Parkinson's disease susceptibility variants and severity of Lewy body pathology

Heckman, Michael G.; Kasanuki, Koji; Diehl, Nancy N.; Koga, Shunsuke; Soto, Alexandra I.; Murray, Melissa E.; Dickson, Dennis W.; Ross, Owen A.

doi:10.1016/j.parkreldis.2017.09.009

Cited by 18 publications

(15 citation statements)

References 21 publications

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“…Although the MAPT H1 haplotype is a well‐known genetic risk factor for LBD (PD in particular), studies to date have not indicated that the common MAPT H1 haplotype modifies neuropathological features in individuals with LBD . However, these previous investigations have not taken into account MAPT haplotype diversity, and it is this gap in knowledge that we set out to address in the current study.…”

Section: Discussionmentioning

confidence: 89%

“…Although the MAPT H1 haplotype is a well-known genetic risk factor for LBD (PD in particular), studies to date have not indicated that the common MAPT H1 haplotype modifies neuropathological features in individuals with LBD. 13,14 However, these previous investigations have not taken into account MAPT haplotype diversity, and it is this gap in knowledge that we set out to address in the current study. Interestingly, although the H2 haplotype was not notably associated with any of the LBD neuropathological outcomes that were assessed as has been previously shown, 13,14 we observed a significant association between the rare H1j subhaplotype and a greater degree of dorsolateral putaminal dopaminergic degeneration, with a similar (but only nominally significant) association with increased dopaminergic depletion in the ventromedial region.…”

Section: Discussionmentioning

confidence: 99%

“…We did not observe any dramatic associations between MAPT haplotypes and severity of LB pathology. In a previous study, PD genetic risk variants that were identified in a meta‐analysis of genome‐wide association studies were assessed for association with severity of LB pathology, and though several nominally significant correlations were noted (as was also the case in our study), no major associations were identified . The findings of our current study provide further support for the hypothesis that factors other than PD susceptibility loci are responsible for the variation in severity of LB pathology in LBD patients.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Previous studies have investigated whether in addition to altering risk of PD and DLB, MAPT H1 may also modify neuropathological features of LBD in general; findings have pointed toward a lack of association. 13,14 However, the MAPT H1 haplotype can be further classified into approximately 20 different common subhaplotypes, 15 and therefore an examination of MAPT H1 without consideration of H1 subhaplotypes has potential to overlook important associations. A number of studies have identified associations between specific H1 subhaplotypes and risk of various neurodegenerative diseases.…”

Section: Mapt; Neuropathologymentioning

confidence: 99%

“…The MAPT gene contains two major haplotypes; the H1 haplotype is common, occurring in approximately 80% of neurologically normal subjects, whereas H2 is the rarer and generally only occurs in individuals of European ancestry . Previous studies have investigated whether in addition to altering risk of PD and DLB, MAPT H1 may also modify neuropathological features of LBD in general; findings have pointed toward a lack of association …”

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confidence: 99%

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Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease

et al. 2019

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Background Genetic variation at the microtubule‐associated protein tau locus is associated with clinical parkinsonism. However, it is unclear as to whether microtubule‐associated protein tau H1 subhaplotypes are associated with the burden of neuropathological features of Lewy body disease. Objectives To evaluate associations of microtubule‐associated protein tau haplotypes with severity of Lewy body pathology and markers of SN neuronal loss in Lewy body disease cases. Methods Five hundred eighty‐five autopsy‐confirmed Lewy body disease cases were included. Six microtubule‐associated protein tau variants (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521) were genotyped to define common microtubule‐associated protein tau haplotypes. Lewy body counts were measured in five cortical regions. Ventrolateral and medial SN neuronal loss were assessed semiquantitatively. Nigrostriatal dopaminergic degeneration was quantified by image analysis of tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen. Results The common microtubule‐associated protein tau H2 haplotype did not show a strong effect on pathological burden in Lewy body disease. The rare H1j haplotype (1.3%) was significantly associated with a lower dorsolateral putaminal tyrosine hydroxylase immunoreactivity (and therefore greater dopaminergic degeneration) compared to other microtubule‐associated protein tau haplotypes (P = 0.0016). Microtubule‐associated protein tau H1j was also nominally (P ≤ 0.05) associated with a lower ventromedial putaminal tyrosine hydroxylase immunoreactivity (P = 0.010), but this did not survive multiple testing correction. Other nominally significant associations between microtubule‐associated protein tau H1 subhaplotypes and neuropathological outcomes were observed. Conclusions A rare microtubule‐associated protein tau H1 subhaplotype (H1j) may be associated with more severe putaminal dopaminergic degeneration in Lewy body disease cases. Microtubule‐associated protein tau H1j has been associated previously with an increased risk of PD, and therefore our exploratory findings provide insight into the mechanism by which H1j modulates PD risk. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mapt; Neuropathologymentioning

confidence: 99%

mentioning

confidence: 99%

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Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease

et al. 2019

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Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics

