Background: Single photon emission computed tomography (SPECT) with dopamine transporter (DAT) and dopamine D2 receptor (D2R) ligands can visualise the integrity of the nigrostriatal dopamine system. Parkinson’s disease (PD) and the atypical parkinsonian diseases (APD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), have similar symptoms and dopamine depletion, but differ in pharmacological response and prognosis. Clinical differentiation between PD and APD is often difficult in the early stages. The aims of the thesis were to evaluate the differential diagnostic and prognostic value of SPECT in early PD, MSA and PSP, to map the pattern of progression with dopamine SPECT, and map the pattern of dopamine SPECT in non-affected elderly volunteers with a prospective approach. Also, we evaluated the methodological aspects of dopamine SPECT with respect to image evaluation tools, reconstruction parameters and gamma cameras. Methods: 172 patients, included in an on-going clinical prospective study on idiopathic parkinsonism, participated in the SPECT study. Also, 31 age-matched healthy controls (HC) were followed within this study. SPECT was done with 123I-FP-Cit (DAT SPECT) and 123I-IBZM (D2R SPECT). Regions of interest (ROI) were used as a standard method for semi-quantitative image analysis. Results: SPECT uptake ratios from different gamma cameras could be equalised through correction equations derived from images of a brain-like phantom, provided that attenuation correction was applied. The ROI method had high reproducibility. SPECT uptake  in HC, measured with the ROI method and a volume based (VOI) method rendered similar trends, but gender and age differences in SPECT uptake were more marked with the VOI method, and less pronounced in DAT SPECT compared to D2R SPECT with both methods. The DAT SPECT uptake was significantly reduced in very early disease stage of PD and APD compared to HC. DATSPECT uptake was more reduced in PD with postural and gait disturbance (PIGD) compared to tremor-dominant PD. Decline in DAT SPECT uptake during the first year was more pronounced in PD and PSP compared to HC. D2R SPECT uptake overlapped between untreated PD and APD. After initiated treatment, the D2R SPECT uptake was significantly higher in MSA patients compared to PD, PSP and HC. Decline in D2R SPECT uptake during the first year was not significantly different between patients or compared to HC. Conclusions: 123I-FP-Cit SPECT is a valuable and sensitive method to detect early stage idiopathic parkinsonism. A different level of uptake between PIGD-PD compared to TD-PD indicates a prognostic potential. It is not possible to differ between PD, MSA and PSP in early stage with 123I-FP-Cit SPECT and no differential diagnostic value was found using 123I-IBZM SPECT in the early, untreated stage of PD, MSA and PSP. A different pattern of uptake of this ligand in MSA compared to PD and PSP during the first years of L-dopa treatment may, however, indicate a diagnostic value during the follow-up period.

Objective: In patients with Parkinson’s disease (PD), deep brainstimulation of the subthalamic nucleus (STN DBS) is well recognizedin improving limb function, but the outcome on swallowing functionhas rarely been studied. The aim of this work was to evaluate theeffect of STN DBS on pharyngeal swallowing function in patientswith PD using self-estimation and fiberoptic endoscopic evaluation ofswallowing. Methods: Eleven patients (aged 41–72, median 61 years)were evaluated preoperatively and at 6 and 12 months after STN DBSsurgery. All patients were evaluated with self-estimation on a visualanalogue scale, and eight of them with a fiberoptic endoscopicexamination with a predefined swallowing protocol includingRosenbek’s Penetration-Aspiration Scale, Secretion Severity Scale,preswallow spillage, pharyngeal residue, and pharyngeal clearance. Results: The self-assessments of swallowing function revealed asubjective improvement with STN DBS stimulation, whereas the datafrom the swallowing protocol did not show any significant effect ofthe STN DBS treatment itself. The prevalence of aspiration was notaffected by the surgery. Conclusions: The results show thatswallowing function was not negatively affected by STN DBS and therisk of aspiration did not increase. Self-estimation of swallowingfunction showed a subjective improvement due to stimulation / Speech, voice and swallowing outcomes after deep brain stimulation (DBS)

