Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia.

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

Transcriptomic profiles in Parkinson's disease.

Transcriptomics in Parkinson's disease offers insights into the pathogenesis of Parkinson's disease but obtaining brain tissue has limitations. In order to bypass this issue, we profile and compare differentially expressed genes and enriched pathways (KEGG) in two peripheral tissues (blood and skin) of 12 Parkinson's disease patients and 12 healthy controls using RNA-sequencing technique and validation with RT-qPCR. Furthermore, we compare our results to previous Parkinson's disease post mortem brain tissue and blood results using the robust rank aggregation method. The results show no overlapping differentially expressed genes or enriched pathways in blood vs. skin in our sample sets (25 vs. 1068 differentially expressed genes with an FDR ≤ 0.05; 1 vs. 9 pathways in blood and skin, respectively). A meta-analysis from previous transcriptomic sample sets using either microarrays or RNA-Seq yields a robust rank aggregation list of cortical gene expression changes with 43 differentially expressed genes; a list of substantia nigra changes with 2 differentially expressed genes and a list of blood changes with 1 differentially expressed gene being statistically significant at FDR ≤ 0.05. In cortex 1, KEGG pathway was enriched, four in substantia nigra and two in blood. None of the differentially expressed genes or pathways overlap between these tissues. When comparing our previously published skin transcription analysis, two differentially expressed genes between the cortex robust rank aggregation and skin overlap. In this study, for the first time a meta-analysis is applied on transcriptomic sample sets in Parkinson's disease. Simultaneously, it explores the notion that Parkinson's disease is not just a neuronal tissue disease by exploring peripheral tissues. The comparison of different Parkinson's disease tissues yields surprisingly few significant differentially expressed genes and pathways, suggesting that divergent gene expression profiles in distinct cell lineages, metabolic and possibly iatrogenic effects create too much transcriptomic noise for detecting significant signal. On the other hand, there are signs that point towards Parkinson's disease-specific changes in non-neuronal peripheral tissues in Parkinson's disease, indicating that Parkinson's disease might be a multisystem disorder.

Community-based genetic study of Parkinson's disease in Estonia.

OBJECTIVE: To examine the genetic variability of Estonian Parkinson's disease (PD) patients using an ongoing epidemiological study in combination with a genetic analysis. METHODS: This study was a community-based genetic screening study of 189 PD patients, and 158 age- and sex-matched controls screened for potential mutations in 9 PD genes using next-generation sequencing and multiplex ligation-dependent probe amplification method. Different clinimetric scales and questionnaires were used to examine PD patients and assess clinical characteristics and severity of the disease. RESULTS: The overall frequency of pathogenic PD-causing variants was 1.1% (2/189), and any rare genetic variant was present in 21.2% (40/189) of the patients and in 8.2% (13/158) of the controls (P < .05). Variants of unknown significance accounted for 10.6% (20/189). Frequency of any GBA variant among PD patients was 10.1% (19/189) and in controls 3.8% (6/158). The frequency of any GBA variant in PD compared to controls was significantly higher (P = .035; OR 2.82; CI 95% 1.05-8.87). Burden of rare variants was not different between patients and controls. Also, a novel GBA pathogenic variant p.E10X was detected. CONCLUSION: Among different genetic variants identified in Estonian PD patients, GBA variants are the most common, while an overall pathogenic variant frequency was 1.1%.

Lack of Accredited Clinical Training in Movement Disorders in Europe, Egypt, and Tunisia.

BACKGROUND: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. OBJECTIVE: To survey the accessible MD clinical training in these regions. METHODS: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. RESULTS: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. CONCLUSION: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.

Increased Serum Levels of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Subjects With Parkinson's Disease.

