Parkinson's Disease and Apolipoprotein E: Possible Association with Dementia but not Age at Onset

University of Louisville Birth Defects Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
Genomics (Impact Factor: 2.28). 03/2002; 79(3):458-61. DOI: 10.1006/geno.2002.6707
Source: PubMed


Idiopathic Parkinson's disease (PD) is an age-dependent, neurodegenerative condition frequently associated with dementia. Although it is predominantly a sporadic disease, 20-30% of cases are familial, suggesting a complex mode of inheritance. Apolipoprotein E (APOE) allele epsilon4 has been associated with familial and sporadic late-onset senile dementia of the Alzheimer's type. To investigate the role of this gene in the development of dementia associated with PD and age at onset of PD, we evaluated the frequency of APOE gene polymorphism in a sample of PD patients with (n=118) and without (n=167) a family history, as well as matched normal controls (n=96). The PD sample was categorized according to age at onset and presence or absence of dementia. Kaplan-Meier survival analysis was used to plot genotype-specific age at onset distribution curves. Allele frequencies of APOE in PD patients with and without a family history and normal controls were not significantly different. APOE genotypes were also similar between the groups. However, the frequencies of epsilon4 allele and epsilon4/- genotype in the PD group with dementia were more than twofold higher than in normal controls, and the differences were statistically significant. There were no differences in the allele and genotype frequencies of the APOE gene between PD groups with different age at onset. The familial PD had significantly earlier age at onset than sporadic PD (Log-rank test, P=0.027). The age at onset distribution curves for different genotype groups were similar, and their differences were not statistically significant (P=0.38). After the Bonferroni's correction for multiple tests, the positive results are not significant at the P<0.05 level. We conclude that APOE does not play an important role in susceptibility to PD or age at onset of PD, but may play a role in dementia associated with PD in our sample.

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    • "Infarct size, survival and performance in behavioral tests after focal ischemia or closed head injury is significantly altered in mice expressing the human APOE4 gene [38]. APOE genotype also worsens outcomes and severity of disease in peripheral neuropathy, in Parkinson's disease and in AIDS dementia [17] [21] [28] [73]. Since activation of the innate immune system is an invariant component of most neurodegenerative disease [4,24,26,69], we hypothesized that APOE4-associated changes in outcome and severity of neurological disease was related to an interaction of apolipoprotein E (apoE), the protein product of the APOE4 gene, with components of the innate immune system in the CNS. "
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    ABSTRACT: Microglia are a primary cellular component of the CNS innate immune system. Their response to conserved pathogen motifs is inherent and leads to the release of cytoactive factors that impact surrounding neurons and glia. The microglial response is modified by the local tissue environment and by "global" factors such as gender. Exposure to estrogen and testosterone, in general, down regulate microglia and peripheral macrophage function, promoting an anti-inflammatory phenotype. Other global factors, however, can "override" the gender-based effects demonstrated by estrogen or testosterone. Apolipoprotein E (APOE) genotype and the expression of specific isoforms of apolipoprotein E differentially regulate microglial and peripheral macrophage function. Our studies have shown that the presence of the APOE4 gene, a known risk factor for AD and other neurodegenerative diseases, promotes a pro-inflammatory macrophage phenotype in neonatal microglia. However, in adult mice, the APOE genotype-specific effect depends on gender. Peritoneal macrophages from female adult APOE3 and APOE4 targeted replacement mice do not demonstrate an APOE genotype-specific response, whereas adult male APOE4 targeted replacement mice show enhanced macrophage responsiveness compared to adult male APOE3 mice. At least part of the altered macrophage response in APOE4 male mice may be due to differences in androgen receptor sensitivity to testosterone. These data re-enforce the concept that classical activation in macrophages has multiple levels of regulation, dictated by competing or synergistic factors and genotype.