The disturbances and abnormalities occurring in the components of the Acetylcholine (ACh) neurocycle are considered one of the main features of cholinergic sicknesses like Parkinson’s and Alzheimer’s diseases. A fundamental understanding of the ACh neurocycle is therefore very critical in order to design drugs that keep the ACh concentrations in the normal physiological range. In this dissertation, a novel two-enzyme-two-compartment model is proposed in order to explore the bifurcation, dynamics, and chaotic characteristics of the ACh neurocycle. The model takes into consideration the physiological events of the choline uptake into the presynaptic neuron and the ACh release in the postsynaptic neuron. In order to approach more realistic behavior, two complete kinetic mechanisms for enzymatic processes pH-dependent are built: the first mechanism is for the hydrolysis reaction catalyzed by the acetylcholinesterase (AChE) and the other is for the synthesis reaction catalyzed by the cholineacetyltransferase (ChAT). The effects of hydrogen ion feed concentrations, AChE activity, ChAT activity, feed ACh concentrations, feed choline concentrations, and feed acetate concentrations as bifurcation parameters, on the system performance are studied. It was found that hydrogen ions play an important role, where they create potential differences through the plasma membranes. The concentrations of ACh, choline and acetate in compartments 1 and 2 are affected by the activity of AChE through a certain range of their concentrations, where the activity of AChE is inhibited completely after reaching certain values. A detailed bifurcation analysis over a wide range of parameters is carried out in order to uncover some important features of the system, such as hysteresis, multiplicity, Hopf bifurcation, period doubling, chaotic characteristics, and other complex dynamics. The effects of the feed choline concentrations and the feed acetate concentrations as bifurcation parameters are studied in this dissertation. It is found that the feed choline concentrations play an important role and have a direct effect on the ACh neurocycle through a certain important range of the parameters. However, the feed acetate concentrations have less effect. It is concluded from the results that the feed choline is a more important factor than the feed acetate in ACh processes. The effects of ChAT activity and the choline recycle ratio as bifurcation parameters, on the system performance are investigated. It was found that as the ChAT activity increases, ACh concentrations in compartments 1 and 2 increase continuously. The effect of the choline recycle ratio shows that choline reuptake plays a very critical role in the synthesis of ACh in compartment 1, where it supplies the choline as a substrate for the synthesis reaction by ChAT. The concentrations of ACh, choline and acetate in compartments 1 and 2 are affected by the choline recycle ratio through a certain range of the choline recycle ratio; then, they become constant as the choline recycle ratio increases further. It is concluded from our results that choline uptake is the rate limiting step in the ACh processes in both compartments in comparison to ChAT activity. Based on partial dissociation of the acetic acid in compartments 1, and 2 of the ACh cholinergic system, the two-parameter continuation technique has been applied to investigate the pH range to be closer to physiological ranges of pH values. In addition, static/dynamic solutions of the ACh cholinergic neurocycle system based on feed choline concentration as the main bifurcation parameter in both compartments have been investigated. The findings of the above studies are related to the real phenomena occurring in the neurons, like periodic stimulation of neural cells and non-regular functioning of ACh receptors. It was found that ACh, choline, acetate, and pH exist inside the physiological range associated with taking into consideration the partial dissociation of the acetic acid. The disturbances and irregularities (chaotic attractors) occurring in the ACh cholinergic system may be good indications of cholinergic diseases such as Alzheimer’s and Parkinson’s diseases. The results have been compared to the results of physiological experiments and other published models. As there is strong evidence that cholinergic brain diseases like Alzheimer’s disease and Parkinson’s disease are related to the concentration of ACh, the present findings are useful for uncovering some of the characteristics of these diseases and encouraging more physiological research.

