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1.
Mov Disord ; 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32353202

RESUMO

BACKGROUND: The phenotype of Parkinson's disease (PD) is milder among patients with LRRK2-PD and more severe among patients with GBA-PD; however, whether an additive phenotypical effect occurs among dual-mutation carriers requires validation. OBJECTIVE: The objective of this study was to explore the phenotypic expression of patients with PD who carry mutations in both genes compared with a single-mutation presentation. METHODS: Patients with PD were genotyped for the G2019S-LRRK2 mutation and 9 mutations in the GBA gene. Subjects were classified into 5 groups: idiopathic PD, mild GBA-PD, severe GBA-PD, LRRK2-PD, and LRRK2+GBA-PD. Clinical symptoms were evaluated using performance-based measures. RESULTS: A total of 1090 patients with idiopathic PD, 155 patients with LRRK2-PD, 155 patients with mild GBA-PD, 56 patients with severe GBA-PD, and 27 patients with LRRK2+GBA-PD participated in this study. The patients with LRRK2-PD and LRRK2+GBA-PD exhibited lower scores on total Unified Parkinson's Disease Rating Scale (P < 0.01) and better olfaction (P < 0.01) compared with GBA-PD. CONCLUSIONS: Patients with LRRK2+GBA-PD were symptomatically similar to patients with LRRK2-PD, suggesting a dominant effect of LRRK2 over GBA in the phenotypic presentation. © 2020 International Parkinson and Movement Disorder Society.

2.
J Neurol ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32383040

RESUMO

Evaluating freezing of gait (FOG) and quantifying its severity in patients with Parkinson's disease (PD) is challenging; objective assessment is not sufficiently established. We aimed to improve the ability to objectively evaluate FOG severity by investigating the value of measuring the duration of the test and its components. Seventy-one patients with PD and FOG completed a previously validated FOG-provoking test. The test was performed under three conditions: (1) usual, single task; (2) dual task (walking while carrying a tray); and (3) triple task (walking while holding a tray and subtracting 7 s). FOG and festination were scored using standard procedures. We evaluated effect sizes based on both the original scoring and the test duration for the motor-cognitive cost and before and after anti-Parkinsonian medication intake. Additionally, video recording of the test and total time frozen were measured. As expected, the original test score and the test duration increased across the three conditions of the task and were higher in OFF than in the ON-medication state (p < 0.036). For motor-cognitive cost, higher effect sizes were observed for the test duration of each condition, compared to the original scoring in OFF state (0.85 vs. 0.68, respectively). Change in effect size category was more pronounced in the ON state vs. OFF (0.87 vs. 0.55, respectively). Test duration was the only independent predictor for the self-report of FOG severity and the total time frozen during the test. These findings suggest that quantifying the duration of each condition of the FOG-provoking test improves its sensitivity to medications and task complexity. Timing can be used to provide immediate, objective feedback of freezing severity, and a clear interpretation of a patient's performance.

3.
Mov Disord ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080891

RESUMO

BACKGROUND: Sleep disturbances and nocturnal hypokinesia are common in Parkinson's disease (PD). Recent work using wearable technologies showed fewer nocturnal movements in PD when compared with controls. However, it is unclear how these manifest across the disease spectrum. OBJECTIVES: We assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication. METHODS: A total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [H&Y] stage 1 = 47, H&Y stage 2 = 181, H&Y stage 3 = 77) and 205 healthy controls continuously wore a tri-axial accelerometer on the lower back for at least 2 days. Lying, turning, and upright -time at night were extracted from the acceleration signals. Percent upright time and nighttime walking were classified as sleep interruptions. The number, velocity, time, side, and degree of rotations in bed were used to evaluate nocturnal movements. RESULTS: Nocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; H&Y stage 1, 7.3 ± 0.9 hours; H&Y stage 2, 7.2 ± 1.3 hours; H&Y stage 3, 7.4 ± 1.6 hours; P = 0.501). However, patients with advanced PD had more upright periods, whereas the number and velocity of their turns were reduced (P ≤ 0.021). Recently diagnosed patients (<1 year from diagnosis) were similar to controls in the number of nocturnal turns (P = 0.148), but showed longer turning time (P = 0.001) and reduced turn magnitude (P = 0.002). Reduced nocturnal movements were associated with increased PD motor severity and worse dysautonomia and cognition and with dopaminergic medication. CONCLUSIONS: Using wearable sensors for continuous monitoring of movement at night may offer an unbiased measure of disease severity that could enhance optimal nighttime dopaminergic treatment and utilization of turning strategies. © 2020 International Parkinson and Movement Disorder Society.

