Screening for diabetic peripheral neuropathy at community pharmacies in Slovakia.

AIM: To identify diabetic patients with a potential risk of developing diabetic peripheral neuropathy (DPN) in community pharmacies in Slovakia using a modified Michigan Neuropathy Screening Instrument questionnaire (MNSIq-12). METHODS: This cross-sectional study enrolled 703 patients with type 1 and type 2 diabetes mellitus who had not been diagnosed with DPN. The study took place in selected community pharmacies across Slovakia in October 2019. The MNSIq-12 was administered by pharmacy students, and a Michigan score <1.5 was considered risky. The groups divided based on the Michigan score were compared in terms of duration of diabetes, age, body mass index (BMI), sex, weekly physical activity, level of education, and smoking. RESULTS: The risk of developing DPN was detected in 6.6% of respondents with type 1 diabetes and 13.4% with type 2 diabetes. Patients with both types of diabetes (38.2%; 67.0%) reported fatigue and heaviness in the legs as the most common clinical symptoms that may indicate the development of DPN. Those with a Michigan score <1.5 were older (P<0.0001), had a higher BMI (P<0.0001), a lower level of education (P=0.0020), and were less physically active (P<0.0001). Conclusion Approximately one-eighth of patients with diabetes who visited community pharmacies were potentially at risk for developing DPN. The modified MNSIq-12 was shown to be a simple, time-effective, and non-invasive indicative screening tool that can be applied in the environment of community pharmacies.

Imaging Methods Applicable in the Diagnostics of Alzheimer's Disease, Considering the Involvement of Insulin Resistance.

Alzheimer's disease (AD) is an incurable neurodegenerative disease and the most frequently diagnosed type of dementia, characterized by (1) perturbed cerebral perfusion, vasculature, and cortical metabolism; (2) induced proinflammatory processes; and (3) the aggregation of amyloid beta and hyperphosphorylated Tau proteins. Subclinical AD changes are commonly detectable by using radiological and nuclear neuroimaging methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Furthermore, other valuable modalities exist (in particular, structural volumetric, diffusion, perfusion, functional, and metabolic magnetic resonance methods) that can advance the diagnostic algorithm of AD and our understanding of its pathogenesis. Recently, new insights into AD pathoetiology revealed that deranged insulin homeostasis in the brain may play a role in the onset and progression of the disease. AD-related brain insulin resistance is closely linked to systemic insulin homeostasis disorders caused by pancreas and/or liver dysfunction. Indeed, in recent studies, linkages between the development and onset of AD and the liver and/or pancreas have been established. Aside from standard radiological and nuclear neuroimaging methods and clinically fewer common methods of magnetic resonance, this article also discusses the use of new suggestive non-neuronal imaging modalities to assess AD-associated structural changes in the liver and pancreas. Studying these changes might be of great clinical importance because of their possible involvement in AD pathogenesis during the prodromal phase of the disease.

Oxidative stress parameters and their relation to motor subtype of Parkinson's disease and levodopa treatment status.

Parkinson's disease (PD) is an oxidative stress-linked neurodegenerative disorder, with the highest prevalence among seniors. The objective of this study were: (1) to analyse levels of following oxidative stress parameters: total antioxidant capacity (TAC), uric acid (UA), total glutathione (tGSH), bilirubin (Bil) and albumin (Alb), in blood of PD patients and healthy controls; (2) to find possible associations of examined oxidative stress parameters with PD subtypes and levodopa treatment status; and (3) to evaluate power and relevance of the aforementioned oxidative stress parameter for the prediction of onset and progression of PD by utilizing Random Forest machine learning (RFML). Oxidative stress parameters were determined in 125 PD patients and 55 healthy controls. Evaluated with frequentist statistics, our data revealed that UA is the only oxidative stress parameter associated with PD. However, when the PD cohort was divided in gender-dependent manner, tGSH and Bil were also significantly associated with PD in subgroup of female patients. RFML rendered no predictive power of any of the tested oxidative stress parameters in respect to PD, its subtypes, and/or status of levodopa treatment. In conclusion, despite the positive association of UA with PD (in complete cohort of PD patients) and of tGSH and Bil with PD but only in female patients, these oxidative stress parameters are of no use in clinical practice due to the lack of the predictive/diagnostic power.

Backward leaning during gait: An underrecognized sign in Niemann-Pick type C.

Niemann-Pick type C (NPC) is a rare but treatable lysosomal disorder with heterogeneous clinical presentations including cognitive impairment, movement disorders and vertical gaze palsy. We illustrate five cases of genetically confirmed NPC and highlight backward leaning during gait as a relevant clinical sign and a useful diagnostic clue.

