APOE, MAPT, and COMT and Parkinson’s Disease Susceptibility and Cognitive Symptom Progression

Paul, Kimberly C.; Rausch, Rebecca; Creek, Michelle M.; Sinsheimer, Janet S.; Bronstein, Jeff M.; Bordelon, Yvette; Ritz, Beate

doi:10.3233/jpd-150762

Cited by 55 publications

(58 citation statements)

References 39 publications

(55 reference statements)

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“…Although patients in that study underwent detailed neuropsychological assessments, association tests between the H1 haplotype and change over time in the other cognitive measures were not performed. In contrast, a recent longitudinal study of 246 PD patients from the Parkinson’s Environment and Gene Study observed no association between the MAPT H1 haplotype and change in MMSE score over time (Paul et al, 2016). We recently reported that the MAPT H1 haplotype was not associated with any of the PDCGC core cognitive variables in a PD cohort that largely overlapped with the one studied here (Mata et al, 2014).…”

Section: Discussionmentioning

confidence: 95%

“…Because APOE ε4 is known to influence cognitive performance in PD (Mata et al, 2014, Morley et al, 2012, Paul et al, 2016), we separately genotyped rs429358 on all subjects using a TaqMan assay as previously described (Mata et al, 2014) and analyzed the ε4 allele using the methods employed for all other common variants. After correction for multiple testing, APOE ε4 was not associated with any of the core cognitive variables (Supplementary Table 11).…”

Section: Resultsmentioning

confidence: 99%

“…(Alcalay et al, 2012, Alcalay et al, 2015, Mata et al, 2016, Mata et al, 2014, Paul et al, 2016, Srivatsal et al, 2015) Furthermore, we have shown that these genes have a differential impact on specific cognitive domains. For example, in PD patients without dementia the APOE ε4 allele is associated with lower performance on word list learning and semantic verbal fluency while GBA variants predict worse scores on tests of working memory/executive function and visuospatial abilities.…”

Section: Introductionmentioning

confidence: 92%

“…Other studies have nominated variants in several other genes, including COMT and MAPT , as modifiers of cognitive dysfunction in PD,(Foltynie et al, 2004, Williams-Gray et al, 2009) but these results have not been uniformly replicated. (Hoogland et al, 2010, Mata et al, 2014, Paul et al, 2016)…”

Section: Introductionmentioning

confidence: 99%

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Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

Mata

Johnson

Leverenz

et al. 2017

Neurobiology of Aging

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Cognitive impairment is a common and disabling problem in Parkinson’s disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1,105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). For common variants we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate corrected P-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 × 10−4) for JoLO, PARP4 rs9318600 (PFDR = 0.006) and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.

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Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

Mata

Johnson

Leverenz

et al. 2017

Neurobiology of Aging

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“…For these participants, validated weights were applied to make scores comparable with the 30-point in-person interview [58]. For patients with an MMSE score ≥26, in-depth assessment of cognitive function was performed at the next two follow-up exams with a detailed neuropsychological battery that included tests of global cognition, executive function, language, memory, and visuospatial skills described in greater detail elsewhere [59, 60]. …”

Section: Methodsmentioning

confidence: 99%

Vitamin D receptor gene polymorphisms and cognitive decline in Parkinson's disease

Gatto

Paul²,

Sinsheimer

et al. 2016

Journal of the Neurological Sciences

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We and others have suggested that vitamin D receptor gene (VDR) polymorphisms influence susceptibility for Parkinson’s disease (PD), Alzheimer’s disease (AD), mild cognitive impairment (MCI) or overall cognitive functioning. Here we examine VDR polymorphisms and cognitive decline in patients with PD. Non-Hispanic Caucasian PD patients (n=190) in the Parkinson Environment Gene (PEG) study were successfully genotyped for seven VDR polymorphisms. Cognitive function was assessed with the Mini-Mental State Exam (MMSE) at baseline and at a maximum of three follow-up exams. Using repeated-measures regression we assessed associations between VDR SNP genotypes and change in MMSE longitudinally. PD cases were on average 67.4 years old at diagnosis and were followed for an average of 7.1 years into disease. Each additional copy of the FokI A allele was associated with a 0.115 decrease in the total MMSE score per year of follow-up (β = −0.115, SE(β) = 0.05, p=0.03) after adjusting for age, sex, education and PD duration. The effect on MMSE by the FokI A allele was comparable in absolute magnitude to the effect for disease duration in years prior to first interview (β = −0.129 per year, SE(β) = 0.08, p=0.13), and years of education (β = 0.118 per year, SE(β) = 0.03, p<0.001). When LD/LED use and PD subtype were added to the model, the effect of the FokI A allele on total MMSE score was magnified (β = −0.141, SE(β) = 0.05, p=0.005). Results point to Fokl, a functional VDR polymorphism, as being associated with cognitive decline in PD. Future studies examining the contributions of the vitamin D metabolic pathway to cognitive dysfunction in PD are needed.

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The absorption of apolipoprotein E by damaged neurons facilitates neuronal repair

Chen

Xie

Peng

et al. 2019

Cell Biology International

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Traumatic brain injury (TBI) is one of the common diseases diagnosed in departments of neurosurgery. Apolipoprotein E (apoE) can improve the prognosis of TBI. In this study, we aimed to explore the effect of apoE in mechanically damaging neurons as well as its underlying molecular mechanism. Western blot analysis and immunofluorescence assay was performed to detect the expressions of associated proteins. The expressions of apoE, p38, and phosphorylation of P38 were increased in mechanically injured neurons compared with those of the non‐injured ones. Neurons transfected into silencing apoE had no clear difference in the expression of apoE between injured and non‐injured neurons. However, in the injured neurons, silencing apoE could significantly decrease apoE and p‐P38 expressions. Oligodendrocytes were cultured in the medium collected from mechanically damaged si‐apoE neurons. Furthermore, we found that mechanically injured si‐apoE neurons could absorb the secreted apoE from the oligodendrocyte medium of the injured si‐apoE‐neuron, along with increasing of p‐P38 expression at 24 h. The p38 MAPK inhibitor BIRB 796 almost did not affect the apoE expression at 24 h, but significantly reduced the p‐P38 level at 24 and 72 h in injured si‐apoE neurons cultured with oligodendrocyte medium of the injured si‐apoE‐neurons. Moreover, our result showed that neuronal repair effects in normal neurobasal medium (lowest levels of apoE and p‐P38) and BIRB 796 medium (low level of p‐P38) were more slow than those in the oligodendrocyte medium of the injured si‐apoE‐neurons. To conclude, our data demonstrated that mechanical injury of neurons stimulated oligodendrocytes to secrete apoE. The injured neurons could absorb secreted apoE. The expression of apoE contributed to the activation of p38 MAPK, which facilitated neuron repair.

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APOE, MAPT, and COMT and Parkinson’s Disease Susceptibility and Cognitive Symptom Progression

Cited by 55 publications

References 39 publications

Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease

Vitamin D receptor gene polymorphisms and cognitive decline in Parkinson's disease

The absorption of apolipoprotein E by damaged neurons facilitates neuronal repair

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