BACKGROUND: Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) promote the survival of midbrain dopamine neurons in animal models of Parkinson's disease (PD). However, little is known about endogenous concentrations of MANF and CDNF in human PD patients, and their relation to PD pathogenesis. Our main objective was to study whether circulating concentrations of MANF and CDNF differ between PD patients and controls, and if they correlate with clinical parameters. Levels of circulating CDNF were studied for the first time. METHODS: MANF and CDNF levels were measured from serum samples of 34 PD patients and 35 controls using validated in-lab-designed enzyme-linked immunosorbent assay (ELISAs). MANF and CDNF mRNA levels in whole blood samples of 60 PD patients and 30 controls were measured by quantitative real time polymerase chain reaction (qRT-PCR). MANF concentrations in different blood cell types were measured by ELISA. RESULTS: Circulating MANF concentrations were significantly higher in PD patients compared to controls (P < 0.001) and were positively correlated with Beck Depression Inventory (BDI) depression rating. MANF protein was present in blood cells, however, MANF mRNA levels in the blood did not differ between PD patients and controls (P = 0.44). The mean concentration of serum CDNF was 33 pg/ml in the controls. CDNF levels were not altered in PD patients (P = 0.25). CONCLUSION: MANF but not CDNF level was increased in the blood of PD patients. It would be interesting to examine the blood level of MANF from early stage PD patients in future studies to test whether MANF can be used as a clinical marker of PD.

Incidence and Mortality of Parkinson's Disease in Estonia.

BACKGROUND: There is lack of data on the incidence of Parkinson's disease (PD) based on repeat studies. Mortality rates of PD in Estonia have never been studied before. OBJECTIVES: To estimate the incidence and mortality rates of PD in -Estonia, to compare current incidence rates with those of the prior epidemiological study in Estonia, and to examine the reported causes of death of the study population. METHODS: Eligible subjects were identified from multiple case-finding sources. Subjects were subsequently tracked on the Electronic-Health Record until either the end of the study, or their death. Incidence rates and standardized mortality ratios (SMR) were calculated. Causes of death were identified, based on the data from death certificates. RESULTS: In the current study, the overall age-adjusted incidence rate was 28.0/100,000 person-years (95% CI 25.2-30.8). Compared with the previous study, the age-adjusted incidence rate inEstonia has not significantly changed (rate ratio 1.11; p = 0.19). Overall SMR for the inception cohort of PD cases with a median follow-up time of 5 years was 1.12 (95% CI 0.88-1.36; p = 0.3). For those deceased subjects known to have had clinically diagnosed PD, this was mentioned on 46.8% of death certificates. CONCLUSIONS: Over the last 20 years, the overall incidence of PD in Estonia has remained comparatively stable. The data did not show an excess mortality in PD patients (vs. general population) in the first 5 years of the disease.

Analysis of repetitive element expression in the blood and skin of patients with Parkinson's disease identifies differential expression of satellite elements.

Repetitive elements (RE) constitute the majority of the human genome and have a range of functions both structural and regulatory on genomic function and gene expression. RE overexpression has been observed in several neurodegenerative diseases, consistent with the observation of aberrant expression of RE posing a mutagenic threat. Despite reports that associate RE expression with PD no study has comprehensively analysed the role of these elements in the disease. This study presents the first genome-wide analysis of RE expression in PD to date. Analysis of RNA-sequencing data of 12 PD patients and 12 healthy controls identified tissue-specific expression differences and more significantly, differential expression of four satellite elements; two simple satellite III (repName = CATTC_n and _GAATG_n) a high-copy satellite II (HSATII) and a centromeric satellite (ALR_Alpha) in the blood of PD patients. In support of the growing body of recent evidence associating REs with neurodegenerative disease, this study highlights the potential importance of characterization of RE expression in such diseases.

Serum Amyloid Alpha Is Downregulated in Peripheral Tissues of Parkinson's Disease Patients.