4.
Gait Posture ; 76: 128-135, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31760316

RESUMO

BACKGROUND: Walking is a volitional behavior that requires planning and initiation before a step is observed. Following a signal to begin walking, studies of gait initiation in specialized labs have identified three phases that occur during the transition from a standing position via anticipatory postural adjustment (APA) to the first step. Routine instrumented gait testing outside of the laboratory setting focuses on gait execution and does not include gait initiation measures. RESEARCH QUESTION: Can a single IMU sensor be used for performing gait initiation evaluations outside the lab? METHODS: We recorded walking in young (N = 41) and older (N = 26) adults using an instrumented gait mat while they were wearing a 3D accelerometer on their lower back. Subjects were instructed to begin walking following an auditory signal. An algorithm was developed to extract the following measures from the acceleration signal: gait initiation time, measured from the start of the auditory cue to begin walking and ends at the heel-strike of the swing leg, time-to-APA (reaction time), APA duration and swing time (execution of the first step). RESULTS: Intraclass correlation coefficient analysis showed good to excellent agreement between gait initiation metrics obtained with the gait mat and the wearable sensor (mean 0.88, range [0.75-0.96]). Except for swing time, all measures were longer in the older subjects, compared to the young adults (p < 0.01). SIGNIFICANCE: Extracting gait initiation measures from routine instrumented gait testing may facilitate studies that can better determine the extent to which impaired gait planning and execution contribute to mobility impairments.

5.
Isr Med Assoc J ; 12(21): 812-816, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31814345

RESUMO

BACKGROUND: The effect of repeated intravenous amantadine (IVAM) in advanced Parkinsonism has not been studied in depth. OBJECTIVES: To report the experience of our medical center with repeated IVAM infusions in patients with advanced Parkinsonism. METHODS: Thirty patients with advanced Parkinsonism of various etiologies were enrolled in an open-label retrospective study. All patients were treated with IVAM infusions in a neurological daycare center. Treatment was initiated with a loading dose of 200/400 mg per day for 5 days followed by a once-daily maintenance dose of 200/400 mg every 1 to 3 weeks. Patients and their caregivers participated in a structured interview and independently completed a clinical global impression of changes scale questionnaire on various motor and non-motor symptoms. RESULTS: Patient mean age was 73.3 ± 9.7 years, average disease duration was 6.2 ± 5.7 years, and mean Hoehn and Yahr score was 3.2 ± 0.84. Mean duration of the IVAM treatment was 15.1 ± 11.6 months. An improvement in general function was reported by 91% of the patients and 89% of the caregivers. Most of the patients reported improvement in tremor and rigidity, as well as in gait stability, freezing of gait, and reduced falls. The treatment was safe with few side effects. CONCLUSIONS: Our data suggest that repeated IVAM infusions could be an effective treatment against various motor symptoms and for improvement of mobility in patients with advanced Parkinsonism. Further randomized clinical trials with a larger sample size using objective measures are warranted to validate our results.


