Alzheimer's Disease-Associated SNP rs708727 in SLC41A1 May Increase Risk for Parkinson's Disease: Report from Enlarged Slovak Study.

SLC41A1 (A1) SNPs rs11240569 and rs823156 are associated with altered risk for Parkinson's disease (PD), predominantly in Asian populations, and rs708727 has been linked to Alzheimer's disease (AD). In this study, we have examined a potential association of the three aforementioned SNPs and of rs9438393, rs56152218, and rs61822602 (all three lying in the A1 promoter region) with PD in the Slovak population. Out of the six tested SNPs, we have identified only rs708727 as being associated with an increased risk for PD onset in Slovaks. The minor allele (A) in rs708727 is associated with PD in dominant and completely over-dominant genetic models (ORD = 1.36 (1.05-1.77), p = 0.02, and ORCOD = 1.34 (1.04-1.72), p = 0.02). Furthermore, the genotypic triplet GG(rs708727) + AG(rs823156) + CC(rs61822602) might be clinically relevant despite showing a medium (h ≥ 0.5) size difference (h = 0.522) between the PD and the control populations. RandomForest modeling has identified the power of the tested SNPs for discriminating between PD-patients and the controls to be essentially zero. The identified association of rs708727 with PD in the Slovak population leads us to hypothesize that this A1 polymorphism, which is involved in the epigenetic regulation of the expression of the AD-linked gene PM20D1, is also involved in the pathoetiology of PD (or universally in neurodegeneration) through the same or similar mechanism as in AD.

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients.

Parkinson disease (PD) is a chronic neurodegenerative movement disorder characterized by selective loss of nigrostriatal dopaminergic neurons and formation of Lewy bodies. Clinical manifestations include motor impairments involving tremor, bradykinesia, postural instability and rigidity. Using dHPLC method we screened exons 31, 35, 41, 48 of the Leucine-rich repeat kinase 2 (LRRK2) gene and exons 2, 6 and 7 of Parkinson protein 2 (parkin, PARK2) genes in a cohort of 216 consecutive, unrelated Slovak patients with familial or sporadic PD, including early and late onset. By this means we aimed to detect the most common pathogenic mutations within LRRK2 (Arg1441Cys, Arg1441Gly, Arg1628Pro, Tyr1699Cys, Gly2019Ser, Ile2020Thr, Gly2385Arg) and parkin genes responsible for late and early onset forms of disease, respectively. However, none of these mutations was identified in our cohort. Heterozygous point mutation p.Arg275Trp in exon 7 of parkin gene was identified in one patient with age at onset 61 years. Furthermore, we observed the presence of one exonic (LRRK2 ex 48: 7155A>G) and eight intronic polymorphisms (in LRRK2: IVS35+23T>A, IVS47-91insGCCAT, IVS47-91insGCAT, IVS47-41A>G, IVS47-9delT, IVS47-20C>T, IVS47-90A>G, in parkin: IVS2+25T>C), three of which were novel.

Psychosocial Impact of Huntington's Disease and Incentives to Improve Care for Affected Families in the Underserved Region of the Slovak Republic.

INTRODUCTION: Huntington's disease (HD) is often on the margin of standard medical practice due to its low prevalence, the lack of causal treatment, and the typically long premanifest window prior to the onset of the symptoms, which contrasts with the long-lasting burden that the disease causes in affected families. METHODS: To capture these socio-psychological aspects of HD and map the experiences of affected individuals, persons at risk of HD, and caregivers, we created a questionnaire using a qualitative research approach. The questionnaire containing 16 questions was conducted online for a period of three months through patient associations in Slovakia and their infrastructures. RESULTS: In total, we received 30 responses. The survey results, in particular, indicate insufficient counselling by physicians with explicitly missing information about the possibility of preimplantation genetic diagnostic. There was also a necessity to improve comprehensive social and health care in the later stages of the disease, raise awareness of the disease in the general health community, and provide more information on ongoing clinical trials. CONCLUSION: The psychosocial effects, as well as the burden, can be mitigated by comprehensive genetic counselling as well as reproductive and financial guidelines and subsequent therapeutic programs to actively support patients, caregivers, children, and adolescents growing up in affected families, preferably with the help of local HD community association. LIMITATIONS: We have used online data collection to reach a wider HD community, but at the same time, we are aware that the quality of the data we would obtain through face-to-face interviews would be considerably better. Therefore, future studies need to be conducted to obtain more detailed information.

Adherence to Pharmacotherapy in Patients With Parkinson's Disease Taking Three and More Daily Doses of Medication.