Effect of Pillbox Organizers with Alarms on Adherence to Pharmacotherapy in Parkinson Disease Patients Taking Three and More Daily Doses of Dopaminergic Medications.

Improvement of adherence to pharmacotherapy in patients with Parkinson's disease (PD) is a challenge in routine clinical practice. Our study was aimed at the effect of pillbox organizers with alarms improving adherence to pharmacotherapy and its impact on clinical outcomes. Forty nonadherent patients with PD being treated with ≥ 3 daily doses of levodopa and/or dopamine agonists were pseudorandomized and consecutively ranked to groups A (early-start intervention) and B (delayed-start intervention). We used the following validated diagnostic instruments: MMAS-8 (adherence), PDQ-8 (quality of life, QoL), GDS (depression), NMSS (non-motor symptoms), MDS-UPDRS III (motor involvement), MDS-UPDRS IV, and WOQ-9 (motor and non-motor fluctuations and dyskinesias). We proved a significantly improved rate of adherence with the use of pillbox organizers with alarms. Moreover, after only four weeks of using the pillbox organizer, we detected an improvement in QoL scores, motor involvement, motor-, and non-motor fluctuations. Our study showed that pillbox organizers with alarms are efficient in improving adherence to pharmacotherapy in PD. It also could contribute to better motor states, less severe fluctuations, and improved QoL.

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.

Atypical presentation of Charcot-Marie-Tooth disease type 1C with a new mutation: a case report.

BACKGROUND: Charcot-Marie-Tooth 1C (CMT1C) is a rare form of dominantly inherited CMT1 neuropathy caused by a mutated gene encoding lipopolysaccharide-induced tumour necrosis alpha factor (LITAF). CASE PRESENTATION: We report a 56-year-old patient with an atypical clinical phenotype of CMT1C, which started as progressive weakness of a single upper limb resembling acquired inflammatory neuropathy. Nerve conduction studies (NCS) and temporarily limited and partial effects of immunotherapy supported the diagnosis of inflammatory neuropathy. Significant progression of polyneuropathy, despite intensive long-lasting immunotherapy, together with repeatedly negative auxiliary investigations (CSF, MRI and antibodies) and genetic testing results finally led to the diagnosis of CMT1C neuropathy. CONCLUSIONS: CMT1C should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy.

SNPs rs11240569, rs708727, and rs823156 in SLC41A1 Do Not Discriminate Between Slovak Patients with Idiopathic Parkinson's Disease and Healthy Controls: Statistics and Machine-Learning Evidence.

Gene SLC41A1 (A1) is localized within Parkinson's disease-(PD)-susceptibility locus PARK16 and encodes for the Na+/Mg2+-exchanger. The association of several A1 SNPs with PD has been studied. Two, rs11240569 and rs823156, have been associated with reduced PD-susceptibility primarily in Asian populations. Here, we examined the association of rs11240569, rs708727, and rs823156 with PD in the Slovak population and their power to discriminate between PD patients and healthy controls. The study included 150 PD patients and 120 controls. Genotyping was performed with the TaqMan® approach. Data were analyzed by conventional statistics and Random Forest machine-learning (ML) algorithm. Individually, none of the three SNPs is associated with an altered risk for PD-onset in Slovaks. However, a combination of genotypes of SNP-triplet GG(rs11240569)/AG(rs708727)/AA(rs823156) is significantly (p < 0.05) more frequent in the PD (13.3%) than in the control (5%) cohort. ML identified the power of the tested SNPs in isolation or of their singlets (joined), duplets and triplets to discriminate between PD-patients and healthy controls as zero. Our data further substantiate differences between diverse populations regarding the association of A1 polymorphisms with PD-susceptibility. Lack of power of the tested SNPs to discriminate between PD and healthy cases render their clinical/diagnostic relevance in the Slovak population negligible.

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.

Paramyotonia congenita in a Slovak population: Genetic and pedigree analysis of 3 families.

BACKGROUND: Paramyotonia congenita is a non-dystrophic myotonia, in which muscle relaxation is delayed after voluntary or evoked contraction. This condition cannot be distinguished on the basis of symptoms and signs alone. It requires consideration of genetics as more than 100 mutations in the CLCN1 gene and at least 20 mutations in the SCN4A gene are associated with the clinical features of the non-dystrophic myotonias. Only a few families with the described features but no genetic testing have been reported in Slovakia. This prompted us to investigate genetic mutations in the SCN4A gene in 3 Slovak families clinically diagnosed with paramyotonia. SUBJECTS AND METHODS: Genomic DNA of the family members was extracted from peripheral blood and amplified by polymerase chain reaction. SCN4A variants were screened by Sanger sequencing. RESULTS: Our results revealed 2 potential disease-causing mutations present in the probands and affected family members - mutations c.3938C > T (p.T1313M) in two families and mutation c.2111C>T (p. T704M) in one family. CONCLUSION: Our results may help to identify genetic determinants as well as clarify genotype-phenotype relationships in patients with paramyotonia in Slovakia.