Assuntos
Acidentes por Quedas/prevenção & controle , Amantadina , Destreza Motora/efeitos dos fármacos , Doença de Parkinson , Recuperação de Função Fisiológica/efeitos dos fármacos , Idoso , Amantadina/administração & dosagem , Amantadina/efeitos adversos , Progressão da Doença , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
6.
Mol Genet Metab ; 128(4): 470-475, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31662221

RESUMO

BACKGROUND: GBA variants are the most common genetic risk factors for Parkinson's disease (PD) world-wide, and can be found in up to 20% of Ashkenazi PD patients. The E326K variant, which is not considered a Gaucher's disease causing mutation, was recently shown to increase the risk for PD. Since E326K is a common variant among Europeans, Finnish and Ashkenazi (2.4, 8.6 and 1.2% carrier rate, respectively), we aimed to refine its involvement in PD. METHODS: 1200 consecutively recruited PD patients of a full Ashkenazi origin were genotyped for 10 GBA variants, the LRRK2-G2019S and the SMPD1-L302P. Alleles' frequencies were compared to controls, composed of 378 elderly healthy individuals and the non-neuro gnomAD Ashkenazi database. Odds-Ratio (OR) and age-at-motor-symptom-onset (AAO) were also calculated for all genotypes. RESULTS: All allelic variations tested had significant allelic ORs, demonstrating a wide range (1.86-12.84). The lowest allelic OR was observed for E326K (p = .013). Forty-five patients (of 1200, 3.75%) had at least two mutations (of the 12 tested), compared to 2 (0.53%) among 378 controls (p = .0013). Of the E326K carrier patients, 37% (10/27) carried additional mutations and the genotypic OR for individuals who carried only the E326K variant was 1.07. It did not reach statistical significance even when simulating the expected carrier frequency of E326K in 100,000 Ashkenazi controls (p = .39). In addition, an additive effect was demonstrated for risk in carriers of two mutations, the LRRK2-G2019S and a mild-GBA mutation (N370S or R496H), compared to carriers of only one mutation in one of these genes (simulated OR 11.79 compared to 7.58 and 2.49, respectively). An additive effect was also suggested for earlier AAO (5.0 years earlier than in non-carriers, compared to 3.1 and 2.2 years, respectively). CONCLUSIONS: Compared to previous studies, we demonstrate here a higher frequency of PD patients that carry two mutations. The GBA-E326K is more likely to affect PD risk when accompanied by another mutation, and an additive effect on risk and earlier AAO was proposed for carriers of LRRK2/mild-GBA double mutations. Altogether, these data support an oligogenic approach to PD genetics.

7.
Gerontology ; : 1-10, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31461708

RESUMO

BACKGROUND: Tripping over an obstacle is one of the most common causes of falls among older adults; however, the impact of obstacle parameters and subject characteristics are not well described. OBJECTIVES: To evaluate age-associated changes in the ability to negotiate obstacles and the role of obstacle parameters (e.g., anticipated vs. unanticipated, height, and available response time [ART]), and subject characteristics. METHODS: Twenty healthy older adults (77.7 ± 3.4 years; 50% women) and 20 healthy young adults (29.3 ± 3.8 years; 50% women) underwent cognitive, gait, and balance testing before negotiating a computer-controlled obstacle course. The primary outcome measure was the ability to successfully negotiate the obstacles (without touching them). RESULTS: The success rate for all subjects was higher when the obstacle was anticipated (99.0 ± 2.8%) than when unanticipated (66.0 ± 20.2%; p < 0.001). The obstacle height had a significant effect on the success rate (p = 0.022); the success rate was lower when the obstacle height was lower. No significant interaction between group and obstacle height was observed (p = 0.096). ART had no significant effect on the success rate (p = 0.294) in both of the groups (ART × group, p = 0.136). However, a significant interaction between group, obstacle height, and ART was found (p = 0.013), reflecting a lower success rate in the older adults when the obstacles were low and unanticipated. In general, older adults demonstrated a trend towards a lower success rate in all types of obstacles compared to the young adults (p = 0.057). Among the older adults, the success rate in the anticipated obstacle condition was correlated with stride length (ρ = 0.600, p = 0.005), step time coefficient of variation (ρ = -0.635, p = 0.003), and gait speed (rho = 0.530, p = 0.016). Montreal Cognitive Assessment scores tended to be related to the difference in the success rate between the anticipated and unanticipated conditions. CONCLUSIONS: These findings support the idea that motor and, to some degree, cognitive functions are needed to successfully negotiate obstacles, and provide new insights into the ability of older adults to successfully negotiate obstacles. Furthermore, the present results suggest that when it comes to the physical properties of obstacles, not all is as expected, and low obstacles may impose a greater danger to tripping than obstacles that have a higher height.

