedural memory, the ability to execute skills that have been learned in earlier life stages, is essential for a person’s ability to complete routine, procedural activities like walking. As FOG is characterized as a de-automatization disorder, we hypothesized an impairment of the retrograde procedural memory in patients with FOG. Methods: A total of 194 patients from the Luxembourg Parkinson’s study were included into the cross-sectional study. All patients were assigned to the FOG+ / FOG- groups based on a semi-structured interview conducted by a study physician. The extended evaluation system of the cube copying test was applied to evaluate both the cube-drawing procedure, representing the retrograde procedural memory, and the final result, representing the visuo-constructive abilities (Pauly et al., 2020, MDS abstract). We compared the cube copying performance of n=97 FOG+ with n=97 age-, gender- and education-matched FOG-. Results: FOG+ scored lower on the cube copying procedure compared to the FOG- (p=0.027), which is suggestive of an impaired retrograde procedural memory in FOG+. No significant differences in the visuo-constructional abilities were detected (p=0.945). Conclusion: In line with FOG being considered a de-automatization of walking, a skill acquired in earlier life stages, the present results suggest that PwP with FOG have an impaired retrograde procedural memory in comparison to PwP without FOG. The results lend support to the ability of the extended evaluation system of the cube copying test to assess impaired retrograde procedural memory and help improve our understanding of behavioral symptoms in PwP. [less ▲]

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See detailThe evolution and social determinants of mental health during the first wave of the COVID-19 outbreak in Luxembourg
Ribeiro, Fabiana UL; Schröder, Valerie UL; Krüger, Rejko UL et al

in Psychiatry Research (2021), 303

Studies have been showing a negative impact of pandemic control measures on mental health. However, few studies assessed these effects longitudinally during the peak of the first wave of the COVID-19 ... [more ▼]

Studies have been showing a negative impact of pandemic control measures on mental health. However, few studies assessed these effects longitudinally during the peak of the first wave of the COVID-19 pandemic. The goals of this study were to explore whether differential effects of COVID-19 restrictions on mental health could be observed by sex and age in a Luxembourgish nationally representative sample during the initial outbreak of COVID-19. Furthermore, we aimed to assess whether there are differences in risk and protective factors longitudinally at two assessment times. A total of 1,756 respondents aged 18 years and older (50.74% women) reported sociodemographic and socio-economic characteristics, depression, anxiety, stress, and loneliness. Women and younger respondents reported higher rates of severe depression and anxiety symptoms, suggesting higher vulnerability to the pandemic control measures. This study contributes to the investigation of mental health consequences of the pandemic and the pandemic control measures, particularly related to shifts in care task responsibilities, gender and socio-economic inequalities, as well as younger groups' uncertainty about the future. [less ▲]

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See detailDJ-1 depletion slows down immunoaging in T-cell compartments
Zeng, Ni; Capelle, Christophe; Baron, Alexandre et al

Report (2021)

Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance ... [more ▼]

Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7 /DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly delayed immunoaging in both human and mice. Compared with two gender-matched unaffected sibling carriers of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled frequencies of non-senescent T cells. The observation of a ‘younger’ immune system in the index patient was further consolidated by the results in aged DJ-1 knockout mice. Our data from bone marrow chimera models and adoptive transfer experiments demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases. [less ▲]

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See detailGP2: The Global Parkinson's Genetics Program
Krüger, Rejko UL; The Global Parkinson's Genetics Program, ; The Global Parkinson's Genetics Program,

in Movement Disorders (2021), 36(4), 842-851

To facilitate the rapid expansion of our understanding of the genetic architecture of PD, both in terms of the depth and global context of this knowledge, we have created the Global Parkinson's Genetics ... [more ▼]

To facilitate the rapid expansion of our understanding of the genetic architecture of PD, both in terms of the depth and global context of this knowledge, we have created the Global Parkinson's Genetics Program (GP2; www.gp2.org). GP2 is the first supported resource project of the Aligning Science Across Parkinson's (ASAP) initiative, an audacious effort supporting PD research.9 GP2 is geared toward creating a worldwide collaborative effort that will first dramatically accelerate the identification of genetic contributors to disease and second establish a network of researchers who can best leverage this understanding to research, diagnose, and treat PD worldwide. Here we describe our mission, the path we have proposed to achieve this, and the core principles of data democratization, transparency, and diversity. [less ▲]

