Senescence and Inflammatory Markers for Predicting Clinical Progression in Parkinson’s Disease: The ICICLE-PD Study

Martin-Ruiz, Carmen; Williams‐Gray, Caroline H.; Yarnall, Alison J.; Boucher, John J; Lawson, Rachael A.; Wijeyekoon, Ruwani; Barker, Roger A.; Kolenda, Claire; Parker, Craig; Burn, David J.; Zglinicki, Thomas von; Saretzki, Gabriele

doi:10.3233/jpd-191724

Cited by 39 publications

(36 citation statements)

References 70 publications

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“…This is consistent with other evidence that inflammatory markers appear to be increased years before the development of AD dementia, 9 though no studies seem to have assessed MCI‐AD. To our knowledge there have been no previous prospective studies of inflammation in DLB, and the only previous prospective studies in PD have been from our centers in people without cognitive impairment, which have supported a role for peripheral inflammation in disease progression in PD 12 . In addition, a CSF study in PD which did not include anyone with dementia but found increasing levels of the inflammatory marker YKL‐40, a marker of macrophages, which correlated with cognitive decline 31 .…”

Section: Discussionmentioning

confidence: 86%

“…In addition, increased disease severity was associated with lower levels of IL‐1β, IL‐2 and IL‐4 in both AD and DLB. Reviews of the literature show PD patients have higher serum levels of inflammatory markers such as IL‐1β, IL‐6, IL‐8, TNFα, IFNγ and RANTES 10,11 and studies from our centers have also reported that inflammatory markers predict disease progression in PD 12 . Numerous studies in PD show polymorphisms in several inflammation‐related genes as being risk factors for the disease, including TREM2 , IL1β , TNFα , LRRK2 and HLA‐DR 13,14 .…”

Section: Introductionmentioning

confidence: 90%

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Prospective longitudinal evaluation of cytokines in mild cognitive impairment due to AD and Lewy body disease

Thomas

Hamilton

Donaghy

et al. 2020

Int J Geriat Psychiatry

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Objectives We conducted a prospective longitudinal study of plasma cytokines during the Mild Cognitive Impairment (MCI) stage of Lewy body disease and Alzheimer's disease, hypothesizing that cytokine levels would decrease over time and that this would be correlated with decline in cognition. Methods Older (≥60) people with MCI were recruited from memory services in healthcare trusts in North East England, UK. MCI was diagnosed as due to Alzheimer's disease (MCI‐AD) or Lewy body disease (MCI‐LB). Baseline and repeat annual clinical and cognitive assessments were undertaken and plasma samples were obtained at the same time. Cytokine assays were performed on all samples using the Meso Scale Discovery V‐Plex Plus Proinflammatory Panel 1, which included IFNγ, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13 and TNFα. Results Fifty‐six patients (21 MCI‐AD, 35 MCI‐LB) completed prospective evaluations and provided samples up to 3 years after baseline. Six cytokines (IFNγ, IL‐1β, IL‐2, IL‐4, IL‐6 and IL‐10) showed highly significant (P < .002) decreases over time. AD and LB did not differ in rate of decrease nor were there any effects related to age or general morbidity. Decrease in five of these cytokines (IFNγ, IL‐1β, IL‐2, IL‐4, and IL‐10) was highly correlated with decrease in cognition (P < .003). Conclusions Peripheral inflammation decreased in both disease groups during MCI suggesting this may be a therapeutic window for future anti‐inflammatory agents.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 90%

Prospective longitudinal evaluation of cytokines in mild cognitive impairment due to AD and Lewy body disease

Thomas

Hamilton

Donaghy

et al. 2020

Int J Geriat Psychiatry

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“…In particular, it was demonstrated that shorter LTL was associated with various neurodegenerative disorders. For example, a latest study showed LTL at baseline and 18 months was shorter in patients of Parkinson's disease (PD) compared to healthy controls 12 , although prior studies found nonsignificant association between LTL and PD (Table 1 ). In addition, telomere shortening was recognized as an indicator of progression for Alzheimer’s disease (AD) (Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Gao¹,