We report the changed levels of serum amyloid alpha, an immunologically active protein, in Parkinson's disease (PD) patients' peripheral tissues. We have previously shown that Saa-1 and -2 (serum amyloid alpha-1,-2, genes) were among the top downregulated genes in PD patients' skin, using whole-genome RNA sequencing. In the current study, we characterized the gene and protein expression profiles of skin and blood samples from patients with confirmed PD diagnosis and age/sex matched controls. qRT-PCR analysis of PD skin demonstrated downregulation of Saa-1 and -2 genes in PD patients. However, the lowered amount of protein could not be visualized using immunohistochemistry, due to low quantity of SAA (Serum Amyloid Alpha, protein) in skin. Saa-1 and -2 expression levels in whole blood were below detection threshold based on RNA sequencing, however significantly lowered protein levels of SAA1/2 in PD patients' serum were shown with ELISA, implying that SAA is secreted into the blood. These results show that SAA is differentially expressed in the peripheral tissues of PD patients.

Effect of Age on Substantia Nigra Hyper-echogenicity in Parkinson's Disease Patients and Healthy Controls.

Substantia nigra (SN) hyper-echogenicity (SN+) describes an enlargement (>90th percentile) of the area of echogenicity at the anatomic site of the SN in the midbrain detected by transcranial sonography. This ultrasound sign has proven to be a valuable marker supporting the clinical diagnosis of Parkinson's disease (PD). Although there is considerable variation in the extent of echogenic signals at the anatomic site of the SN among PD patients, previous work suggests that SN+ is a stable marker throughout the course of the disease. The present study focused on two aspects: (i) determining whether SN+ values differ between the sides, mirroring the asymmetric character of the disease; and (ii) determining whether age has an influence on SN echogenicity. This cross-sectional study included 300 PD patients and 200 healthy controls. SN+ was measured planimetrically by transcranial sonography. Echogenicity was analyzed separately for onset and non-onset sides, with onset side defined as the SN contralateral to the side of the body that first manifested PD-related motor impairment. Age of the patients and healthy controls at study time was used for correlation. We found that the onset SN+ contralateral to the side of initial motor symptoms was on average 17.6% larger than its counterpart. However, we also found that contrary to the control group, where an increase in age was associated with an increase in size of SN+, age of PD patients was associated with a decline in size of the onset SN+. Furthermore, SN measured at the onset side of PD patients correlated significantly with patient age and Hoehn and Yahr stage, a scale that grades PD severity, although this was not the case for the non-onset side. The present study indicates that changes in SN echogenicity have a different dynamic depending on the onset side of the disease. The age at study time had a significantly negative effect on the size of onset SN+, the effect on the non-onset side was non-significant. We conclude that for appropriate PD analysis, onset SN+ is a more important marker than the average of both sides of SN. Furthermore, we found that among healthy controls, the size of SN+ increases with age.

Relationship between the MDS-UPDRS and Quality of Life: A large multicenter study of 3206 patients.

BACKGROUND: The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients. METHODS: We collected demographic and disease-related data as well as MDS-UPDRS and PDQ8 scales. Data were analyzed using correlations between PDQ8 and all MDS-UPDRS items, subsequently two hierarchical multiple regressions were performed, first between the scores of the MDS-UPDRS Parts and PDQ8 and second between individual items from those Parts demonstrating significant relationship to PDQ8 scores in the first regression. LASSO regression analyses were performed to evaluate the relationship between PDQ8 and all individual MDS-UPDRS items. RESULTS: A total of 3206 PD patients were included in the study. In the first regression analysis, PDQ8 was significantly related to MDS-UPDRS parts I and II, but not to III and IV. In the second regression model, significant contributions to PDQ8 were found for Part I items Fatigue, Pain, Depressed mood, Apathy; and Part II items Dressing, Doing hobbies, Freezing, Speech and Tremor. In the LASSO analysis, six Part I, seven Part II, three Part III and one Part IV items contributed to PDQ8 scores. The five items most significantly related to the model were Depressed mood, Dressing, Apathy, Pain and Fatigue. CONCLUSIONS: This is so far the largest study related to HRQoL issues in PD. Restrictions in activities of daily living and non-motor symptoms significantly contribute to HRQoL in PD.

Saliva changes in Parkinson's disease patients after injection of Botulinum neurotoxin type A.