Background: Once-daily treatment formulation is associated with better adherence in comparison to more complex medication regimens. The study aimed to detect the extent of adherence to pharmacotherapy in Parkinson disease (PD) patients who take a minimum of three daily doses of drugs, and to identify factors associated with lower levels of adherence. Methods: The cohort was selected from non-demented PD patients. The 8-Item Morisky Medication Adherence Scale (MMAS-8), 8-Item Parkinson's Disease Questionnaire (PDQ-8), Geriatric Depression Scale (GDS), Non-Motor Symptom Assessment Scale (NMSS), 9-Item Wearing-off Questionnaire (WOQ-9), MDS-UPDRS III (motor examination), and IV (motor complications) scales were used in this study. Results: From a total of 124 subjects, 33.9% reported a high level of adherence, 29.8% reported a medium level of adherence, and 36.3% reported a low level of adherence to their pharmacotherapy. The level of non-adherence correlated with gender, longer disease duration, higher scores of PDQ-8, NMSS, WOQ-9, and MDS-UPDRS IV. Detailed analysis of NMSS demonstrated a correlation between the level of adherence and domains sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, and urinary symptoms. Independent risk factors for non-adherence were excessive daytime sleepiness, anhedonia, and forgetfulness. Conclusion: Non-adherence to more complicated medication regimens is frequent in PD patients and is associated with gender, longer PD duration, poorer quality of life, frequency and severity of non-motor symptoms, and more severe motor and non-motor fluctuations. Non-adherence was predicted by non-motor symptoms including fatigue, mood disturbances, and subjective cognitive complaints.

Push-and-release test predicts Parkinson fallers and nonfallers better than the pull test: comparison in OFF and ON medication states.

The aim of this study was to compare the Pull Test--Retropulsion Test and the Push and Release Test (P&R) as regards their ability to predict Parkinson (PD) fallers and nonfallers in relation to their medication state. Eighty-two PD patients participated in the study. Fallers (N = 36) and nonfallers (N = 46) were grouped on the basis of their fall history. Fallers were those who had fallen at least once within the last 6 months. The two groups were compared on the basis of the patients' performance in the Pull and the P&R tests, both in their "OFF" and "ON" medication state. The overall accuracy of the classification of PD patients as fallers and nonfallers was determined by means of binomial logistic regression (BLR) and the analysis of the "area under the receiver operating characteristics curve" (AUC). In the OFF medication state, the statistical analysis revealed that the Pull Test was accurate (methods BLR (AUC)) in 85.4% (0.87) of cases and the P&R Test in 86.6% (0.90). In the ON medication state, the Pull Test was only 76.8% (0.78) accurate, while the P&R Test was 87.8% (0.87) accurate. Both clinical tests are valid and relatively equivalent when assessing patients in their OFF medication state; however, the P&R Test is more accurate than the Pull Test in the ON state. This indicates that it is more widely applicable in clinical practice.

Efficacy and safety of abobotulinumtoxinA in spastic lower limb: Randomized trial and extension.

OBJECTIVE: To demonstrate single abobotulinumtoxinA injection efficacy in lower limb vs placebo for adults with chronic hemiparesis and assess long-term safety and efficacy of repeated injections. METHODS: In a multicenter, double-blind, randomized, placebo-controlled, single-cycle study followed by a 1-year open-label, multiple-cycle extension, adults ≥6 months after stroke/brain injury received one lower limb injection (abobotulinumtoxinA 1,000 U, abobotulinumtoxinA 1,500 U, placebo) followed by ≤4 open-label cycles (1,000, 1,500 U) at ≥12-week intervals. Efficacy measures included Modified Ashworth Scale (MAS) in gastrocnemius-soleus complex (GSC; double-blind primary endpoint), physician global assessment (PGA), and comfortable barefoot walking speed. Safety was the open-label primary endpoint. RESULTS: After a single injection, mean (95% confidence interval) MAS GSC changes from baseline at week 4 (double-blind, n = 381) were as follows: -0.5 (-0.7 to -0.4) (placebo, n = 128), -0.6 (-0.8 to -0.5) (abobotulinumtoxinA 1,000 U, n = 125; p = 0.28 vs placebo), and -0.8 (-0.9 to -0.7) (abobotulinumtoxinA 1,500 U, n = 128; p = 0.009 vs placebo). Mean week 4 PGA scores were as follows: 0.7 (0.5, 0.9) (placebo), 0.9 (0.7, 1.1) (1,000 U; p = 0.067 vs placebo), and 0.9 (0.7, 1.1) (1,500 U; p = 0.067); walking speed was not significantly improved vs placebo. At cycle 4, week 4 (open-label), mean MAS GSC change reached -1.0. Incremental improvements in PGA and walking speed occurred across open-label cycles; by cycle 4, week 4, mean PGA was 1.9, and walking speed increased +25.3% (17.5, 33.2), with 16% of participants walking >0.8 m/s (associated with community mobility; 0% at baseline). Tolerability was good and consistent with the known abobotulinumtoxinA safety profile. CONCLUSIONS: In chronic hemiparesis, single abobotulinumtoxinA (Dysport Ipsen) administration reduced muscle tone. Repeated administration over a year was well-tolerated and improved walking speed and likelihood of achieving community ambulation. CLINICALTRIALGOV IDENTIFIERS: NCT01249404, NCT01251367. CLASSIFICATION OF EVIDENCE: The double-blind phase of this study provides Class I evidence that for adults with chronic spastic hemiparesis, a single abobotulinumtoxinA injection reduces lower extremity muscle tone.