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See detailReplication of a Novel Parkinson's Locus in a European Ancestry Population
Grover, Sandeep; Kumar-Sreelatha, Ashwin Ashok; Bobbili, Dheeraj R. et al

in Movement Disorders (2021)

ABSTRACT Background A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17. Objectives The objective of this study were to ... [more ▼]

ABSTRACT Background A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17. Objectives The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations. Methods We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled. Results Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean = 6.64 × 10−4, pooled PD P = 1.15 × 10−11). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10−8). Conclusions Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [less ▲]

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See detailPeripheral decarboxylase inhibitors paradoxically induce aromatic L-amino acid decarboxylase
Krüger, Rejko UL; Pavelka, Lukas UL; Mollenhauer, Brit et al

in NPJ Parkinson's Disease (2021)

Peripheral decarboxylase inhibitors (PDIs) prevent the conversion of levodopa to dopamine in the blood by the enzyme aromatic L-amino acid decarboxylase (AADC). Alterations in enzyme activity may ... [more ▼]

Peripheral decarboxylase inhibitors (PDIs) prevent the conversion of levodopa to dopamine in the blood by the enzyme aromatic L-amino acid decarboxylase (AADC). Alterations in enzyme activity may contribute to the required higher dosages of levodopa observed in many patients with Parkinson’s disease. We evaluated the effect of levodopa/PDI use on serum AADC enzyme activity. Serum AADC enzyme activity was evaluated in three independent cohorts of patients with Parkinson’s disease or parkinsonism (n = 301) and compared between patients on levodopa/PDI vs. patients not on this medication. AADC enzyme activity was elevated in 62% of patients on levodopa/PDI treatment, compared to 19% of patients not on levodopa/PDI (median 90 mU/L vs. 50 mU/L, p < 0.001). Patients with elevated AADC activity had longer disease duration and higher doses of levodopa/PDI. These findings may implicate that peripheral AADC induction could underlie a waning effect of levodopa, necessitating dose increases to maintain a sustained therapeutic effect. [less ▲]

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See detailDeep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson’s disease progression
Krüger, Rejko UL; Kern, Fabian; Fehlmann, Tobias et al

in Nature Aging (2021)

Noncoding RNAs have diagnostic and prognostic importance in Parkinson’s disease (PD). We studied circulating small non coding RNAs (sncRNAs) in two large-scale longitudinal PD cohorts (Parkinson’s ... [more ▼]

Noncoding RNAs have diagnostic and prognostic importance in Parkinson’s disease (PD). We studied circulating small non coding RNAs (sncRNAs) in two large-scale longitudinal PD cohorts (Parkinson’s Progression Markers Initiative (PPMI) and Luxembourg Parkinson’s Study (NCER-PD)) and modeled their impact on the transcriptome. Sequencing of sncRNAs in 5,450 blood samples of 1,614 individuals in PPMI yielded 323 billion reads, most of which mapped to microRNAs but covered also other RNA classes such as piwi-interacting RNAs, ribosomal RNAs and small nucleolar RNAs. Dysregulated microRNAs associated with disease and disease progression occur in two distinct waves in the third and seventh decade of life. Originating predominantly from immune cells, they resemble a systemic inflammation response and mitochondrial dysfunction, two hall marks of PD. Profiling 1,553 samples from 1,024 individuals in the NCER-PD cohort validated biomarkers and main findings by an independent technology. Finally, network analysis of sncRNA and transcriptome sequencing from PPMI identified regulatory modules emerging in patients with progressing PD [less ▲]

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See detailGenome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
Chia, Ruth; Sabir, Marya S.; Bandres-Ciga, Sara et al

in Nature Genetics (2021)

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic ... [more ▼]

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition. [less ▲]

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See detailPathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
Dewan, Ramita; Chia, Ruth; Ding, Jinhui et al

in Neuron (2021), 109(3), 448-460

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients ... [more ▼]

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. [less ▲]

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