8.
Mov Disord ; 34(9): 1392-1398, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31348549

RESUMO

BACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.

9.
Front Neurol ; 10: 531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164863

RESUMO

Mutations in the LRRK2 and GBA genes are the most common inherited causes of Parkinson's disease (PD). Studies exploring phenotypic differences based on genetic status used hypothesis-driven data-gathering and statistical-analyses focusing on specific symptoms, which may influence the validity of the results. We aimed to explore phenotypic expression in idiopathic PD (iPD) patients, G2019S-LRRK2-PD, and GBA-PD using a data-driven approach, allowing screening of large numbers of features while controlling selection bias. Data was collected from 1525 Ashkenazi Jews diagnosed with PD from the Tel-Aviv Medical center; 161 G2019S-LRRK2-PD, 222 GBA-PD, and 1142 iPD (no G2019S-LRRK2 or any of the 7 AJ GBA mutations tested). Data included 771 measures: demographics, cognitive, physical and neurological functions, performance-based measures, and non-motor symptoms. The association of the genotypes with each of the measures was tested while accounting for age at motor symptoms onset, gender, and disease duration; p-values were reported and corrected in a hierarchical approach for an average over the selected measures false discovery rate control, resulting in 32 measures. GBA-PD presented with more severe symptoms expression while LRRK2-PD had more benign symptoms compared to iPD. GBA-PD presented greater cognitive and autonomic involvement, more frequent hyposmia and REM sleep behavior symptoms while these were less frequent among LRRK2-PD compared to iPD. Using a data-driven analytical approach strengthens earlier studies and extends them to portray a possible unique disease phenotype based on genotype among AJ PD. Such findings could help direct a more personalized therapeutic approach.

10.
Neuroepidemiology ; 53(1-2): 13-19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31203291

RESUMO

BACKGROUND: To estimate the survival of a population-based cohort of Parkinson's disease (PD) patients stratified by age and sex over a 13-year period. METHODS: The dynamic PD cohort included 6,622 incident PD patients who initiated anti-parkinsonian medications at age >40 years. The reference population (n = 401,498) consisted of members of a large health maintenance organization. We estimated the PD patients' death risk and sex- and age-specific standardized mortality ratio (SMR). RESULTS: During a follow-up of 5.2 ± 3.3 years, 36% of the cohort died. Older age at first PD treatment was associated with a 55% increase in mortality (for 5-year increase, p < 0.01). More PD patients died when compared to the same age and sex reference population in all age groups, with significant results at age groups >60 years at first treatment. The age-pooled SMR was twofold (SMR for the males = 2.05, 95% CI 1.73-2.42; SMR females = 2.13, 95% CI 1.74-2.62). The highest excess death for males was 2.5-fold for those aged 60-69 years, decreasing to twofold for those in the age range 70-79 years and to 1.5-fold for those aged 80+ years. A similar trend was found among females. CONCLUSION: Our large-scale cohort enabled us to find an age-differential standardized death risk among PD patients, with the largest increased risk at ages 60-69 years. Comorbidities and other contributory factors warrant further investigation.