Många närstående till en sjuk familjemedlem tar sig an rollen som vårdgivare vilket annars hade antagits av hälso- och sjukvårdspersonal. Nedskärningar inom den offentliga sektorn fortskrider och inte tillräckligt med fokus läggs på hur detta påverkar de närstående som vårdar en sjuk närstående i hemmet. Syftet med litteraturstudien var att beskriva upplevelsen och vad som påverkar upplevelsen av att vara vårdgivare i hemmet till en närstående med Parkinsons sjukdom. Studien utfördes som en litteraturstudie. I resultatet framkom fyra kategorier: Tid och relation, Stöd och information, Sjukdomsförlopp och Symtom. Resultatet visade att vårdgivare upplevde det svårt att ha en normalt fungerande vardag till följd av deras roll som vårdgivare. Vårdgivares upplevda börda ökade även i takt med den närståendes sjukdomsförlopp. En bra relation och mycket ömsesidighet mellan parterna minskade den upplevda bördan hos vårdgivarna samt ökade deras upplevda livskvalitet. Vårdgivare upplevde att stödgrupper minskar deras mentala börda genom att de fick möjlighet att dela med sig av sina erfarenheter till andra och att det hjälpte dem att förstå och själva handskas med sin situation. Vårdgivare upplevde att de inte fick tillräcklig information och stöd från hälso- och sjukvården. Vårdgivare ansåg att den fysiska funktionsnedsättningen var mer påtaglig vid direkt vård och gav mer fysisk påfrestning hos vårdgivaren än vad de psykiska symtomen gjorde. De psykiska symtomen hade större inverkan på vårdgivarens mentala hälsa och deras upplevda börda. Då antalet vårdgivare som vårdar en närstående i hemmet ökar är det av stor vikt att forskning genomförs och uppmärksammas. / Many people related to a sick person take on the role of caregiver, which would otherwise have been adopted by healthcare professionals. Cut downs in the public sector are progressing, and there is not enough focus on how this affects the persons who cares for a sick loved one at home. The purpose of this study was to describe the experience of being a caregiver and what factors affects the experience of a caregiver who cares for a loved one at home with Parkinson’s disease. The results revealed four categories: Time and relationship, Support and information, Disease duration and Symptoms. The results showed that caregivers find it difficult to have a normally functioning everyday life due to their role as caregivers. The caregivers perceived burden increases as the loved ones disease processes. A good relationship and a lot of mutuality between the parties reduce the perceived burden among caregivers, and increase their perceived quality of life. Caregivers feel that support groups reduce their mental workload by enabling them to share their experiences with others and that it helps them to understand and cope with their situation. Caregivers feel they do not receive adequate information and support from health care. The caregivers feel that the loved ones physical disability is more pronounced at the direct care and involves more physical stress than the mental symptoms makes. The psychological symptoms have a greater impact on caregivers’ mental health and their perceived burden. As the number of caregivers who care for a loved one at home increases it is of great importance to maintain research and attention to made research.

The disturbances and abnormalities occurring in the components of the Acetylcholine (ACh) neurocycle are considered one of the main features of cholinergic sicknesses like Parkinson’s and Alzheimer’s diseases. A fundamental understanding of the ACh neurocycle is therefore very critical in order to design drugs that keep the ACh concentrations in the normal physiological range. In this dissertation, a novel two-enzyme-two-compartment model is proposed in order to explore the bifurcation, dynamics, and chaotic characteristics of the ACh neurocycle. The model takes into consideration the physiological events of the choline uptake into the presynaptic neuron and the ACh release in the postsynaptic neuron. In order to approach more realistic behavior, two complete kinetic mechanisms for enzymatic processes pH-dependent are built: the first mechanism is for the hydrolysis reaction catalyzed by the acetylcholinesterase (AChE) and the other is for the synthesis reaction catalyzed by the cholineacetyltransferase (ChAT). The effects of hydrogen ion feed concentrations, AChE activity, ChAT activity, feed ACh concentrations, feed choline concentrations, and feed acetate concentrations as bifurcation parameters, on the system performance are studied. It was found that hydrogen ions play an important role, where they create potential differences through the plasma membranes. The concentrations of ACh, choline and acetate in compartments 1 and 2 are affected