Patients with Parkinson's disease (PD) are compromised by poor oral condition due to oropharyngeal bradykinesia, dysphagia, and the side effects of treatment. Intrasalivary gland injections of Botulinum neurotoxin type A (BNT-A) have been known to treat sialorrhea effectively in these patients. However, the decreased amount of saliva reduces self-cleaning ability that deteriorates oral hygiene and increases dental caries. The aim of this study was to determine the changes in the oral microflora and saliva in patients with PD treated for sialorrhea by means of sonography-controlled BNT-A injections into the bilateral parotid and submandibular glands. Altogether, 38 persons participated in the study: 12 PD patients who were injected with BNT-A for treatment of sialorrhea and passed salivary tests before and 1 month after the injections; and 13 PD patients and 13 healthy subjects who were not injected with BNT-A and passed salivary tests once. The condition of oral health was measured by the amount of saliva, salivary flow rate, and salivary composition. A good outcome with a significant decrease in salivary flow rate occurred at 1-month follow-up in the BNT-A-treated group while no significant change was found in salivary composition. BNT-A treatment did not change the Streptococcus mutans levels in saliva but there was statistically significant increase in levels of Lactobacilli. BNT-A injections can effectively treat sialorrhea while considering the change of oral microflora, and the patients should be under dentists' care more frequently. EudraCT clinical trial number: 2015-000682-30.

Factors associated with motor complications in Parkinson's disease.

OBJECTIVES: Levodopa is the most effective therapy for treating Parkinson's disease (PD); however, side effects such as dyskinesias and motor fluctuations may occur after some years of its usage. The aims of this study were to assess the frequency of and factors associated with motor complications among PD patients on levodopa treatment. METHODS: In a cross-sectional study carried out in 2010-2013, clinical data and treatment details were collected. Logistic regression expressed by odd ratios (OR) and 95% confidence intervals (CI) was conducted to examine the effects of several independent variables on the occurrence of motor complications. RESULTS: A total of 455 patients were enrolled, among whom 374 were on levodopa. Analysis was performed in 328 patients whose exact duration of levodopa treatment was known. Among patients included in the analysis, 25.9% experienced motor complications; of these, 21% had dyskinesias and 20.1% had motor fluctuations. Based on logistic regression, statistically significant factors associated with the occurrence of motor complications were younger age at onset of the disease, higher levodopa equivalent daily dose (LEDD), shorter time to levodopa initiation, and akinetic-rigid dominant phenotype of PD. CONCLUSIONS: This study suggests that postponing the start of levodopa therapy and maintaining low daily doses of levodopa might reduce the risk of motor complications. Our results confirm that due to higher risk of motor complications, effectively treating patients with akinetic-rigid dominant phenotype of PD might be more challenging than for patients whose dominant symptom is tremor.

Prevalence of depressive symptoms and their association with brainstem raphe echogenicity in patients with Parkinson's disease and non-PD controls.

Despite advances in diagnostics and clinical recognition, depressive symptoms in Parkinson's disease (PD) exceeding normal limits remain effectively untreated. In this study, we report on the prevalence and severity of depressive symptoms as well as their association with brainstem raphe echogenicity in patients with PD and non-PD controls. The study included 266 Estonian PD patients and 168 age- and education-matched controls. Demographic and clinical data was documented. Brainstem raphe (BR) was visualized by transcranial sonography (TCS). The prevalence of depressive symptoms in the patient sample was found to be significantly higher than in controls. BR echogenicity in both patients and controls was directly related to their total BDI score, although we found a significantly greater reduction of BR echogenicity in patients with PD and depressive symptoms compared to depressed non-PD controls. The present results corroborate the hypothesis that morphological alteration of the BR is involved in the pathogenesis of depressive disorders. TCS of BR could be used as a non-invasive biomarker to improve detection of depressive symptoms in early PD stages where clinicians may not recognize affective disturbances in the context of PD phenomena.

Looking beyond the brain to improve the pathogenic understanding of Parkinson's disease: implications of whole transcriptome profiling of Patients' skin.

