Theory of Cognitive Aging in Parkinson Disease

Nguyen, Hoang Thuy Linh; Hall, Brianna; Higginson, Christopher I.; Sigvardt, Karen A.; Zweig, Richard M.; Disbrow, Elizabeth A.

doi:10.4172/2161-0460.1000369

Cited by 4 publications

(4 citation statements)

References 72 publications

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“…Research has shown that Parkinson disease causes loss of dopamine-producing neurons in the substantia nigra and dopaminergic processes are shown to be involved in cognitive functions such as processing speed. 52 Controlling for HbA1c, we identify rs71467481 in the intronic region of PPFIA1 as another significant hit for complex processing speed. Our eQTL analysis shows that variants around 500 kbp of this SNP can significantly regulate expression of PPFIA1 in many brain regions ( Figure S8 ; Table S30 ).…”

Section: Resultsmentioning

confidence: 92%

Exome-wide analysis reveals role of LRP1 and additional novel loci in cognition

Chakraborty

Kahali

2023

Human Genetics and Genomics Advances

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Section: Resultsmentioning

confidence: 92%

Exome-wide analysis reveals role of LRP1 and additional novel loci in cognition

Chakraborty

Kahali

2023

Human Genetics and Genomics Advances

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“…However, findings of sex differences in processing speed in PD remain mixed with some studies reporting superior female performance (Bayram et al, 2020; Cholerton et al, 2018; Reekes et al, 2020) while others report no differences between male and females with PD (Chen et al, 2021; Liu et al, 2015). Our lab has previously shown that deficits in processing speed mediate the relationship between age and executive dysfunction in persons with PD (Nguyen et al, 2017). Moreover, in individuals with PD, processing speed deficits have been associated with progression from PD mild cognitive impairment to PD Dementia (Cholerton et al, 2018).…”

Section: Discussionmentioning

confidence: 92%

“…PD is known to affect an array of cognitive functions. Inhibition, switching, sequencing (Kudlicka et al, 2011; Litvan et al, 1991; Muslimovic et al, 2005; Shook et al, 2005), spatial working memory (Caballol et al, 2007; Emre, 2003), processing speed (Disbrow et al, 2014; Hansch et al, 1982; Lanni et al, 2014; Nguyen et al, 2017; Pal et al, 2016; Vriend et al, 2020; Zweig et al, 2016), and working and recognition memory (Dubois & Pillon, 1997; Higginson et al, 2005) have all been implicated. Therefore, the Movement Disorder Task Force (Litvan et al, 2012) suggest five cognitive domains relevant to the evaluation of cognitive impairment in PD: attention and working memory, executive function, language, memory (unspecified), and visuospatial function.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in Parkinson disease-associated episodic memory and processing speed deficits

Reekes

Higginson

Sigvardt

et al. 2023

J Int Neuropsychol Soc

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Objectives: This study aims to address a gap in the data on cognitive sex differences in persons living with Parkinson disease (PD). There is some evidence that cognitive dysfunction is more severe in male PD, however data on episodic memory and processing speed is incomplete. Methods: One hundred and sixty-seven individuals with a diagnosis of PD were included in this study. Fifty-six of those individuals identified as female. The California Verbal Learning Test 1st edition and the Wechsler Memory Scale 3rd edition were used to evaluate verbal and visuospatial episodic memory and the Wechsler Adult Intelligence Scale 3rd edition was used to evaluate processing speed. Multivariate analysis of covariance was used to identify sex-specific differences across groups. Results: Our results show that males with PD performed significantly worse than females in verbal and visuospatial recall as well as a trend for the processing speed task of coding. Conclusions: Our finding of superior performance among females with PD in verbal episodic memory is consistent with reports in both healthy and PD individuals; however, females outperforming males in measures of visuospatial episodic memory is unique to PD. Cognitive deficits preferentially affecting males appear to be associated with frontal lobe-related function. Therefore, males may represent a disease subgroup more susceptible to disease mechanisms affecting frontal lobe deterioration and cognitive disturbances in PD.

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“…Research has shown that Parkinson's disease causes loss of dopamine producing neurons in the substantia nigra and dopaminergic processes have been shown to be involved in cognitive functions like processing speed. 57 Controlling for HbA1c, we identify rs71467481 in intronic region of PPFIA1 as another novel significant hit for complex processing speed. Our eQTL analysis shows that variants around 500 kbp of this SNP can significantly regulate expression of PPFIA1 in many brain regions (Supplementary Fig.…”

Section: Eqtl Analysis Of Significant Loci Associated With Complex Pr...mentioning

confidence: 95%

Exome-wide analysis reveals role ofLRP1and additional novel loci in cognition

Chakraborty

Kahali

2022

Preprint

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Cognitive functioning is heritable, with metabolic risk factors known to accelerate age-associated cognitive decline. Identifying genetic underpinnings of cognition is thus crucial. Here, we undertake single-variant and gene-based association analyses upon six neurocognitive phenotypes across six cognition domains in whole-exome sequencing data from 157,160 individuals in the UK Biobank to expound the genetic architecture of human cognition. We further identify genetic variants interacting with APOE, a significant genetic risk factor for cognitive decline, while controlling for lipid and glycemic risks, towards influencing cognition. Additionally, considering lipid and glycemic traits, we conduct bivariate analysis to underscore pleiotropic effects and also highlight suggestive mediation effects of metabolic risks on cognition. We report 18 independent novel loci associated with five cognitive domains while controlling for APOE isoform-carrier status and metabolic risk factors. Our novel variants are mostly in genes which could also impact cognition via their functions on synaptic plasticity and connectivity, oxidative stress, neuroinflammation. Variants in or near these identified loci show genetic links to cognitive functioning in association with APOE, Alzheimers disease and related dementia phenotypes and brain morphology phenotypes, and are also eQTLs significantly controlling expression of their corresponding genes in various regions of the brain. We further report four novel pairwise interactions between exome-wide significant loci and APOE variants influencing episodic memory, and simple processing speed while accounting for serum lipid and serum glycemic traits. We obtain both APOC1 and LRP1 as significantly associated with complex processing speed and visual attention in our gene-based analysis. They also exhibit significant interaction effect with APOE variants in influencing visual attention. We find that variants in APOC1 and LRP1 act as significant eQTLs for regulating their expression in basal ganglia and cerebellar hemispheres, crucial to visual attention. Taken together, our findings suggest that APOC1 and LRP1 have plausible roles along pathways of amyloid-beta, lipid and/or glucose metabolism in affecting visual attention and complex processing speed. Interestingly, variants in MTFR1L, PPFIA1, PCDHB16, ATP2A1 show evidence of pleiotropy and mediation effects through serum glucose/HDL levels affecting four different cognition domains. This is the first report from large-scale exome-wide study with evidence underscoring the effect of LRP1 on cognition. Our research highlights a novel set of loci that augments our understanding of the genetic underpinnings of cognition during ageing, considering co-occurring metabolic conditions that can confer genetic risk to cognitive decline in addition to APOE, which can aid in finding causal determinants of cognitive decline.

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Theory of Cognitive Aging in Parkinson Disease

Cited by 4 publications

References 72 publications

Exome-wide analysis reveals role of LRP1 and additional novel loci in cognition

Exome-wide analysis reveals role of LRP1 and additional novel loci in cognition

Sex differences in Parkinson disease-associated episodic memory and processing speed deficits

Exome-wide analysis reveals role ofLRP1and additional novel loci in cognition

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