by the activity of AChE through a certain range of their concentrations, where the activity of AChE is inhibited completely after reaching certain values. A detailed bifurcation analysis over a wide range of parameters is carried out in order to uncover some important features of the system, such as hysteresis, multiplicity, Hopf bifurcation, period doubling, chaotic characteristics, and other complex dynamics. The effects of the feed choline concentrations and the feed acetate concentrations as bifurcation parameters are studied in this dissertation. It is found that the feed choline concentrations play an important role and have a direct effect on the ACh neurocycle through a certain important range of the parameters. However, the feed acetate concentrations have less effect. It is concluded from the results that the feed choline is a more important factor than the feed acetate in ACh processes. The effects of ChAT activity and the choline recycle ratio as bifurcation parameters, on the system performance are investigated. It was found that as the ChAT activity increases, ACh concentrations in compartments 1 and 2 increase continuously. The effect of the choline recycle ratio shows that choline reuptake plays a very critical role in the synthesis of ACh in compartment 1, where it supplies the choline as a substrate for the synthesis reaction by ChAT. The concentrations of ACh, choline and acetate in compartments 1 and 2 are affected by the choline recycle ratio through a certain range of the choline recycle ratio; then, they become constant as the choline recycle ratio increases further. It is concluded from our results that choline uptake is the rate limiting step in the ACh processes in both compartments in comparison to ChAT activity. Based on partial dissociation of the acetic acid in compartments 1, and 2 of the ACh cholinergic system, the two-parameter continuation technique has been applied to investigate the pH range to be closer to physiological ranges of pH values. In addition, static/dynamic solutions of the ACh cholinergic neurocycle system based on feed choline concentration as the main bifurcation parameter in both compartments have been investigated. The findings of the above studies are related to the real phenomena occurring in the neurons, like periodic stimulation of neural cells and non-regular functioning of ACh receptors. It was found that ACh, choline, acetate, and pH exist inside the physiological range associated with taking into consideration the partial dissociation of the acetic acid. The disturbances and irregularities (chaotic attractors) occurring in the ACh cholinergic system may be good indications of cholinergic diseases such as Alzheimer’s and Parkinson’s diseases. The results have been compared to the results of physiological experiments and other published models. As there is strong evidence that cholinergic brain diseases like Alzheimer’s disease and Parkinson’s disease are related to the concentration of ACh, the present findings are useful for uncovering some of the characteristics of these diseases and encouraging more physiological research.

Background/Aim: Little is known about the clinical significance of phantosmia. The literature on phantosmia indicates that this symptom has a wide range of differential diagnoses. However, most cases of phantosmia remain of unknown origin. Our goal was to follow up patients with idiopathic phantosmia, with special regard to improvement rates and possible severe health conditions preceded by phantosmia of unknown origin. Methods: Forty-four patients with idiopathic phantosmia which had consulted our Ear-Nose-Throat Smell and Taste Clinic over the last 10 years were contacted by telephone and underwent a structured medical interview. Results: None of the patients had eveloped any severe health condition or Parkinson’s disease. More than 5 years after the occurrence of hantosmia, more than 50% of the patients experienced disappearance (31.8%) or improvement (25%). In the remaining cases, phantosmia did not change (38.7%) or became worse ( ! 5%). Conclusion: The main findings of the present study were that idiopathic phantosmia improves or disappears in almost two thirds of the patients after more than 5 years, and that idiopathic phantosmia seems to be more likely a harmless symptom rather than a reliable predictor of early Parkinson’s disease or other severe diseases. