Periventricular white matter hyperintensity burden and cognitive impairment in early Parkinson's disease.

BACKGROUND AND PURPOSE: This study quantified the total brain and periventricular white matter hyperintensity (WMH) burdens in patients with early Parkinson's disease (PD) and explored their associations with cardiovascular risk factors and cognitive performance. METHODS: A total of 175 non-demented patients with early PD who had undergone baseline brain magnetic resonance imaging were included. Comprehensive neurocognitive testing was conducted to identify PD with mild cognitive impairment (PD-MCI) and to evaluate performances in individual cognitive domains. Cardiovascular risk was expressed as a modified Framingham 10-year cardiovascular risk score (mFRS). RESULTS: A total of 53.7% of this early PD cohort fulfilled the diagnostic criteria for PD-MCI. An increase in mFRS was significantly associated with increases in the total brain WMH (P = 0.015) and periventricular WMH (P = 0.040) burden, independent of age and gender. The periventricular WMH burden was significantly associated with PD-MCI (P = 0.046) in early PD, independent of cardiovascular risk factors. Patients in the 5th quintile of periventricular WMH burden were 8.6 times more likely to have PD-MCI compared with patients in the 1st quintile of periventricular WMH burden (P = 0.004). However, total brain WMH burden was not associated with PD-MCI (P = 0.158). In individual cognitive domains, heavier periventricular WMH burden was associated with worse executive function and visuospatial function independent of cardiovascular risk factors. CONCLUSION: Periventricular WMHs are a useful imaging biomarker for cognitive impairment in early PD. Cardiovascular risk factors, although associated with periventricular WMHs, were unable to fully explain the association between periventricular WMHs and cognitive impairment in early PD.

No association of DNM3 with age of onset in Asian Parkinson's disease.

BACKGROUND AND PURPOSE: Genetic variability in DNM3 has been shown to modify age of onset of Parkinson's disease (PD) among LRRK2 Gly2019Ser carriers in North African Arab-Berber populations. In Asian populations, the Gly2019Ser mutation is rare or absent but two other LRRK2 variants, Gly2385Arg and Arg1628PPro, increase PD risk. We aimed to determine whether the DNM3 locus was associated with age of PD onset in both carriers and non-carriers of LRRK2 risk variants in Asians. METHODS: We analyzed the association of DNM3 rs2421947 genotypes with age of PD onset in 3645 Chinese samples, of which 369 carried at least one of two Asian LRRK2 risk variants. RESULTS: DNM3 rs2421947 genotypes were not associated with age of PD onset in Chinese samples. We observed no heterogeneity in the effect of rs2421947 between the Asian LRRK2 risk variant carriers and non-carriers. CONCLUSIONS: DNM3 rs2421947 was not associated with age of PD onset in LRRK2 risk variant carriers and non-carriers in Chinese samples. Further studies in other Asian populations will be of interest.

Non-motor symptoms in early Parkinson's disease with different motor subtypes and their associations with quality of life.

BACKGROUND AND PURPOSE: The aim of this study was to examine non-motor symptoms in different Parkinson's disease (PD) motor subtypes and their associations with quality of life (QoL). METHODS: A total of 132 patients with early PD with comprehensive motor examinations and non-motor symptom assessments were included. Motor subtypes were classified based on Stebbins' method. Non-motor symptoms were assessed by the Non-Motor Symptom Scale (NMSS) and validated by more comprehensive instruments, including the Pittsburgh Sleep Quality Index (PSQI) and Fatigue Severity Scale (FSS). QoL was measured by the Parkinson's Disease Questionnaire-8. RESULTS: We identified 66 patients (50%) with tremor-dominant (TD) subtype, 47 (35.6%) with postural instability and gait disorder (PIGD) subtype and 19 (14.4%) with Intermediate subtype. By comparing NMSS scores, patients with the PIGD subtype had more severe sleep impairment and fatigue (domain 2 score: 5.64 vs. 2.52, P < 0.001), urinary symptoms (domain 7 score: 6.96 vs. 3.48, P = 0.005) and overall more severe non-motor symptoms (NMSS total score: 25.89 vs. 17.27, P = 0.031), compared with patients with the TD subtype. Validation using the PSQI and FSS again suggested that patients with the PIGD subtype had independently and significantly more severe sleep impairment (PSQI score: 5.57 vs. 4.29, P = 0.020) and fatigue (FSS score: 34.81 vs. 25.85, P = 0.003) compared with patients with the TD subtype. Several non-motor symptoms had significant associations with QoL, among which sleep impairment and fatigue (P < 0.0001, partial r2 = 0.273) explained the largest proportion of QoL variability in patients with PD. CONCLUSIONS: Patients with the PIGD subtype had more severe sleep impairment, fatigue and urinary disturbance compared with patients with the TD subtype. Sleep impairment and fatigue were the most important factors affecting QoL independent of motor subtypes. Prompt identification and treatment of these non-motor symptoms may improve patients' QoL.

