SPECT-aided diagnostics and genetic risk factors in Parkinson's disease

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

Kajoavan hoidon mahdollisuudet edenneessä Parkinsonin taudissa

VertaisarvioituParkinsonin taudin edenneessä vaiheessa optimaalinenkaan lääkehoito ei kontrolloi riittävästi motorisia tilanvaihteluja. Hoitoon ovat käytettävissä syväaivostimulaatio-, levodopainfuusio- jaapomorfiini-infuusiohoito. Ne eivät paranna eivätkä estä taudin etenemistä, vaan tavoitteena on elämänlaadun parantaminen. Oikea potilasvalinta ja asianmukainen seuranta varmistavat parhaan tuloksen.Peer reviewe

Polyneuropathy monitoring in Parkinson's disease patients treated with levodopa/carbidopa intestinal gel

Objectives Levodopa-carbidopa-intestinal-gel (LCIG) infusion is an effective treatment for advanced PD with motor fluctuations. Polyneuropathy occurs as a complication in 10-15% of patients. We wanted to assess the frequency of polyneuropathy in Finnish advanced Parkinson's disease (PD) patients with continuous LCIG infusion, and the value of different clinical monitoring parameters during follow-up. Materials and methods Patient records of PD patients started on LCIG infusion at Helsinki University Hospital who received nerve conduction studies at baseline and 6 months after treatment initiation were reviewed for epidemiological information, mini mental state examination, baseline and 6 months' UPRDS-III, weight, body mass index, levodopa dose (LD), plasma homocysteine levels, folate, vitamin B6 and B12. Results Out of 19 patients (n = 6 on B-vitamin substitution), two (10.5%) developed new-onset polyneuropathy after initiation of LCIG therapy (n = 0 with vitamin substitution). Neuropathy was associated with significant weight loss (BMI reduction > 1.5), but not with other monitoring parameters. Homocysteine rose significantly in patients not substituted with B-vitamin complex, but not in patients with B-vitamin substitution. Homocysteine changes correlated with LD changes in the absence of vitamin B substitution. After oral B-vitamin substitution, both patients' polyneuropathy remained electrophysiologically and clinically stable. Conclusions Rates of polyneuropathy in Finnish PD patients with LCIG treatment are comparable to previous studies. Patients' weight should be included in regular follow up monitoring and can be used for patient self-monitoring. Vitamin B substitution appears to reduce coupling between levodopa dose and homocysteine and may be useful to prevent polyneuropathy related to LCIG.Peer reviewe

Real-Life Experience on Directional Deep Brain Stimulation in Patients with Advanced Parkinson’s Disease

Directional deep brain stimulation (dDBS) is preferred by patients with advanced Parkinson’s disease (PD) and by programming neurologists. However, real-life data of dDBS use is still scarce. We reviewed the clinical data of 53 PD patients with dDBS to 18 months of follow-up. Directional stimulation was favored in 70.5% of dDBS leads, and single segment activation (SSA) was used in 60% of dDBS leads. Current with SSA was significantly lower than with other stimulation types. During the 6-month follow-up, a 44% improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS-III) points and a 43% decline in the levodopa equivalent daily dosage (LEDD) was observed. After 18 months of follow-up, a 35% LEDD decrease was still noted. The Hoehn and Yahr (H&Y) stages and scores on item no 30 “postural stability” in UPDRS-III remained lower throughout the follow-up compared to baseline. Additionally, dDBS relieved non-motor symptoms during the 6 months of follow-up. Patients with bilateral SSA had similar clinical outcomes to those with other stimulation types. Directional stimulation appears to effectively reduce both motor and non-motor symptoms in advanced PD with minimal adverse effects in real-life clinical care

Real-Life Experience on Directional Deep Brain Stimulation in Patients with Advanced Parkinson's Disease

Directional deep brain stimulation (dDBS) is preferred by patients with advanced Parkinson's disease (PD) and by programming neurologists. However, real-life data of dDBS use is still scarce. We reviewed the clinical data of 53 PD patients with dDBS to 18 months of follow-up. Directional stimulation was favored in 70.5% of dDBS leads, and single segment activation (SSA) was used in 60% of dDBS leads. Current with SSA was significantly lower than with other stimulation types. During the 6-month follow-up, a 44% improvement in the Unified Parkinson's Disease Rating Scale (UPDRS-III) points and a 43% decline in the levodopa equivalent daily dosage (LEDD) was observed. After 18 months of follow-up, a 35% LEDD decrease was still noted. The Hoehn and Yahr (H&Y) stages and scores on item no 30 "postural stability" in UPDRS-III remained lower throughout the follow-up compared to baseline. Additionally, dDBS relieved non-motor symptoms during the 6 months of follow-up. Patients with bilateral SSA had similar clinical outcomes to those with other stimulation types. Directional stimulation appears to effectively reduce both motor and non-motor symptoms in advanced PD with minimal adverse effects in real-life clinical care.Peer reviewe

Genetic risk factors in Finnish patients with Parkinson's disease

Introduction Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. Methods The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). Results We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients. Conclusions The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.Peer reviewe

SNCA mutation p.Ala53Glu is derived from a common founder in the Finnish population

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