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.

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.

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.

Validation of the Official Slovak Version of the Unified Dyskinesia Rating Scale (UDysRS).

After successful clinimetric testing of the Unified Dyskinesia Rating Scale (UDysRS), a program for translation and validation of non-English versions of the UDysRS was initiated. The aim of this study was to validate and confirm the factor structure of the Slovak translation of the UDysRS. We examined 251 patients with Parkinson's disease and dyskinesia using the Slovak version of the UDysRS. The average age of our sample was 65.2 ± 9.2 years and average disease duration was 10.9 ± 5.0 years. Slovak data were compared using confirmatory factor analysis with the Spanish data. To be designated as the official Slovak UDysRS translation, the comparative fit index (CFI) had to be ≥0.90 relative to the Spanish language version. Exploratory factor analysis was performed to explore the underlying factor structure without the constraint of a prespecified factor structure. For all four parts of the Slovak UDysRS, the CFI, in comparison with the Spanish language factor structure, was ≥0.98. Isolated differences in the factor structure of the Slovak UDysRS were identified by exploratory factor analysis compared with the Spanish version. The Slovak version of the UDysRS was designated as an official non-English translation and can be downloaded from the website of the International Parkinson and Movement Disorder Society.

Relationship between the non-motor items of the MDS-UPDRS and Quality of Life in patients with Parkinson's disease.

The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed comprehensive tool to assess Parkinson's disease (PD), which covers a wider range of non-motor PD manifestations than the original UPDRS scale. The aim of this study was to assess the relationship between the MDS-UPDRS and Quality of Life (QoL) and to analyze the relationship between individual MDS-UPDRS non-motor items and QoL. A total of 291 PD patients were examined in a multicenter Slovak study. Patients were assessed by the MDS-UPDRS, HY scale and PDQ39. Data were analyzed using the multiple regression analyses. The mean participant age was 68.0 ± 9.0 years, 53.5% were men, mean disease duration was 8.3 ± 5.3 years and mean HY was 2.7 ± 1.0. In a multiple regression analysis model the PDQ39 summary index was related to MDS-UPDRS parts II, I and IV respectively, but not to part III. Individual MDS-UPDRS non-motor items related to the PDQ39 summary index in the summary group and in the non-fluctuating patients subgroup were pain, fatigue and features of dopamine dysregulation syndrome (DDS). In the fluctuating PD patient subgroup, PDQ39 was related to pain and Depressed mood items. Other MDS-UPDRS non-motor items e.g. Anxious mood, Apathy, Cognitive impairment, Hallucinations and psychosis, Sleep problems, Daytime sleepiness and Urinary problems were related to some PDQ39 domains. The overall burden of NMS in PD is more important in terms of QoL than motor symptoms. Individual MDS-UPDRS non-motor items related to worse QoL are especially pain and other sensations, fatigue and features of DDS.

Proton magnetic resonance spectroscopy in patients with early stages of amyotrophic lateral sclerosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder primarily affecting upper and lower motor neurons. Due to relative fast progression of the disease, early diagnosis is essential. Proton magnetic resonance spectroscopy ((1)H-MRS) is used for objectivization of upper motor neuron (UMN) lesions. The aim of this study was to assess the use of (1)H-MRS in the early stages of ALS. METHODS: Eleven patients with clinically definite (n=2), probable (n=7), and probable laboratory-supported (n=2) diagnosis of ALS with disease duration of less than 14 months were studied. Control group consists of 11 sex- and age-matched healthy subjects. All subjects underwent assessment of functional disability using revised ALS Functional Rating Scale (ALSFRS-R) and single-voxel (1)H-MRS examination of both precentral gyri, pons, medulla oblongata, and occipital lobe. Spectra were evaluated with LCModel software. RESULTS: The mean disease duration was 6.5 ± 3.5 months. The median ALSFRS-R was 42. Significant decrease between patient and control groups was found in the NAA/Cre ratio in the left and right precentral gyri (p=0.008, p=0.040). Other metabolite ratios in other areas did not show significant differences. Total ALSFRS-R score weakly positively correlated with NAA/Cre ratio in the left precentral gyrus (p=0.047). CONCLUSIONS: (1)H-MRS is sensitive to detect metabolic changes caused by neurodegeneration processes during ALS and can be used for detection of UMN dysfunction. These MRS changes in the early stages of ALS are most prominent in motor cortex.