11.
Parkinsonism Relat Disord ; 65: 131-138, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176632

RESUMO

INTRODUCTION: Dopamine replacement via levodopa (LD) remains the most effective treatment for Parkinson's disease (PD), yet its use is often associated with motor complications within several years of continued use. The Accordion Pill® (AP-CD/LD) is a novel drug delivery system based on gastric retention of multilayer films containing immediate-release (IR) carbidopa (CD) and immediate- and controlled-release LD. The AP-CD/LD was designed to improve the consistency of LD in the bloodstream while offering patients with PD more consistent symptom management. METHODS: This phase 2, multicenter, open-label, two-way randomized crossover study included 4 cohorts of participants with PD, each receiving AP-CD/LD (50/250 mg, 50/375 mg or 50/500 mg) twice daily in one treatment period and an active comparator in the other treatment period. Pharmacokinetics (PK) and efficacy were evaluated for AP-CD/LD vs IR-CD/LD. Treatment-emergent adverse events (TEAEs) and patient- and investigator-reported measures were also evaluated. RESULTS: Compared with IR-CD/LD, treatment with either AP-CD/LD dose resulted in more stable LD plasma concentrations in both fluctuating and non-fluctuating PD patients, and significantly decreased Cmax (57.1% and 66.8% decreases among fluctuating and non-fluctuating patients, respectively). Both AP doses significantly improved standard measures of motor symptoms: (daily OFF time, total ON time, and good ON time), as well as patient- and investigator-assessed measures, versus IR-CD/LD. The safety and tolerability profile of AP-CD/LD was consistent with the known properties of IR-CD/LD. CONCLUSIONS: AP technology demonstrated effective controlled-release PK performance and reduced motor response fluctuations in advanced PD patients. A phase 3 randomized controlled trial is currently underway.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31073340

RESUMO

Background: The traditional evaluation of gait in the laboratory during structured testing has provided important insights, but is limited by its "snapshot" character and observation in an unnatural environment. Wearables enable monitoring of gait in real-world environments over a week. Initial findings show that in-lab and real-world measures differ. As a step towards better understanding these gaps, we directly compared in-lab usual-walking (UW) and dual-task walking (DTW) to daily-living measures of gait. Methods: In-lab gait features (e.g., gait speed, step regularity, and stride regularity) derived from UW and DTW were compared to the same gait features during daily-living in 150 elderly fallers (age: 76.5 ± 6.3 years, 37.6% men). In both settings, features were extracted from a lower-back accelerometer. In the real-world setting, subjects were asked to wear the device for 1 week and pre-processing detected 30-s daily-living walking bouts. A histogram of all walking bouts was determined for each walking feature for each subject and then each subject's typical (percentile 50, median), worst (percentile 10) and the best (percentile 90) values over the week were determined for each feature. Statistics of reliability were assessed using Intra-Class correlations and Bland-Altman plots. Results: As expected, in-lab gait speed, step regularity, and stride regularity were worse during DTW, compared to UW. In-lab gait speed, step regularity, and stride regularity during UW were significantly higher (i.e., better) than the typical daily-living values (p < 0.001) and different (p < 0.001) from the worst and best values. DTW values tended to be similar to typical daily-living values (p = 0.205, p = 0.053, p = 0.013 respectively). ICC assessment and Bland-Altman plots indicated that in-lab values do not reliably reflect the daily-walking values. Conclusions: Gait values measured during relatively long (30-s) daily-living walking bouts are more similar to the corresponding values obtained in the lab during dual-task walking, as compared to usual walking. Still, gait performance during most daily-living walking bouts is worse than that measured during usual and dual-tasking in the lab. The values measured in the lab do not reliably reflect daily-living measures. That is, an older adult's typical daily-living gait cannot be estimated by simply measuring walking in a structured, laboratory setting.