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Parkinson’s disease (PD) is a complex disease with a multi-factorial aetiology, comprising both genetic and environmental risk factors. The disease pathology is progressive and neurodegenerative where dopaminergic nerve cell death occurs predominantly in the substantia nigra pars compacta (SNpc) with the subsequent loss of the dopamine neurotransmitter in the basal ganglia. The most significant risk factors for PD include an advancing age and a family history of the disease, while environmental and lifestyle risk factors such as pesticide exposure and smoking are widely accepted as risk altering exposures. Currently up to 10% of PD is attributed to Mendelian inherited PD at one of 13 PARK loci in 9 genes. The pursuit of common susceptibility alleles for idiopathic PD has proven challenging with only a few loci reproducibility associated with an altered risk. The aim of this thesis is to study, using a candidate gene case-control design, the potential role of genetic variants in PD. The APOE candidate gene was hypothesized to modify the risk of PD as it is a proven modifier of Alzheimer’s disease (AD). The common pathological finding in PD of elevated levels of iron within the SNpc is proposed to increase the oxidative state of the nerve cells and predispose the dopaminergic neurons to apoptosis. Therefore, susceptibility alleles within the candidate genes that regulate iron metabolism and homeostasis are hypothesized to alter iron metabolism and predispose to iron-induced neurodegeneration in PD. Missense variants and common “tagging” SNPs with the HFE, Transferrin and Transferrin Receptor genes are investigated extensively in this thesis. Finally, autosomal recessively inherited PD can result from mutations in the parkin gene at the PARK2 locus. The final hypothesis explored in this thesis suggests that non-deleterious missense variants in the parkin gene modify the risk for developing sporadic PD. Further genetic variation in the parkin gene such as exon rearrangements is a frequently reported mutation where heterozygosity for these rearrangements may increase the risk of PD. Heterozygous deletions or duplications of exons in the parkin gene provide technical challenges for their detection. In this thesis a novel assay for the detection of these mutations is investigated. Methods: Genotyping was performed using PCR-RFLP for genetic variants in the APOE (E2 and E4 alleles), HFE (C282Y, H63D and S65C), Transferrin receptor (TfR; S142G), Transferrin (Tfn; P570S and G258S), IREB2 genes (L159V) and the parkin gene (S167N, R366W and V380L) in a cohort of 425 PD cases and 387 controls recruited from throughout Queensland, Australia. A tagged SNP high-throughput genotyping approach was then employed to try to replicate single SNP associations in 6 iron-related genes using a cohort of 1034 PD cases and 774 controls. These genetic variants were analysed for direct association with PD risk, age of onset effects as well as potential gene x gene (GxG) and gene x environment (GxE) interactions. Additionally, a quantitative PCR assay was developed to detect heterozygous deletions and duplications within the parkin gene and utilised to screen 43 YOPD cases for these mutations. Results: The initial study of the HFE C282Y variant revealed a significant protective association with PD in the two independent cohorts studied. Further study did not reveal significant associations with PD for the other HFE variants or missense variants within the Tfn and TfR genes. When analysed for GxE interactions, the C282Y, P589S and G277S variants showed evidence for an increased risk of PD in synergy with pesticide and herbicide exposure. Carriers of the risk variant and with toxin exposure were at two-fold increased risk of PD, although the number of individuals in this category was small. A further investigation of the role of common genetic polymorphisms in iron genes revealed only one of the 20 SNPs genotyped using high-throughput multiplex methods, remained significantly associated with PD after correction for age and sex. The rs198855 SNP is downstream of the HFE gene and further implicates a role for HFE in PD. The APOE E4 allele demonstrated modifying effects for the age of PD onset, restricted to the female cases. Analysis of the parkin missense variants also demonstrated a modifying effect on the age of PD onset in carriers of the S167N variant, with putative interactions between the APOE E4 allele, a family history of PD and toxin exposure that further reduced the age of onset. Twenty individuals of the 43 YOPD cases screened demonstrated heterozygous parkin exon rearrangements using the novel qPCR method. Conclusions: Non-synonymous variants within iron-related genes or the parkin gene putatively interact with herbicide and pesticide exposure to increase the risk of PD or modify the phenotype, highlighting the need for future studies to address the multi-factorial aetiology of PD in their study design and analysis. This thesis provides evidence for the association between genetic variation within the HFE locus and PD and for the APOE E4 allele as a modifier of PD.