Progression of subcortical atrophy in mild Parkinson's disease and its impact on cognition.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)-MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD. METHODS: Sixty-five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD-NCI (n = 54) and PD-MCI (n = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD-stable (n = 42) and those who converted to MCI over 18 months were classified as PD-converters (n = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow-up. RESULTS: Parkinson's disease-MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2-3, and significant memory and executive dysfunction compared with PD-NCI. PD-converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains. CONCLUSIONS: Progression of cognitive impairment in non-demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia.

Clinical evolution of Parkinson's disease and prognostic factors affecting motor progression: 9-year follow-up study.

BACKGROUND AND PURPOSE: There have been few long-term studies that have characterized and charted the clinical progression of Parkinson's disease (PD). This study was therefore undertaken to understand the natural clinical evolution of treated PD patients and to identify the variables that predict greater progression in these patients. METHODS: A longitudinal linear mixed model analysis of motor score progression was performed on 576 PD patients derived from the National Neuroscience Institute Movement Disorders Database. Clinical and demographic variables were taken at baseline and formed the subgroups for comparison (gender, age at diagnosis, subtype, Mini-Mental State Examination score and baseline motor score). Motor score progression was calculated at each patient follow-up time point as the difference between Unified Parkinson's Disease Rating Scale (UPDRS) motor score at baseline and follow-up scores. RESULTS: The overall annual motor score progression as measured by the change of UPDRS motor scores from baseline ranged from 0.62% to 3.67%. There are three distinct phases: improvement, stability, and steady progression. Patients returned to baseline score 2-2.5 years after diagnosis, with stability lasting to 7 years, followed by a period of steady progression. When analyzed longitudinally, male gender (P < 0.03), older age at diagnosis (P < 0.05), akinetic-rigid subtype (P < 0.04), cognitive impairment (P < 0.005) and lower baseline motor score (P < 0.04) were associated with greater progression of motor scores. CONCLUSIONS: Our results show that, when measured clinically, motor progression was non-linear and that it occurred in distinct phases, all of which were affected by baseline demographic and clinical variables such as gender, age at diagnosis, disease subtype, cognitive status and baseline motor score.

Clinico-genetic comparisons of paroxysmal kinesigenic dyskinesia patients with and without PRRT2 mutations.

BACKGROUND AND PURPOSE: Mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesias (PKD); however, not many detailed clinico-genetic correlations have been performed. METHODS: To investigate PRRT2 mutations in a mixed Asian PKD population and perform clinico-genetic correlations, we recruited patients between 2002 and 2011 and administered a standardized questionnaire. RESULTS: Amongst 29 unrelated patients with PKD recruited, five PRRT2 mutations were present in 15 patients. Three mutations (c.649dupC, c.649delC, c.649C>T) were previous reported, while three were novel mutations (c.604delT; c.609_611delACC/p.Ser202Hisfs; c.697_698delAG/p.Ser233Trp fsX5). Clinico-genetic correlations revealed that a history of seizures was more common in patients with PRRT2 mutations, although this did not reach statistical significance (P= 0.08). A younger age of onset, non-Chinese, and the presence of premonitory sensations were significantly associated with PRRT2 mutations in the univariate analysis. Multivariate logistic regression analysis demonstrated that age of onset [odds ratio (OR) = 0.59, P = 0.025] and premonitory sensation (OR = 10.67, P = 0.028) were independently associated with positive PRRT2 mutation. CONCLUSIONS: PRRT2 mutations are common in patients with PKD, and a double PRRT2 mutation is reported for the first time. PRRT2 mutations are significantly associated with a younger age of onset and the presence of premonitory sensation in our population.

Association of HLA locus variant in Parkinson's disease.

A variant (rs3129882) in the genome-wide association study (GWAS)-linked variant [in the human leukocyte antigen (HLA) gene region] has been reported to associate with an increased risk of Parkinson's disease (PD) in Caucasian population. Studies among Chinese are limited. To address this, we analysed rs3129882 in a total of 1312 subjects of Chinese ethnicity from independent Asian centers comprising of 675 controls and 637 PD cases. The rs3129882 variant was associated with a decreased risk in our ethnic Chinese PD patients. Logistic regression analysis taking into consideration variables of age, gender and race showed that allele A reduced the risk of PD via a dominant model [odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.62, 0.96, p = 0.018]. As HLA is a highly polymorphic region, it is possible that ethnic-specific effect or environmental agents may modulate the effect of this GWAS-linked locus in influencing the risk of PD.