13.
J Neural Transm (Vienna) ; 126(6): 699-710, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31115669

RESUMO

The potential of using wearable technologies for the objective assessment of motor symptoms in Parkinson's disease (PD) has gained prominence recently. Nonetheless, compared to tremor and gait impairment, less emphasis has been placed on the quantification of bradykinesia and rigidity. This review aimed to consolidate the existing research on objective measurement of bradykinesia and rigidity in PD through the use of wearables, focusing on the continuous monitoring of these two symptoms in free-living environments. A search of PubMed was conducted through a combination of keyword and MeSH searches. We also searched the IEEE, Google Scholar, Embase, and Scopus databases to ensure thorough results and to minimize the chances of missing relevant studies. Papers published after the year 2000 with sample sizes greater than five were included. Studies were assessed for quality and information was extracted regarding the devices used and their location on the body, the setting and duration of the study, the "gold standard" used as a reference for validation, the metrics used, and the results of each paper. Thirty-one and eight studies met the search criteria and evaluated bradykinesia and rigidity, respectively. Several studies reported strong associations between wearable-based measures and the gold-standard references for bradykinesia, and, to a lesser extent, rigidity. Only a few, pilot studies investigated the measurement of bradykinesia and rigidity in the home and free-living settings. While the current results are promising for the future of wearables, additional work is needed on their validation and adaptation in ecological, free-living settings. Doing so has the potential to improve the assessment and treatment of motor fluctuations and symptoms of PD more generally through real-time objective monitoring of bradykinesia and rigidity.

14.
Lancet Neurol ; 18(7): 697-708, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30975519

RESUMO

Gait impairments are among the most common and disabling symptoms of Parkinson's disease. Nonetheless, gait is not routinely assessed quantitatively but is described in general terms that are not sensitive to changes ensuing with disease progression. Quantifying multiple gait features (eg, speed, variability, and asymmetry) under natural and more challenging conditions (eg, dual-tasking, turning, and daily living) enhanced sensitivity of gait quantification. Studies of neural connectivity and structural network topology have provided information on the mechanisms of gait impairment. Advances in the understanding of the multifactorial origins of gait changes in patients with Parkinson's disease promoted the development of new intervention strategies, such as neurostimulation and virtual reality, aimed at alleviating gait impairments and enhancing functional mobility. For clinical applicability, it is important to establish clear links between specific gait impairments, their underlying mechanisms, and disease progression to foster the acceptance and usability of quantitative gait measures as outcomes in future disease-modifying clinical trials.

15.
Parkinsonism Relat Disord ; 64: 90-96, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30922776

RESUMO

OBJECTIVE: To evaluate the association between anemia and Parkinson's disease risk (PD) in men and women. METHODS: A population-based cohort of 474,129 individuals (aged 40-79 years at date of first Hb test, 47.4% men) with repeated Hb levels was derived from a large Healthcare Maintenance Organization that serves 2 million citizens in Israel (study-period 1.1.1999-31.12.2012). An annual anemia indicator [Hb levels (g/dL) for men <13; for women <12.0] was assessed for each individual and they were followed from first Hb test until the date of PD incidence, death or end of the study. Cox-proportional hazards models, stratified by sex and age, with time-dependent anemia covariate were used to estimate adjusted Hazard Ratio with 95% of confidence intervals (HR, 95%CI) for PD. RESULTS: During a mean follow up of 8.8 ±â€¯3.9 years (7.0 ±â€¯3.6 for men and 7.9 ±â€¯4.1 for women), 2427 incident PD cases were detected. Cumulative PD incidence at ages over 65 years was 3.3%. The mean levels of Hb at baseline was 14.8 ±â€¯1.1 g/dL among men; 12.8 ±â€¯1.1 g/dL among women. Anemia was associated with significant PD risk among men, age-pooled HR = 1.19 (95%CI: 1.04-1.37), with the highest risk between ages 60-64 years [HR = 1.41 (95%CI: 1.03-1.93)]. Anemia was not associated with PD risk among women across all age-groups. The age-pooled HR for women was 1.02 (95%CI 0.95-1.09). CONCLUSIONS: The finding that anemia was associated with PD risk in men, especially in middle age, warrants further investigations on common pathophysiologic processes between Hb abnormalities and brain dysfunction.