Parkinson’s Disease (PD) is the second most common neurodegenerative disease in the Western world. It shows a high degree of genetic and phenotypic complexity with many implicated factors, various disease manifestations but few clear causal links. Ongoing research has identified a growing number of molecular alterations linked to the disease. Dopaminergic neurons in the substantia nigra, specifically their synapses, are the key-affected region in PD. Therefore, this work focuses on understanding the disease effects on the synapse, aiming to identify potential genetic triggers and synaptic PD associated mechanisms. Currently, one of the main challenges in this area is data quality and accessibility. In order to study PD, publicly available data were systematically retrieved and analysed. 418 PD associated genes could be identified, based on mutations and curated annotations. I curated an up-to-date and complete synaptic proteome map containing a total of 6,706 proteins. Region specific datasets describing the presynapse, postsynapse and synaptosome were also delimited. These datasets were analysed, investigating similarities and differences, including reproducibility and functional interpretations. The use of Protein-Protein-Interaction Network (PPIN) analysis was chosen to gain deeper knowledge regarding specific effects of PD on the synapse. Thus I generated a customised, filtered, human specific Protein-Protein Interaction (PPI) dataset, containing 211,824 direct interactions, from four public databases. Proteomics data and PPI information allowed the construction of PPINs. These were analysed and a set of low level statistics, including modularity, clustering coefficient and node degree, explaining the network’s topology from a mathematical point of view were obtained. Apart from low-level network statistics, high-level topology of the PPINs was studied. To identify functional network subgroups, different clustering algorithms were investigated. In the context of biological networks, the underlying hypothesis is that proteins in a structural community are more likely to share common functions. Therefore I attempted to identify PD enriched communities of synaptic proteins. Once identified, they were compared amongst each other. Three community clusters could be identified as containing largely overlapping gene sets. These contain 24 PD associated genes. Apart from the known disease associated genes in these communities, a total of 322 genes was identified. Each of the three clusters is specifically enriched for specific biological processes and cellular components, which include neurotransmitter secretion, positive regulation of synapse assembly, pre- and post-synaptic membrane, scaffolding proteins, neuromuscular junction development and complement activation (classical pathway) amongst others. The presented approach combined a curated set of PD associated genes, filtered PPI information and synaptic proteomes. Various small- and large-scale analytical approaches, including PPIN topology analysis, clustering algorithms and enrichment studies identified highly PD affected synaptic proteins and subregions. Specific disease associated functions confirmed known research insights and allowed me to propose a new list of so far unknown potential disease associated genes. Due to the open design, this approach can be used to answer similar research questions regarding other complex diseases amongst others.

Base teórica: A doença de Parkinson (DP) é a segunda enfermidade neurodegenerativa mais frequente, crescendo proporcionalmente com o aumento da idade. É uma doença de comprometimento motor e não motor. Levodopa e agonistas dopaminérgicos (AD) são usados no tratamento da DP, permitindo um controle ótimo dos sintomas nos primeiros anos. Entretanto, em 5 anos, metade dos pacientes terão complicações motoras e nãomotoras induzidas pelo uso de antiparkinsonianos. Manifestações neuropsiquiátricas são frequentes, entre elas depressão, ansiedade, prejuízos cognitivos, sintomas psicóticos e transtorno de descontrole dos impulsos(DI). O DI é uma condição caracterizada pela falência em resistir a impulsos ou tentação de executar atos. O DI está associado ao uso de antiparkinsonianos, em especial, os agonistas dopaminérgicos A identificação desta condição é primordial para seu tratamento e estudo adequados. Na literatura atual, o questionário padrão-ouro foi validado na língua inglesa (QUIP), não existindo uma validação para língua portuguesa. Objetivo: Traduzir e validar o questionário QUIP-CS, em sua versão curta e aplicável no momento presente da DP, para lingua Portuguesa do Brasil Métodos: A versão curta da QUIP (QUIP-CS) foi traduzida para o Português por tradutor juramentado. Após, esta foi avaliada por 5 especialistas em DP no Brasil, sendo sugeridas pequenas correções. A versão corrigida em português foi retrotraduzida para o inglês por 2 tradutores juramentados nativos na língua