Estimating the lifetime economic burden of Parkinson's disease in Singapore.

BACKGROUND AND PURPOSE: We aimed to estimate the lifetime cost of Parkinson's disease (PD) from the societal perspective. METHODS: A convenience sample of English or Chinese-speaking patients with PD was recruited from a PD and Movement Disorders Centre in Singapore to complete a financial burden questionnaire. Sociodemographic and clinical data were retrieved from hospital databases. Markov cohort model analysis was performed (cycle length, 1-year; duration, death or reached 100 years old). Patients were assumed to progress from one Markov state to the next state or death without skipping states or regressing. All model parameters were based on published local data. RESULTS: In 195 patients with PD (median age: 68.9, male: 51.8%), the simulated lifetime cost of PD was Singapore Dollar (SGD) 60,487 (EUR purchasing power parity 56,253) per patient. Direct medical, non-medical and indirect cost accounted for 18.8%, 12.8% and 68.4% of total lifetime cost, respectively. The top three components of total lifetime cost were productivity losses (67.6%), pharmacotherapy (11.4%) and home care (8.7%). One-way sensitivity analysis and probabilistic sensitivity analyses revealed that estimates were sensitive to cost at H&Y stage 1, 2 and 2.5 and productivity losses. CONCLUSIONS: The lifetime cost of PD is evaluated for the first time. This cost is substantial and comparable to the lifetime cost of intracerebral haemorrhage in at least one study. Our study identified several priority areas for research and policy formulation: reducing productivity losses, reducing cost of pharmacotherapy, avoiding hospitalization and reducing home care cost.

Application of dermal microdialysis for the determination of bioavailability of clobetasol propionate applied to the skin of human subjects.

Dermal microdialysis was used to assess the bioavailability of a topical corticosteroid, clobetasol propionate, following application onto the skin of human subjects. The penetration of clobetasol propionate from a 4% m/v ethanolic solution applied onto 4 sites on one forearm of healthy human volunteers was studied. A lipid emulsion, Intralipid®, was used as the perfusate and linear microdialysis probes with a 2-kDa cutoff were inserted intradermally at the designated sites. The results indicated that Intralipid could be used as a suitable perfusate for in vivo microdialysis of this lipophilic drug of interest. Furthermore, the study clearly demonstrated the application of dermal microdialysis as a valuable tool to assess the bioavailability/bioequivalence of clobetasol propionate penetration into the skin following topical application.

Economic burden of Parkinson's disease in Singapore.

BACKGROUND: This study was carried out to evaluate the economic burden of Parkinson's disease (PD) and factors independently associated with individual components of total cost in Singapore. METHODS: A consecutive sample of 195 patients with PD (mean age: 68.2, men: 51.8%) attending a tertiary neuroscience clinic were identified and interviewed using standardized questionnaires including a financial burden questionnaire, two Health Related Quality of Life (HRQoL) questionnaires and the Beck Depression Inventory questionnaire. RESULTS: Annual total cost of PD from a societal perspective was SGD11345 (USD10129) per patient, with direct cost accounted for 38.5% and indirect cost 61.5%. The main cost components for direct medical cost, direct non-medical cost, and indirect cost was pharmacotherapy (50.4%), home care (76.1%), and productivity loss (97.9%), respectively. In multiple linear regression analysis, higher education, younger age and longer duration of PD were associated with higher total cost. CONCLUSIONS: Parkinson's disease exerts a considerable burden on patients, health care system and society in Singapore. As productivity loss accounts for a large share of the economic burden imposed by PD, treatments and health care programmes with potential for returning patients to higher productivity are urgently needed.

Convolutional Neural Network for Freezing of Gait Detection Leveraging the Continuous Wavelet Transform on Lower Extremities Wearable Sensors Data.

Freezing of Gait is the most disabling gait disturbance in Parkinson's disease. For the past decade, there has been a growing interest in applying machine learning and deep learning models to wearable sensor data to detect Freezing of Gait episodes. In our study, we recruited sixty-seven Parkinson's disease patients who have been suffering from Freezing of Gait, and conducted two clinical assessments while the patients wore two wireless Inertial Measurement Units on their ankles. We converted the recorded time-series sensor data into continuous wavelet transform scalograms and trained a Convolutional Neural Network to detect the freezing episodes. The proposed model achieved a generalisation accuracy of 89.2% and a geometric mean of 88.8%.

Creutzfeldt-Jakob disease: which diffusion-weighted imaging abnormality is associated with periodic EEG complexes?

