Striatal dopamine in <scp>P</scp>arkinson disease: A meta‐analysis of imaging studies

Kaasinen, Valtteri; Vahlberg, Tero

doi:10.1002/ana.25103

Cited by 115 publications

(110 citation statements)

References 40 publications

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“…In particular, our results demonstrate that whereas fatigue prevalence is not modulated by demographic and motor features or disease progression, it is moderately associated with nonmotor symptoms in PD, such as apathy, anxiety, and sleep disturbances. It is well known that degeneration of the nigrostriatal dopaminergic system in PD progresses along the disease course and is closely associated with disease severity . The absence of an association between fatigue and motor symptoms in our analyses provides indirect support for the hypothesis that fatigue in PD results from disruption of nondopaminergic pathways .…”

Section: Discussionsupporting

confidence: 55%

Fatigue in Parkinson's disease: A systematic review and meta‐analysis

et al. 2018

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We conducted a systematic review and meta‐analysis aimed at establishing robust prevalence estimates and identifying clinical correlates of fatigue in PD. From 2,459 titles and abstracts, we selected 44 relevant studies (n = 7427 patients). Overall, the meta‐analysis showed a prevalence of fatigue of 50% in PD. This prevalence estimate, however, was significantly moderated by study heterogeneity in measurement scales and cut‐off thresholds. In contrast, demographic features, disease severity, cognitive impairment, and depression did not moderate prevalence estimates. Moreover, fatigue prevalence did not differ between de novo and treated PD patients. Compared to nonfatigued patients, fatigued patients had sligthly higher age (1.44 years), disease duration (0.93 years), l‐dopa equivalent daily dose (50.89 units), UPDRS‐III (4.99 points), and H & Y (0.33 points), as well as risk of comorbid depression (risk ratio = 1.89) and had a little lower MMSE score (–0.66 points). Fatigue was moderately associated with apathy (Hedges' g = 0.55), anxiety (Hedges' g = 0.67), daytime somnolence (Hedges' g = 0.43), sleep disturbances (Hedges' g = 0.66), and poorer quality of life (Hedges' g = 1.23). Our analyses suggest that fatigue is a frequent, independent nonmotor symptom in PD appearing early and persisting throughout the disease course, and that establishing uniform diagnostic criteria for PD‐related fatigue is critical. In addition, several nonmotor symptoms appear to be associated with fatigue and negatively impact quality of life. Pharmacological and nonpharmacological interventions targeting fatigue and associated symptoms may improve quality of life in patients with PD. © 2018 International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 55%

Fatigue in Parkinson's disease: A systematic review and meta‐analysis

et al. 2018

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“…In PD, the most striking clinical symptoms become obvious only after around 60% of nigral dopaminergic neurons are lost [27], and dopamine concentration in the striatum has declined by around 70% [43]. Thus, it is reasonable to assume that, after PD is initiated and the nigro-striatal circuit starts to be stressed, complex interactions of the two different angles of injury response takes place, possibly over decades, and even before nigro-striatal degeneration occurs.…”

Section: Discussionmentioning

confidence: 99%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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Understanding Parkinson's disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD. 1/30 models provide a useful means to investigate PD-associated molecular changes, in particular those preceding nigro-striatal degeneration. The elucidation of such early changes can shed light into disease causation and drivers of disease progression, thus in turn pointing to novel targets for intervention as well as biomarkers [16,45].Whole transcriptome analysis enables to compare thousands of genes between two or more groups [9], and provides a valuable method for identifying coordinated changes in gene expression patterns that are not captured by single-gene or protein measurement approaches [59]. Despite of these advantages, only a limited amount of studies have used transcriptomics on α-synuclein-based transgenic mouse models for PD [13, 67, 71-73, 94, 98]. Alpha-synuclein, a pre-synaptic protein believed to be a moderator of the synaptic vesicle cycle, is a major component of Lewy bodies [87]. In addition, mutations or multiplications in its genes leads to familiar forms of PD [26,46]. Transcriptomics studies on α-synuclein-based transgenic mouse models for PD have only looked at differentially expressed genes (DEGs) in relation to pre-defined cellular pathways or gene sets from public annotation databases [13,67,[71][72][73]94]. Most of them used only one [71][72][73] or two age groups [13,67,94,98] of the mouse model for their analyses, and some of them were perform...

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“…With PARK2, there is a posited role of dopaminergic systems in PTSD and epidemiological evidence for association of Parkinson Disease and PTSD. [34][35][36] PODXL is involved in neural development and synapse formation, 37,38 SH3RF3 is associated with neurocognition and dementia, 39,40 and ZDHHC14 is associated with regulation of β -adrenergic receptors. 41,42 Finally, the HLA-B complex may be related through the known role of immunity and inflammation in stress-related disorders.…”

Section: Discussionmentioning

confidence: 99%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

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Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.Comparability of PGC2 studies PGC2 compiled the largest collection of global PTSD GWAS to date, with subjects recruited from both clinically deeply characterized, small patient groups and large cohorts with self-reported PTSD symptoms. We did not restrict the type of trauma subjects were exposed to, and trauma included both civilian and/or military events, often with pre-existing exposure to childhood trauma. To evaluate the comparability of these phenotypically heterogeneous studies we first estimated genetic correlations with LDSC, 15 a method that leverages GWAS summary results, the only data type available to PGC-PTSD for several of the larger military and non-US cohorts. We found significant genetic correlations (r g ) between studies using a cross-validation approach including all PGC2 EUA subjects (10 runs with studies randomly placed into 2 groups; mean r g = 0.56, mean SE = 0.23, mean p = 0.029, Supplementary Table 8).Next, additional analyses on the UK Biobank cohort (UKBB) were performed. This cohort comprises a very large proportion of the data, with almost as many EUA cases as the rest of the EUA PGC2 combined (referred to as PGC1.5). PTSD screening in UKBB was based on self-reported symptoms from a mental health survey. 16 We found a considerable genetic correlation between the UKBB and PGC1.5 EUA subjects (r g = 0.73, SE = 0.21, p = 0.0005; Supplementary Table 9). Further, sensitivity analyses in the UKBB using 3 alternative inclusion criteria for PTSD cases and controls showed stable correlations with PGC1.5 (P1 -P3; r g = 0.72 -0.79; Supplementary Table 10). Subsequent analyses were based on the UKBB phenotype including the largest number of subjects (P1; N = 126,188). Sex-stratified genetic correlations support the findings of a significant genetic signal...

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Striatal dopamine in Parkinson disease: A meta‐analysis of imaging studies

Cited by 115 publications

References 40 publications

Fatigue in Parkinson's disease: A systematic review and meta‐analysis

Fatigue in Parkinson's disease: A systematic review and meta‐analysis

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

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