original da escala (inglês), que compararam suas versões posteriormente, chegando-se a uma nova versão final neste idioma. Esta foi enviada ao autor da escala original, que concordou com esta versão, ou seja, foram mantidas as propriedades semânticas do instrumento. Após, a versão final em Português foi auto-aplicada em 65 indivíduos com diagnóstico de DP em tratamento no ambulatório especializado no HCPA, sendo que, de forma aleatória, para 30 foi aplicado um questionário de avaliação sobre o grau de dificuldade de compreensão de suas perguntas. Resultados: Em uma escala de 1 a 5 pontos, onde 1 era nenhuma compreensão das perguntas e 5, clara compreensão, a média de entendimento pelos pacientes foi de 4,06 +/- 0,69 DP. Conclusão: A avaliação desta versão foi considerada de fácil compreensão pelos próprios pacientes. O artigo para validação da tradução do conteúdo da versão em Português da QUIP-CS está em fase de revisão para publicação. / Background: Parkinson’s disease (PD) is the second most often neurodegenerative disease and proportionally growing with people aging. PD is a disease with motor and nonmotor clinical features. Levodopa and dopaminergic agonists (DA) are used for PD treatment, allowing an exquisite control of the motor symptoms during the first years. However, in five years, half patients will present motor or non-motor complications induced by cronic use of these medications. Neuropsychiatric symptoms are often, for example, depression, anxiety, cognitive impairment, psychotic symptoms and impulse control disorders (ICD). The ICD is characterized by failure on resisting an impulse or on performing an specific act. Identification of the PD affected patients is crucial for proper management and study of this condition. There is an already validated self-reported questionnaire for this purpose, the Parkinson's Disease Impulsive-Compulsive Disorders Questionnaire (QUIP), without equivalent in portuguese language. Objective: To translate and to validate the Portuguese short version of the gold-standard questionnaire for identifying ICDs PD affected patients, applicable at the current moment of PD Methods: QUIP-CS was first translated to Portuguese by a professional translator. This translated version was shown to 5 PD neurologist specialists. in Brazil, being suggested minor modifications on it. This new Portuguese revised version was back translated to English by two independent native English speakers. They were both asked to compare the version one another and checked for differences. Then, they contacted each other and got a final back translated version. This one was sent for the original author, that approved its new version comparing to his original and validated one, with no loss of it’s original properties. The Portuguese corrected version was applied to 65 patients in a random way at PD’s ambulatory at HCPA. From these, 30 were asked to answer a number that would represent their level of QUIP-CS questions’ comprehension. Results: In a 1 to 5 point scale, being 1 no comprehension and 5, total comprehension, the average was 4,06 +/- 0,69 DP. Conclusion: Our results on Portuguese version of QUIP-CS show that QUIP-CS translated and corrected version was easily understood and easily self-applied. The article is under revision to be submitted for publication.

A Doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum. Atinge 3,3% das pessoas com mais de 64 anos. Com o envelhecimento populacional, sua prevalência deve dobrar. A doença classicamente se caracteriza por degeneração dos neurônios da substantia nigra, afetando principalmente a transmissão dopaminérgica. O tratamento mais eficaz na DP continua sendo a levodopa, um precursor dopaminérgico com excelente resposta motora. Entretanto, à medida que a doença progride, aparece uma série de complicações motoras e não motoras que limitam o tratamento. Para facilitar o reconhecimento destas complicações, foram criados questionários que aumentam a possibilidade de diagnóstico, abordando aspectos motores e não motores. O principal deles é um questionário de 19 itens. Ele consiste em 19 manifestações que o paciente deve assinalar, caso tenha determinado sintoma, e se ele melhora com a próxima dose da medicação. Quando existem pelo menos duas respostas positivas, o questionário tem ótima sensibilidade e especificidade. A Doença de Parkinson tem evolução heterogênea, sendo que uma das causas atribuídas para tal é genética. Tem se estudado muitos genes da rota de dopamina por sua relação íntima com a fisiopatologia e tratamento da doença. O transportador de dopamina (DAT), que realiza a retirada da dopamina da fenda sináptica, desempenha papel fundamental nesta rota. Existe um polimorfismo VNTR com cópias de uma unidade de repetição variando de 3 a 11 com as repetições 9 e 10 sendo os alelos mais comuns. Diversos estudos correlacionaram esse polimorfismo com transtorno do déficit de atenção e hiperatividade