BACKGROUND: Clinical diagnosis of CJD remains important due to lack of access to a genetic or histopathological diagnosis. Using current WHO criteria, diagnostic certainty can be increased from "possible" to "probable" CJD if periodic complexes are recorded on EEG. OBJECTIVE: To study the correlation between patterns of MRI-DWI hyperintensity and typical EEG findings among patients with CJD. METHODS: Demographics, clinical findings, MRI-DWI and EEG findings of CJD patients were retrospectively reviewed. RESULTS: A total of 14 patients ranging in age from 35 to 81 years were identified. All had dementia and cerebellar ataxia. Psychiatric manifestations were seen in 5 patients. Seven patients had both cortical and striatal DWI changes, five had isolated cortical DWI changes and two had isolated striatal DWI changes. All twelve patients with cortical DWI changes also had periodic EEG changes. In ten, periodic EEG was recorded within seven days of the DWI. The two patients with isolated striatal DWI changes did not develop periodic EEG complexes despite serial EEG recordings, 40 and 88 days from their respective DWI scans. CONCLUSIONS: Serial EEGs are not useful for patients with isolated striatal DWI hyperintensity but will increase diagnostic certainty from "possible" to probable" CJD for patients with cortical DWI hyperintensity.

Factors affecting health-related quality of life amongst Asian patients with Parkinson's disease.

BACKGROUND AND PURPOSE: This cross-sectional study was carried out to identify factors predicting health-related quality of life (HRQoL) amongst Asian patients with Parkinson's disease (PD). METHODS: A total of 183 PD patients (mean age: 61 years, male: 68.9%) attending a tertiary neuroscience clinic in Singapore completed the English or Chinese version of the 8-item Parkinson's Disease Questionnaire (PDQ-8). Patients' socio-demographic characteristics and their clinical variables were analysed to identify factors influencing the PDQ-8 Summary Index and responses to its eight dimensions. RESULTS: In the multiple linear regression model, the use of Chinese survey, higher motor score and longer duration of PD were associated with poorer overall HRQoL. The multiple logistic regression analyses showed that female patients and patients with higher Hoehn and Yahr stage were more probably to report worse emotional well-being; patients who completed Chinese survey reported more problems with mobility, cognition and stigma; patients with higher motor scores were more probably to report problems with activities of daily living; patients with longer duration of PD were more probably to report problems with mobility, social support, communication and stigma. CONCLUSION: Both socio-demographic factors and disease-specific variables influence HRQoL in PD patients; the effects of culture-related factors on HRQoL should not be overlooked when assessing HRQoL in multi-cultural settings.

Cortical muscle coupling in Parkinson's disease (PD) bradykinesia.

OBJECTIVES: To determine if novel methods establishing patterns in EEG-EMG coupling can infer subcortical influences on the motor cortex, and the relationship between these subcortical rhythms and bradykinesia. BACKGROUND: Previous work has suggested that bradykinesia may be a result of inappropriate oscillatory drive to the muscles. Typically, the signal processing method of coherence is used to infer coupling between a single channel of EEG and a single channel of rectified EMG, which demonstrates 2 peaks during sustained contraction: one, approximately 10 Hz, which is pathologically increased in PD, and a approximately 30 Hz peak which is decreased in PD, and influenced by pharmacological manipulation of GABAA receptors in normal subjects. MATERIALS AND METHODS: We employed a novel multiperiodic squeezing paradigm which also required simultaneous movements. Seven PD subjects (on and off L-Dopa) and five normal subjects were recruited. Extent of bradykinesia was inferred by reduced relative performance of the higher frequencies of the squeezing paradigm and UPDRS scores. We employed Independent Component Analysis (ICA) and Empirical Mode Decomposition (EMD) to determine EEG/EMG coupling. RESULTS: Corticomuscular coupling was detected during the continually changing force levels. Different components included those over the primary motor cortex (ipsilaterally and contralaterally) and over the midline. Subjects with greater bradykinesia had a tendency towards increased approximately 10 Hz coupling and reduced approximately 30 Hz coupling that was erratically reversed with L-dopa. CONCLUSIONS: These results suggest that lower approximately 10 Hz peak may represent pathological oscillations within the basal ganglia which may be a contributing factor to bradykinesia in PD.

Characterization of the 5'-flanking transcriptional regulatory region of chicken growth hormone gene.