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    ABSTRACT: Hypokinesia, rigidity, tremor, and postural instability are the cardinal symptoms of Parkinson s disease (PD). Since these symptoms are not specific to PD the diagnosis may be uncertain in early PD. Etiology and pathogenesis of PD remain unclear. There is no neuroprotective therapy. Genetic findings are expected to reveal metabolic routes in PD pathogenesis and thereby eventually lead to therapeutic innovations. In this thesis, we first aimed to study the usefulness and accuracy of 123I-b-CIT SPECT in the diagnosis of PD in a consecutive clinic-based material including various movement disorders. We subsequently a genetic project to identify genetic risk factors for sporadic PD using a candidate gene approach in a case-control setting including 147 sporadic PD patients and 137 spouse controls. Dopamine transporter imaging by 123I-b-CIT SPECT could distinguish PD from essential tremor, drug-induced parkinsonism, dystonia and psychogenic parkinsonism. However, b-CIT uptake in Parkinson plus syndromes (PSP and multiple system atrophy) and dementia with Lewy bodies was not significantly different from PD. 123I-b-CIT SPECT could not reliably differentiate PD from vascular parkinsonism. 123I-b-CIT SPECT was 100% sensitive and specific in the diagnosis of PD in patients younger than 55 years but less specific in older patients, due to differential distribution of the above conditions in the younger and older age groups. 123I-b-CIT SPECT correlated with symptoms and detected bilateral nigrostriatal defect in patients whose PD was still in unilateral stage. Thus, in addition to as a differential diagnostic aid, 123I-b-CIT SPECT may be used to detect PD early, even pre-symptomatically in at-risk individuals. 123I-b-CIT SPECT was used to aid in the collection of patients to the genetic studies. In the genetic part of this thesis we found an association between PD and a polymorphic CAG-repeat in POLG1 gene encoding the catalytic subunit of mitochondrial polymerase gamma. The CAG-repeat encodes a polyglutamine tract (polyQ), the two most common lengths of which are 10Q (86-90%) and 11Q. In our Finnish material, the rarer non-10Q or non-11Q length variants (6Q-9Q, 12Q-14Q, 4R+9Q) were more frequent in patients than in spouse controls (10% vs. 3.5 %, p=0.003), or population controls (p=0.001). Therefore, we performed a replication study in 652 North American PD patients and 292 controls. Non-10/11Q alleles were more common in the US PD patients compared to the controls but the difference did not reach statistical significance (p=0.07). This larger data suggested our original definition of variant length allele might need reconsideration. Most previous studies on phenotypic effects of POLG1 polyQ have defined 10Q as the only normal allele. Non-10Q alleles were significantly more common in patients compared to the controls (17.3% vs. 12.3 %, p= 0.005). This association between non-10Q length variants and PD remained significant when compared to a larger set of 1541 literature controls (p=0.00005). In conclusion, POLG1 polyQ alleles other than 10Q may predispose to PD. We did not find association between PD and parkin or DJ-1, genes underlying autosomal recessive parkinsonism. The functional Val158Met polymorphism, which affects the catalytic effect of COMT enzyme, and another coding polymorphism in COMT were not associated with PD in our patient material. The APOE e2/3/4 polymorphism modifies risk for Alzheimer s disease and prognosis of for example brain trauma. APOE promoter and enhancer polymorphisms 219G/T and +113G/C, and APOE e3 haplotypes, have also been shown to modify the risk of Alzheimer s disease but not reported in