Wang²,

Yu³

et al. 2020

Sci Rep

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We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genomewide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population. Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal multisystem neurodegenerative disease, leading to substantial public health threat although it is relatively rare worldwide. However, the cause and pathogenesis underlying ALS mostly remains unknown, with few replicable and definitive risk factors and scarce drugs available 1-4. The number of ALS cases is predicted to increase dramatically due to population aging in the coming years 5 , which would further aggravate the ALS-associated social and economic burden. Therefore, the identification of its risk factors can provide better understanding of ALS and has the potential to pave the way for therapeutic intervention. In the past few years the role of telomere in various complex diseases has attracted much attention 6. Progressive telomere shortening occurs in all dividing normal cells due to incomplete synthesis of DNA lagging-strand, oxidative damage and other factors, which ultimately leads to cellular growth arrest or apoptosis that is thought to be an initial proliferative barrier to tumor development in humans 7. Indeed, recent studies suggested that leukocyte telomere length (LTL) was widely relevant to age-related diseases and disorders (e.g. many types of cancer and coronary heart disease) 8-11. In particular, it was demonstrated that shorter LTL was associated with various neurodegenerative disorders. For example, a latest study showed LTL at baseline and 18 months was shorter in patients of Parkinson's disease (PD) compared to healthy controls 12 , although prior studies found nonsignificant association between LTL and PD (Table 1). In addition, telomere shortening was recognized as an indicator of progression for Alzheimer's disease (AD) (Table 1). However, the knowledge about the relationship between LTL and ALS is very limited. Previous studies proposed th...

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“…However, the role of telomere length in these diseases remains to be fully elucidated. Shorter telomeres have been identified in both Alzheimer's (14) and Parkinson's disease (15) patients and have been found to accelerate both the onset and underlying pathology of neurodegeneration in mice models (16). Shorter telomere length is also associated with a higher risk of coronary heart disease (17), an association that is thought to be causal (18).…”

Section: Introductionmentioning

confidence: 99%

“…Many clinical studies pointing to a relationship between telomere length and age-related disease measure telomere length from blood samples, reporting leukocyte telomere length as a proxy for the tissues relevant to the disease (14,15,17). The true meaning of such research relies upon the fundamental assumption that changes in telomere length are robust across tissues and that leukocyte telomere length accurately reflects the tissue of interest, such as heart or brain.…”

Section: Introductionmentioning

confidence: 99%

Stress reactivity elicits a tissue-specific reduction in telomere length in ageing zebrafish (Danio rerio)

Evans

Torres-Pérez

Petrazzini

et al. 2020

Preprint

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Telomere length reflects cellular ageing. Increased telomere shortening in leukocytes is associated with a range of neurodegenerative and cardiovascular diseases, the onset and progression of which may be mediated by behavioural traits such as anxiety and stress reactivity. However, the effects of the hypothalamus-pituitary-adrenal axis stress response are shown to be tissue specific. As such, leukocyte telomere length may not give an accurate measure of the relationship between stress-reactivity and telomere length in disease relevant tissues. To test the hypothesis that stress-reactivity contributes to age-related telomere shortening in a tissue specific manner, we examined the correlation between telomere length in heart and brain tissue and stress-reactivity in a population of young (6-9 month) and ageing (18 month) zebrafish. Stress-reactivity was assessed by tank diving, a zebrafish version of the rodent open-field test, and through gene expression. Telomere length was assessed using quantitative polymerase chain reaction. We show that ageing zebrafish have shorter telomeres in both heart and brain. Telomere length is inversely related to stress-reactivity in heart but not brain of ageing individuals. These data support the hypotheses that an anxious predisposition contributes to telomere shortening in heart tissue, and by extension age-related heart disease, and that stress-reactivity contributes to age-related telomere shortening in a tissue-specific manner.

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Senescence and Inflammatory Markers for Predicting Clinical Progression in Parkinson’s Disease: The ICICLE-PD Study

Cited by 39 publications

References 70 publications

Prospective longitudinal evaluation of cytokines in mild cognitive impairment due to AD and Lewy body disease

Prospective longitudinal evaluation of cytokines in mild cognitive impairment due to AD and Lewy body disease

Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Stress reactivity elicits a tissue-specific reduction in telomere length in ageing zebrafish (Danio rerio)

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