Cacabelos

Carrera

Martínez

et al. 2021

Medicinal Research Reviews

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Atremorine is a novel bioproduct obtained by nondenaturing biotechnological processes from a genetic species of Vicia faba.Atremorine is a potent dopamine (DA) enhancer with powerful effects on the neuronal dopaminergic system, acting as a neuroprotective agent in Parkinson's disease (PD). Over 97% of PD patients respond to a single dose of Atremorine (5 g, p.o.) 1 h after administration. This response is gender-, time-, dose-, and genotype-dependent, with optimal doses ranging from 5 to 20 g/day, depending upon disease severity and concomitant medication. Drug-free patients show an increase in DA levels from 12.14 ± 0.34 pg/ml to 6463.21 ± 1306.90 pg/ ml; and patients chronically treated with anti-PD drugs show an increase in DA levels from 1321.53 ± 389.94 pg/ml to 16,028.54 ± 4783.98 pg/ml, indicating that Atremorine potentiates the dopaminergic effects of conventional anti-PD drugs. Atremorine also influences the levels of other neurotransmitters (adrenaline, noradrenaline) and hormones which are regulated by DA (e.g., prolactin, PRL), with no effect on serotonin or histamine. The variability in Atremorine-induced DA response is highly attributable to pharmacogenetic factors.

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Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts and controversies

Jellinger¹

2017

J Neural Transm

224

181

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Dementia with Lewy bodies (DLB) and Parkinson's disease-dementia (PDD), although sharing many clinical, neurochemical and morphological features, according to DSM-5, are two entities of major neurocognitive disorders with Lewy bodies of unknown etiology. Despite considerable clinical overlap, their diagnosis is based on an arbitrary distinction between the time of onset of motor and cognitive symptoms: dementia often preceding parkinsonism in DLB and onset of cognitive impairment after onset of motor symptoms in PDD. Both are characterized morphologically by widespread cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is given. The clinical features of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and post-mortem studies revealed more pronounced cortical atrophy, elevated cortical and limbic Lewy pathologies (with APOE ε4), apart from higher prevalence of Alzheimer pathology in DLB than PDD. These changes may account for earlier onset and greater severity of cognitive defects in DLB, while multitracer PET studies showed no differences in cholinergic and dopaminergic deficits. DLB and PDD sharing genetic, neurochemical, and morphologic factors are likely to represent two subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), beginning with incidental Lewy body disease-PD-nondemented-PDD-DLB (no parkinsonism)-DLB with Alzheimer's disease (DLB-AD) at the most severe end, although DLB does not begin with PD/PDD and does not always progress to DLB-AD, while others consider them as the same disease. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with AD and other proteinopathies. Cognitive impairment is not only induced by α-synuclein-caused neurodegeneration but by multiple regional pathological scores. Recent animal models and human post-mortem studies have provided important insights into the pathophysiology of DLB/PDD showing some differences, e.g., different spreading patterns of α-synuclein pathology, but the basic pathogenic mechanisms leading to the heterogeneity between both disorders deserve further elucidation. In view of the controversies about the nosology and pathogenesis of both syndromes, there remains a pressing need to differentiate them more clearly and to understand the processes leading these synucleinopathies to cause one disorder or the other. Clinical management of both disorders includes cholinesterase inhibitors, other pharmacologic and nonpharmacologic strategies, but these have only a mild symptomatic effect. Currently, no disease-modifying therapies are available.

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Parkinson's disease susceptibility variants and severity of Lewy body pathology

Cited by 18 publications

References 21 publications

Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease

Association of MAPT H1 subhaplotypes with neuropathology of lewy body disease

Atremorine in Parkinson's disease: From dopaminergic neuroprotection to pharmacogenomics

Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts and controversies

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