16.
Parkinsonism Relat Disord ; 63: 77-82, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30827838

RESUMO

INTRODUCTION: Deficits in executive function and attention have been associated with freezing of gait (FOG) in patients with Parkinson's disease (PD). However, the exact changes in the ventral and dorsal attentional networks that may contribute to FOG are unknown. Our aim was to examine the changes in connectivity of the attentional networks in patients with PD and their role in FOG. METHODS: Resting-state fMRI was obtained in 20 healthy controls (age: 69.7 ±â€¯1.3yrs), 11 patients without FOG (age: 74.1 ±â€¯1.2yrs), and 26 patients with FOG (age: 72.3 ±â€¯1.3yrs). Graph theory analysis was used to examine differences in previously defined attention networks between groups. RESULTS: We found differences between the groups in the dorsal attentional network (Global Efficiency: p = 0.007, Local Efficiency: p = 0.017, Between Centrality: p = 0.010). Global efficiency was lower in patients with FOG compared to healthy controls (p = 0.003) and patients without FOG (p = 0.025). Local efficiency was higher in patients with FOG compared to healthy controls (p = 0.014) but not compared to patients without FOG (p = 0.109). In contrast, no differences were found in the ventral attentional network between the groups (Global Efficiency: p = 0.258, Local Efficiency: p = 0.114, Between Centrality: p = 0.130). CONCLUSIONS: Altered organization of the dorsal attention network in patients with FOG may explain the higher risk for FOG during complex walking situations. In contrast, the lack of changes in the ventral attention network may partially explain the effectiveness of external cues on gait in patients with PD. Our findings support the idea that attentional networks play an important role in FOG.

17.
Parkinsonism Relat Disord ; 62: 85-90, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30718220

RESUMO

INTRODUCTION: Recent work suggests that wearables can augment conventional measures of Parkinson's disease (PD). We evaluated the relationship between conventional measures of disease and motor severity (e.g., MDS-UPDRS part III), laboratory-based measures of gait and balance, and daily-living physical activity measures in patients with PD. METHODS: Data from 125 patients (age: 71.7 ±â€¯6.5 years, Hoehn and Yahr: 1-3, 60.5% men) were analyzed. The MDS-UPDRS-part III was used as the gold standard of motor symptom severity. Gait and balance were quantified in the laboratory. Daily-living gait and physical activity metrics were extracted from an accelerometer worn on the lower back for 7 days. RESULTS: In multivariate analyses, daily-living physical activity and gait metrics, laboratory-based balance, demographics and subject characteristics together explained 46% of the variance in MDS-UPDRS-part III scores. Daily-living measures accounted for 62% of the explained variance, laboratory measures 30%, and demographics and subject characteristics 7% of the explained variance. Conversely, demographics and subject characteristics, laboratory-based measures of gait symmetry, and motor symptom severity together explained less than 30% of the variance in total daily-living physical activity. MDS-UPDRS-part III scores accounted for 13% of the explained variance, i.e., <4% of all the variance in total daily-living activity. CONCLUSIONS: Our findings suggest that conventional measures of motor symptom severity do not strongly reflect daily-living activity and that daily-living measures apparently provide important information that is not captured in a conventional one-time, laboratory assessment of gait, balance or the MDS-UPDRS. To provide a more complete evaluation, wearable devices should be considered.