A 1727-bp fragment of 5'-flanking region of chicken growth hormone (cGH) gene has been cloned and sequenced. Various lengths of the 5'-flanking region (122 to 1775 bp) was linked to a luciferase reporter gene, and its transcriptional regulation was examined by an in vitro transient transfection coupled with luciferase assay. Our results demonstrated that pituitary-specific transcription factor, Pit-1, is necessary and sufficient to confer a strong tissue-specific expression. Co-transfection with goldfish or chicken Pit-1 expression vectors significantly restored the luciferase expression in HeLa cells. Site-directed mutagenesis and mobility gel-shift assays further confirmed the position of the Pit-1 binding site at -113/-104. Moreover, a repressive thyroid hormone response element (TRE) was identified at -137/-74, and we propose that interactions between the TRE and Pit-1 sites may be required for its repressive effect.

Hemifacial spasm in Singapore: clinical characteristics and patients ' perceptions.

INTRODUCTION: The aim of this study was to determine the clinical characteristics and patients ' perception of hemifacial spasm (HFS) in Singapore. MATERIALS AND METHODS: A clinical survey of 137 consecutive patients with HFS seen in our Botulinum Toxin Clinic over a 15-month period was undertaken. RESULTS: Forty-six men and 91 women were interviewed. Their mean age at onset of HFS was 48 years. The median disease duration was 60 months (range, 2 to 360 months). Left-sided spasm was common in 51.8 % of patients, and the orbicularis oculi was the first muscle to be affected in 86.1 % of them. The majority (65 %) had the spasm aggravated by stress and anxiety. In fact, 32 patients perceived stress and anxiety as a possible aetiology of HFS. Stroke was a main concern in 17 patients and 7 patients thought the spasm was a sign of demonic possession or a bad omen. The spasm embarrassed 75.2 % of the patients, rendered 65 % of them depressed, affected the vision in 60.6 % of them and compromised their work performance in 35.8 %. Overall, treatment was delayed by a median interval of 6 months from onset of symptoms (range, 0 to 132). More than half (53.3 %) tried traditional therapies (acupuncture or herbal medicine), while only 48.2 % had botulinum toxin as the initial treatment. All patients eventually received botulinum toxin injections and more than 90 % showed improvement at 1 month posttreatment. CONCLUSIONS: The clinical characteristics and patients ' perception of HFS in Singapore were presented. HFS affects patients both psychosocially and functionally. Effective treatment with botulinum toxin exists and should be provided early to the patients.

Selegiline use is associated with a slower progression in early Parkinson's disease as evaluated by Hoehn and Yahr Stage transition times.

This study was carried out to evaluate the association between selegiline use and Parkinson's disease (PD) progression in a clinical sample by evaluating modified Hoehn and Yahr Stage (H&Y) stage transition times. Data were obtained from the movement disorder database of the National Neuroscience Institute in Singapore. Cox regression analysis was used to examine the association between baseline variables and H&Y stage transition times. In multi-variate Cox regression analysis, patients who were of younger age, shorter PD duration, lower Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, on selegiline treatment (≥ 3 years) and not on COMT inhibitors were associated with longer transition times from stage 2-2.5. Patients who were treated with selegiline (≥ 3 years) and not on COMT inhibitors experienced longer transition times from stage 2.5-3. In conclusion, selegiline use for 3 years or more in early PD was associated with a slower progression of PD as evaluated by H&Y transition times.

Analysis of GWAS-linked loci in Parkinson disease reaffirms PARK16 as a susceptibility locus.

OBJECTIVE: A genome-wide association study (GWAS) in the Japanese population identified 2 new Parkinson disease (PD) susceptibility loci on 1q32 (PARK16) (OMIM 613164) and BST1. We analyzed single nucleotide polymorphism (SNPs) located at the GWAS-linked loci (PARK16, PARK8, PARK1, and BST1) in a Chinese population and also conducted a meta-analysis in Asians by pooling 2 independent replication studies from Japan. METHODS: We conducted an analysis of 13 SNPs associated with PD GWAS-linked loci in 2 case-control cohorts comprised of 1,349 ethnic Chinese subjects. RESULTS: PARK16, PARK8, and PARK1 loci but not BST1 were found to be associated with PD. PARK16 SNPs were associated with a decreased risk while PARK1 and PARK8 SNPs were associated with an increased risk of PD. A pooled analysis of our Chinese cohorts and 2 Japanese replication cohorts involving 1,366 subjects with PD and 16,669 controls revealed robust association with these 3 loci and also BST1. There was a trend toward a stronger protective effect of SNPs at the PARK16 locus in sporadic PD compared to familial cases and in older compared to younger subjects. CONCLUSIONS: Our study reaffirms the role of GWAS-linked loci in PD in Asian subjects and the strength of association is similar between Chinese and Japanese subjects. Efforts to elucidate the associated gene within PARK16 locus are warranted.