PD. No association was found between PD and APOE e2/3/4 polymorphism, the promoter or enhancer polymorphisms, or the e3 haplotypes. Parkinsonin tauti (PT) on vanhemmalla iällä ilmenevä neurodegeneratiivinen sairaus, jonka pääoireet ovat vapina, jäykkyys, liikkeiden hitaus ja tasapainon ja asennonsäätelyn häiriö. Nämä oireet eivät ole PT:lle spesifisiä, ja diagnoosi on alkuvaiheessa usein epävarma. Taudin syntymekanismi on edelleen epäselvä eikä taudin etenemiseen vaikuttavaa lääkitystä ole. Geneettisten riskitekijöiden löytämisen toivotaan auttavan taudin mekanismien selvittämisessä ja johtavan terapeuttisiin innovaatioihin. Tässä väitöskirjatyössä selvitettiin ensin dopamiinitransportterien (DAT) gammakuvauksen (123I-b-CIT SPECT) hyödyllisyyttä kliinisessä aineistossa, jossa oli useita eri liikehäiriöitä sairastavia potilaita. DAT tiheys kuvastaa nigrostriataalisten neuronien määrää, minkä vuoksi PT-potilailla nähdäänkin 123I-b-CIT SPECT:ssä alentunut DAT-tiheys. 123I-b-CIT SPECT todettiin erottavan PD-potilaat essentielliä tremoria, lääkeaineparkinsonismia ja psykogeenistä parkinsonismia sairastavista. Toisaalta menetelmä ei erotellut Parkinson + -oireyhtymiä tai Lewyn kappale dementiaa sairastavia potilaita PD-potilaista. 123I-b-CIT SPECT ei myöskään varmuudella auta vaskulaarisen parkinsonismin ja PT:n erotusdiagnostiikassa. 123I-b-CIT SPECT yli 100 % sensitiivinen ja spesifinen PD-diagnoosissa alle 55-vuotiaassa aineistossa mutta vähemmän spesifinen vanhemmassa potilasaineistossa yllämainittujen diagnoosien ikäjakaumasta johtuen. 123I-b-CIT SPECT korreloi oireiden vakavuuden kanssa ja havaitsi bilateraalisen DAT-tiheyden aleneman jo siinä vaiheessa kun potilaan oireet vielä rajoittuivat toiselle puolelle. 123I-b-CIT SPECTiä voitaneenkin käyttää, paitsi erotusdiagnostiikassa, myös etsimään PT:a riskihenkilöiltä jo motorisia oireita edeltävässä vaiheessa. 123I-b-CIT SPECTiä käytettiin apuna potilasvalinnassa työn geneettiseen osioon. Geneettisessa potilas-verrokkiaineistossa oli 147 sporadista suomalaista parkinsonpotilasta ja 137 puolisoa kontrolleina. Mitokondriaalista polymeraasi gamma-entsyymiä koodaavan POLG1 geenin eksonissa 2 olevasta polymorfisesta CAG-toistojaksosta löytyi todennäköinen PT:n riskitekijä. Tämä CAG-toisto koodaa polyglutamiiniketjua (polyQ), jonka yleisimmät pituudet ovat 10Q (86-90%) ja 11Q. Suomalaisilla potilailla polyQ-alleellit, jotka olivat lyhyempiä kuin 10Q tai pidempiä kuin 11Q (non-10/11Q) olivat yleisempiä kuin kontrolleilla (10 vs. 3.5 %, p= 0.003). Teimme replikaatiotutkimuksen pohjoisamerikkalaisessa aineistossa (652 PT-potilasta, 292 kontrollia). Non-10/11Q alleelit olivat potilailla yleisempiä kuin kontrolleilla, mutta ei merkittävästi (p=0.07). Monissa aiemmissa POLG1 polyQ:ta muissa ilmiasuissa tutkineissa töissä ainoastaan 10Q alleelia on pidetty normaalina alleelina. Non-10Q-alleelit olivat selvästi yleisempiä PT-potilailla kuin kontrolleilla (17.3% vs. 12.3 %, p= 0.005) tai 1541 kirjallisuuskontrollilla (p=0.00005). POLG1 geenin polyQ-jakson non-10Q pituusvariantit näyttävät lisäävän PT:n riskiä. Aineistossamme ei löytynyt assosiaatiota DJ-1 tai parkin geeneihin, joiden mutaatiot aiheuttavat resessiivisen varhain alkavan PT:n. Myöskään COMT-entsyymin aktiivisuuteen vaikuttava COMT Val158Met substituutio tai Ala72Ser eivät olleet yhteydessä PT:n riskiin. APOE e2/3/4 polymorfismin tiedetään vaikuttavan mm. Alzheimerin taudin riskiin ja aivovamman ennusteeseen, samoin APOE promoottorialueen polymorfismien ja haplotyyppien yhteys Alzheimer-riskiin on raportoitu. Aineistossamme APOE e2/3/4 ei assosioitunut PT riskiin, eivät myöskään -219G/T, +113G/C polymorfismit tai APOE haplotyypit.
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