Effects of rasagiline on freezing of gait in Parkinson's disease - an open-label, multicenter study.

AIMS: Freezing of gait is a disabling symptom in advanced Parkinson's disease. Positive effects have been suggested with MAO-B inhibitors. We report on an open label clinical study on the efficacy of rasagiline as add-on therapy on freezing of gait and quality of life in patients with Parkinson's disease. METHODS: Forty two patients with freezing of gait were treated with 1 mg rasagiline daily as an add-on therapy. Patients were assessed at baseline and after 1, 2 and 3 months of treatment. Freezing of gait severity was assessed using the Freezing of Gait Questionnaire, motor impairment by the modified MDS UPDRS part III, and quality of life using the PDQ-39 questionnaire. RESULTS: Patients treated with rasagiline had a statistically significant decrease in FoG-Q score and modified MDS UPDRS score after 1, 2 and 3 months of therapy. A moderately strong (r = 0.686, P = 0.002) correlation between the effects on mobility and freezing of gait was found. We also observed a statistically significant improvement in global QoL and in the subscales mobility, ADL, stigma and bodily discomfort in patients after 3 months of rasagiline therapy. A significant correlation (r = 0.570, P = 0.02) between baseline FoG-Q score and the baseline score for the PDQ Mobility subscale was found. CONCLUSION: In our study rasagiline as add-on antiparkinsonian therapy significantly improved mobility, freezing of gait and quality of life. The positive effect on freezing of gait appears to be related to improvement of mobility.

Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients.

Hyperhomocysteinemia is not only a major risk factor for atherothrombotic disease, but is also strongly associated with an increased risk of dementia and cognitive impairment, both of which are common in the course of Parkinson's disease (PD). Previous work has found that levodopa increases plasma homocysteine concentrations. Animal studies have indicated that the catechol-O-methyltransferase (COMT) inhibitors can prevent levodopa-induced elevation of homocysteine concentrations by reducing the O-methylation of levodopa. The objective of our study was to assess the impact of entacapone, a COMT inhibitor, on plasma levels of homocysteine, serum folate, and vitamin B12 in levodopa-treated PD patients. Nineteen PD patients receiving only levodopa and 21 PD patients on a combination of levodopa and entacapone participated in the cross-sectional study. The control group consisted of 17 subjects on dopamine agonists. The mean plasma homocysteine concentration in the subjects on only levodopa was higher than that in the subjects on a combination of levodopa and entacapone (P=0.001) or in the control group (P=0.0001). Concentrations of serum vitamin B12 and serum folate were on average normal in all groups, but levodopa-treated subjects (with or without entacapone therapy) were more prone to have hypovitaminosis B12 (45%) than controls on dopamine agonists (6%). We suggest that the COMT inhibition may play a promising role in successfully controlling levodopa-induced hyperhomocysteinemia and in reducing the risk of pathologies probably linked to it. These preliminary findings and postulated hypotheses must now be confirmed in prospective studies.

Pain in Parkinson's Disease: A Cross-Sectional Study of Its Prevalence, Types, and Relationship to Depression and Quality of Life.