18.
Hum Brain Mapp ; 40(8): 2546-2555, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30793410

RESUMO

Non-manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene represent an "at risk" group for future development of Parkinson's disease (PD) and have demonstrated task related fMRI changes. However, resting-state networks have received less research focus, thus this study aimed to assess the integrity of the motor, default mode (DMN), salience (SAL), and dorsal attention (DAN) networks among this unique population by using two different connectivity measures: interregional functional connectivity analysis and Dependency network analysis (DEP NA). Machine learning classification methods were used to distinguish connectivity between the two groups of participants. Forty-four NMC and 41 non-manifesting non-carriers (NMNC) participated in this study; while no behavioral differences on standard questionnaires could be detected, NMC demonstrated lower connectivity measures in the DMN, SAL, and DAN compared to NMNC but not in the motor network. Significant correlations between NMC connectivity measures in the SAL and attention were identified. Machine learning classification separated NMC from NMNC with an accuracy rate above 0.8. Reduced integrity of non-motor networks was detected among NMC of the G2019S mutation in the LRRK2 gene prior to identifiable changes in connectivity of the motor network, indicating significant non-motor cerebral changes among populations "at risk" for future development of PD.

19.
Alzheimer Dis Assoc Disord ; 33(3): 279-281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30640255

RESUMO

Cognitive deficits beyond memory impairment, such as those affecting language production or executive functioning, can be useful in clinically distinguishing between dementia syndromes. We tested the hypothesis that Ashkenazi Jewish (AJ) patients who have dementia with Lewy bodies (DLB) and carry glucocerebrosidase (GBA) mutations will have verbal fluency deficits different from those found in Alzheimer disease (AD), whereas AJ patients with DLB who have no GBA mutations will have similar deficits in verbal fluency to those found in AD. We compared performance in phonemic and semantic verbal fluency tasks in 44 AJ patients with DLB and 20 patients with AD, matched for age, education, and age of immigration. All groups were found to have a deficit in semantic verbal fluency. On conducting the phonemic task, patients with DLB who carried GBA mutations scored more poorly than patients with AD, whereas DLB-noncarriers performed similarly to patients with AD. We suggest that verbal fluency tasks could serve as a possible clinical marker to subtype patients with DLB, with phonemic fluency being a marker for GBA-associated DLB.

20.
Parkinsonism Relat Disord ; 60: 98-104, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30236826

RESUMO

INTRODUCTION: Prospective studies identifying predictors of freezing of gait (FOG) in Parkinson's disease (PD) are limited. We aim to explore which symptoms are associated with future development of FOG in non-freezers. METHODS: Fifty-seven PD patients without FOG at baseline were re-evaluated after a mean of five years. At baseline, disease severity [Unified Parkinson's Disease Rating Scale (MDS-UPDRS)], gait under single and dual-tasking, balance, cognition and other non-motor symptoms were assessed. The new-FOG-questionnaire (NFOG-Q) determined FOG. Multivariate binary logistic regression determined independent predictors of FOG. RESULTS: At follow-up, 26 subjects (46%) had FOG while 31 remained non-freezers. At baseline, non-freezers (FOG-) and future freezers (FOG+) were similar (p > 0.10) with respect to age, gender, disease duration, dopaminergic medications, and cognitive function. However, FOG + had significantly worse scores on the Geriatric Depression Scale (GDS) (FOG+:5.2 ± 3.7; FOG-:2.4 ± 2.0, p = 0.005), PDQ-39, the NMS-questionnaire, UPDRS-part I, UPDRS-part III (off), and the Berg Balance Scale. In binary logistic regression, GDS, gait speed and UPDRS-III (on vs. off) were the only significant independent predictors of future FOG (GDS: OR = 10.93, p = 0.003, ΔUPDRS-III: OR = 1.34, p = 0.006). Moreover, 80% of the subjects who had marked depressive symptoms at baseline (GDS≥5) developed FOG at follow-up. In contrast, only 27% of those with few depressive symptoms at baseline became freezers (p < 0.001). CONCLUSIONS: Depressive symptoms apparently precede the development of FOG. While elucidation of the relationship between depression and FOG needs further study, our findings offer another perspective regarding the pathophysiology of FOG and may help clinicians to estimate the risk of developing this debilitating phenomenon.

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