BACKGROUND: Parkinson's Disease is a progressive neurodegenerative disease, characterized by symptoms of motor impairment, resulting from the loss of dopaminergic neurons in the midbrain, however non-neuronal symptoms are also common. Although great advances have been made in the pathogenic understanding of Parkinson's Disease in the nervous system, little is known about the molecular alterations occurring in other non-neuronal organ systems. In addition, a higher rate of melanoma and non-melanoma skin cancer has been observed in the Parkinson's Disease population, indicating crosstalk between these diseases. METHODS: To understand the molecular pathogenesis and gene expression alterations of Parkinson's Disease in peripheral tissues, and in order to explore the possible link between skin cancer and neurodegeneration, whole transcriptomic profiling of patients' skin was performed. Skin biopsies from 12 patients and matched controls were collected, and processed with high-throughput RNA-sequencing analysis. RESULTS: This analysis resulted in a large collection of over 1000 differentially expressed genes, among which clear biological and functional networks could be distinguished. The central functional processes altered in patients skin can be grouped into six broad categories: impaired cellular metabolism and mitochondrial dysfunction, defective protein metabolism, disturbed skin homeostasis, dysfunctional nuclear processes, altered signalling and tumour pathways, as well as disordered immune regulation. CONCLUSIONS: These results demonstrate that the molecular alterations leading to neurodegeneration in the CNS are systemic and manifest also in peripheral tissues, thereby indicating the presence of "skin-brain" crosstalk in Parkinson's Disease. In addition, the extensive homeostatic imbalance and basal stress can lead to increased susceptibility to external and internal mutagenic hazards in these patients, and thus provide a possible molecular link for the crosstalk between skin cancer and Parkinson's Disease.

Differences in MDS-UPDRS Scores Based on Hoehn and Yahr Stage and Disease Duration.

BACKGROUND: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS-UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. METHODS: For this cross-sectional study, demographic data and MDS-UPDRS scores were collected, including HY stage. Subscores on MDS-UPDRS Parts I through IV were analyzed using 1-way analyses of variance for each HY stage and in 5-year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. RESULTS: The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0-5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS-UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5-year increments of disease duration, MDS-UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. CONCLUSIONS: MDS-UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5-year increments of disease duration in the first 15 years of the disease.

Nonmotor Features in Parkinson's Disease: What Are the Most Important Associated Factors?

Introduction. The purpose of this study was to demonstrate the frequency and severity of nonmotor symptoms and their correlations with a wide range of demographic and clinical factors in a large cohort of patients with Parkinson's disease (PD). Methods. 268 PD patients were assessed using the validated Movement Disorders Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Beck Depression Inventory (BDI), Parkinson's Disease Questionnaire (PDQ-39), the Hoehn and Yahr scale (HY), the Schwab and England Activities of Daily Living (SE-ADL) Scale, and the Minimental State Examination (MMSE). Results. Nonmotor symptoms had a strong positive relationship with depression and lower quality of life. Also, age, duration and severity of PD, cognitive impairment, daily dose, and duration of levodopa treatment correlated with the burden of nonmotor symptoms. Patients with postural instability and gait disorder (PIGD) dominance or with the presence of motor complications had higher MDS-UPDRS Part I scores expressing the load of nonmotor features, compared to participants with other disease subtypes or without motor complications. Conclusions. Though the severity of individual nonmotor symptoms was generally rated by PD patients as "mild" or less, we found a significant cumulative effect of nonmotor symptoms on patients' mood, daily activities, and quality of life.

Substantia Nigra Hyperechogenicity: Validation of Transcranial Sonography for Parkinson Disease Diagnosis in a Large Estonian Cohort.