Pain is an important and distressing symptom in Parkinson's disease (PD). Our aim was to determine the prevalence of pain, its various types and characteristics, as well as its impact on depression and quality of life (QoL) in patients with PD. How pain differs in early- and advanced-stage PD and male and female PD patients was of special interest. One hundred PD patients on dopaminergic medications had a neurological examination and participated in a structured interview on pain characteristics and completed standardized questionnaires. A total of 76% of the patients had pain. The following types of pain were present: musculoskeletal pain accounted for 41% of the total pain, dystonic pain for 17%, central neuropathic pain for 22%, radicular pain for 27%, and other pains (non-radicular low back pain, arthritic, and visceral pain) made up 24%. One type of pain affected 29% of all the subjects, two types 35%, three types 10%, and four types of pain were reported by 2%. All types of pain were more prevalent in advanced-stage PD subjects than in early-stage PD subjects, except for arthritic pain (subclassified under"other pain"). The frequency and intensity of actual, average, and worst experienced pain were significantly more severe in advanced-stage subjects. PD subjects with general pain and in advanced stages were more depressed and had poorer QoL. Depression correlated with worst pain in the last 24 hours and with pain periodicity (the worst depression score in patients with constant pain). QoL correlated with average pain in the last 7 days. Pain is a frequent problem in PD patients, and it worsens during the course of the disease.

Nonmotor symptoms in early- and advanced-stage Parkinson's disease patients on dopaminergic therapy: how do they correlate with quality of life?

To determine the impact of nonmotor symptoms (NMS) on health-related quality of life (HRQoL) we examined 100 Parkinson's disease (PD) patients on dopaminergic medications. An "early-stage" (ES) and an "advanced-stage" (AS) groups were formed. HRQoL was established by the questionnaire PDQ-8, number of NMS by NMSQuest, and severity and frequency of NMS by the assessment scale NMSS. The total NMS averaged 11.3 (ES = 9.6, AS = 12.8). The NMSS domain correlation profiles for ES and AS did not fundamentally differ; however, the domains attention/memory and mood/apathy correlated moderately to strongly with HRQoL in ES, while the sleep/fatigue domain correlated moderately with HRQoL in AS. Weakly correlating domains were sleep/fatigue in ES and cardiovascular, attention/memory, and mood/apathy domains in AS. In view of these findings we strongly recommend systematic, active screening and therapy for neuropsychiatric disorders (mood, cognitive and sleep disorders, and fatigue) at the initial diagnosis and throughout the entire course of PD.

Impulse control disorders associated with dopaminergic medication in patients with pituitary adenomas.

OBJECTIVE: Impulse control disorders (ICDs) such as pathological gambling, compulsive shopping, compulsive eating, and hypersexuality are a matter of growing interest, especially in patients with Parkinson disease who are on dopamine replacement therapy. It was recently reported that ICDs are associated with other disorders also treated with dopaminergic drugs (dopamine agonists) such as restless legs syndrome, multiple system atrophy, progressive supranuclear palsy, and fibromyalgia. The aim of this study was to determine the prevalence of ICDs in patients with pituitary adenomas who take dopamine agonists (DAs). METHODS: Twenty consecutive patients with pituitary adenomas (mostly prolactinomas) taking DAs were assessed. All participated in a structured interview focused on ICDs, which was conducted by a physician. RESULTS: Two (10%) of 20 subjects had a condition diagnosed as ICD. The first patient is a 35-year-old man with giant macroprolactinoma who was alternately treated with different types of DAs (cabergoline, bromocriptine, and quinagolide). He developed compulsive eating and pathological gambling. The second patient is a 53-year-old man with macroprolactinoma who suffered from severe hypersexuality after cabergoline was begun. CONCLUSIONS: This study demonstrates the importance of systematic screening for ICDs in patients taking dopaminergic medication regardless of their primary condition.

Postural reactions to neck vibration in Parkinson's disease.

To test the hypothesis that reduced reactions to proprioceptive input signals contribute to postural instability in Parkinson's disease (PD), pulses of mechanical vibration were applied to the neck muscles of PD patients and healthy controls. This stimulus elicits postural reactions in standing subjects. Participating were 13 moderately affected PD patients, 13 severely affected PD patients, and 13 age-matched healthy subjects. Patients were tested on and off medication. Three-second-long pulses of vibration were regularly (10 times) applied to the posterior neck muscles while subjects kept their eyes open or closed. Postural responses to the stimuli were measured by static posturography. No intergroup difference in the pattern and latencies of responses was found. However, the amplitudes of the postural reactions (shift of center of foot pressure) were significantly larger in advanced PD patients; those of moderately affected PD patients did not differ from those of control subjects. Moreover, the size of postural responses in both latter groups decreased across the trial contrary to that of advanced PD patients. Comparison of the measures during on and off testing revealed no significant differences. These results indicate that neither afferent proprioceptive deficits nor central integrative functions but rather scaling and habituation of erroneous proprioceptive information are disturbed in the postural control of advanced PD. Nondopaminergic structures seem to be responsible for this impairment.