quando há 10 repetições e com a Doença de Parkinson quando há 9 repetições. Seria um candidato ideal para avaliação com relação às complicações do tratamento e progressão. Assim, avaliamos pacientes com Doença de Parkinson longitudinalmente para comparar a progressão da doença com polimorfismo do DAT e verificar as complicações associadas ao tratamento. Inicialmente, realizamos uma revisão sistemática das propriedades clinimétricas dos questionários de wearing off. Esta revisão mostrou que o questionário de 9 itens tem sensibilidade de 0,87-1 e especificidade de 0,1-0,69. Já o questionário de 19 itens tem sensibilidade de 0,81-0,9 e especificidade de 0,63-0,8 com ponto de corte igual a 2 itens positivos. Realizamos a validação deste último para português, com boa estabilidade no teste-reteste com correlação intraclasse de 0,87 (IC 95% 0,69-0,95 p < 0,01) e sensibilidade de 0,97 (IC 95% 0,94-1 p < 0,01) e especificidade de 0,71 (IC 95% 0,56-0,85 p < 0,01). Para progressão, foi demonstrada uma associação de sexo feminino e a presença de alelo com 9 repetições como fatores de risco para progressão mais rápida. A progressão em homens medida pelo UPDRS 3 era menor em 1,277 (IC 95% 2,18-0,38 p < 0,01) e pelo UPDRS total era menor em 1,50 (IC 95% 2,92-0,11 p = 0,031). Com presença de alelo com 9 repetições, a progressão do UPDRS 3 era menor em 1,92 (ICC 95% 0,04-1,01 p = 0,0317), e presente mesmo controlando para sexo. Não houve diferença na escala de discinesias ou questionário wearing off. Assim, os resultados obtidos mostraram que o questionário de 19 itens é uma boa ferramenta diagnóstica, sendo validado para português. Além disso, o polimorfismo DAT está associado à progressão mais rápida da DP com 9 repetições. / Parkinson’s disease (PD) is the second most common neurodegenerative disease. It affects 3.3% of people over 64 years. With population aging, its prevalence should double. The disease is classically characterized by degeneration of substantia nigra neurons, mainly affecting dopaminergic transmission. The most effective treatment for PD continues to be levodopa, a dopaminergic precursor with excellent motor response. However, as the disease progresses, there is a number of motor and non-motor complications that limits the treatment. To facilitate the recognition of these complications, questionnaires were created to increase the possibility of diagnosis, addressing motor and non-motor aspects. The main one is a questionnaire of 19 items. It consists of 19 symptoms that the patients should indicate, if they feel particular symptom, and if they get better with the next dose of medication. When there are at least two positive responses, the questionnaire has optimal sensitivity and specificity. Parkinson’s disease has a heterogeneous evolution, and one of the reasons attributed for that is genetic. Many genes of the dopamine route have been studied for their intimate relationship with the pathophysiology and treatment of the disease. The dopamine transporter, with synaptic cleft reuptake, plays a key role in this route. It has a VNTR polymorphism with copies of a repeating unit ranging from 3 to 11 with repetitions 9 and 10 being the most common alleles. Several studies correlated this polymorphism with Attention Deficit Hyperactivity Disorder with 10 repetition allele and Parkinson’s disease with 9 repetition alleles. It would be an ideal candidate for evaluation regarding treatment complications and progression. Thus, we evaluated patients with Parkinson’s disease longitudinally to compare disease progression with DAT polymorphism and to verify treatment-related complications. Initially we performed a systematic review of the clinimetric properties of the wearing off questionnaires. That showed that the questionnaire of 9 items has sensitivity of 0.87-1 and specificity of 01-0.69. The questionnaire of 19 items has a sensitivity of 0.81-0.9 and a specificity of 0.63-0.8 with a cut-off point of 2 items. We performed the validation of the latter for Portuguese, with good stability in the testretest with intraclass correlation of 0.87 (95% CI 0.69-0.95 p < 0.01) and sensitivity of 0.97 (CI 95% 0.94-1 p < 0.01) and specificity of 0.71 (95% CI 0.56-0.85 p < 0.01). We demonstrated a female association and presence of 9 DAT allele repetition as risk factors for faster progression. The progression in men ofwith UPDRS 3 was lower in 1.277 (95% CI 2.18-0.38 p < 0.01) and total UPDRS was lower in 1.50 (95% CI 2.92-0.11 p = 0.031). With the presence of allele with 9 repetitions the progression of UPDRS 3 was lower in 1.92 (ICC 95% 0.04-1.01 p = 0.0317), and present even correcting sex. There was no difference in the dyskinesia scale or wearing off questionnaire. Thus, the results obtained showed wearing off questionnaire is a good tool for clinical and research, and it is validated to Portuguese. Also, DAT polymorphism is associated with faster PD progression with 9 repetition allele.