OBJECTIVES: Substantia nigra hyperechogenicity is a promising biomarker for Parkinson disease (PD). Substantia nigra hyperechogenicity has previously been established as a useful diagnostic criterion in several European and Asian patient cohorts. However, diagnostic cutoff values for substantia nigra hyperechogenicity remain unknown for most patient populations. This study validated the diagnostic accuracy of substantia nigra hyperechogenicity in a large cohort of patients with PD in Estonia. METHODS: The study included 300 patients with PD from Estonia, representing 10% of the national PD patient population, and 200 healthy control participants. To define the optimal cutoff value in the PD cohort, data from a single assessment versus repetitive assessments by transcranial sonography were compared. With the use of 3 repetitive assessments, the diagnostic accuracy of the data was measured. In addition, calculations for percentile values were used to define substantia nigra hyperechogenicity among controls. RESULTS: Our data showed that the multiassessment approach yielded higher diagnostic accuracy than a single assessment (P = .021). The highest diagnostic accuracy was achieved by using the measurement mean to define substantia nigra hyperechogenicity, which was 0.23 cm(2) (sensitivity, 88.7%; specificity, 92.2%), whereas single measurements detected PD with higher sensitivity (sensitivity, 93.2%; specificity, 85.1%). No significant difference was found between mean and median measurements (P= .18). CONCLUSIONS: This study indicates the diagnostic merit of transcranial sonography in PD diagnosis in an additional population and demonstrates that transcranial sonography of the substantia nigra is a relevant and useful diagnostic tool for patients with PD.

Health-related quality of life in Parkinson's disease: a cross-sectional study focusing on non-motor symptoms.

BACKGROUND: The objective of this study was to investigate factors affecting health-related quality of life (HRQoL) among Estonian persons with Parkinson's disease (PD). METHODS: 268 persons with PD were evaluated using: the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS); the Hoehn and Yahr scale (HY); the Schwab and England Activities of Daily Living scale (SE-ADL); the Beck Depression Inventory (BDI); the Mini Mental State Examination (MMSE); the Parkinson's Disease Questionnaire (PDQ-39). Additional questions on clinical and socio-demographic variables were asked during a semi-structured interview. Predictors of HRQoL were tested using multiple regression analysis. RESULTS: The main predictors of low HRQoL were depression and motor and non-motor aspects of daily living. 59.9 % of the variation in the PDQ-39 summary index (SI) score was explained by the predictive variables identified in this study. None of the socio-demographic variables (age, gender, urban/rural living, marital status, living alone/with others, education level) were significant predictors of HRQoL. Prevalence of non-motor Parkinson's symptoms were high (99.6 %); cognitive impairment, sleep and urinary problems were the most common. All non-motor symptoms correlated significantly with low HRQoL, except the features of impulse control disorders (ICDs). CONCLUSIONS: Depression and motor and non-motor daily living experiences were found to be significant and independent factors of low HRQoL in persons with PD. Depression was the strongest determinant of low HRQoL. Our results highlight the importance of recognition and management of non-motor symptoms, as these features had more impact on patients' HRQoL than clinically assessed motor symptoms.

Adapting the Sniffin' Sticks olfactory test to diagnose Parkinson's disease in Estonia.

UNLABELLED: The aim of the study was to develop a culturally adapted translation of the 12-item smell identification test from Sniffin' Sticks (SS-12) for the Estonian population in order to help diagnose Parkinson's disease (PD). METHODS: A standard translation of the SS-12 was created and 150 healthy Estonians were questioned about the smells used as response options in the test. Unfamiliar smells were replaced by culturally familiar options. The adapted SS-12 was applied to 70 controls in all age groups, and thereafter to 50 PD patients and 50 age- and sex-matched controls. RESULTS: 14 response options from 48 used in the SS-12 were replaced with familiar smells in an adapted version, in which the mean rate of correct response was 87% (range 73-99) compared to 83% with the literal translation (range 50-98). In PD patients, the average adapted SS-12 score (5.4/12) was significantly lower than in controls (average score 8.9/12), p < 0.0001. A multiple linear regression using the score in the SS-12 as the outcome measure showed that diagnosis and age independently influenced the result of the SS-12. A logistic regression using the SS-12 and age as covariates showed that the SS-12 (but not age) correctly classified 79.0% of subjects into the PD and control category, using a cut-off of <7 gave a sensitivity of 76% and specificity of 86% for the diagnosis of PD. CONCLUSIONS: The developed SS-12 cultural adaption is appropriate for testing olfaction in Estonia for the purpose of PD diagnosis.