78 research outputs found
Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at-risk observational study (PHAROS)
Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine-adenine-guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG < 37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support
Multiphoton Ionization as Time-Dependent Tunneling
A new semiclassical approach to ionization by an oscillating field is
presented. For a delta-function atom, an asymptotic analysis is performed with
respect to a quantity h, defined as the ratio of photon energy to ponderomotive
energy. This h appears formally equivalent to Planck's constant in a suitably
transformed Schroedinger equation and allows semiclassical methods to be
applicable. Systematically, a picture of tunneling wave packets in complex time
is developped, which by interference account for the typical ponderomotive
features of ionization curves. These analytical results are then compared to
numerical simulations and are shown to be in good agreement.Comment: 36 pages (also printable half size), uuencoded compressed tarred
Latex file with 9 Postscript figures included automaticall
On the Influence of Pulse Shapes on Ionization Probability
We investigate analytical expressions for the upper and lower bounds for the
ionization probability through ultra-intense shortly pulsed laser radiation. We
take several different pulse shapes into account, including in particular those
with a smooth adiabatic turn-on and turn-off. For all situations for which our
bounds are applicable we do not find any evidence for bound-state
stabilization.Comment: 21 pages LateX, 10 figure
Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.
OBJECTIVE: We hypothesized that specific mutations in the ÎČ-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (pâ=â0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; pâ=â0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685
Ionization Probabilities through ultra-intense Fields in the extreme Limit
We continue our investigation concerning the question of whether atomic bound
states begin to stabilize in the ultra-intense field limit. The pulses
considered are essentially arbitrary, but we distinguish between three
situations. First the total classical momentum transfer is non-vanishing,
second not both the total classical momentum transfer and the total classical
displacement are vanishing together with the requirement that the potential has
a finite number of bound states and third both the total classical momentum
transfer and the total classical displacement are vanishing. For the first two
cases we rigorously prove, that the ionization probability tends to one when
the amplitude of the pulse tends to infinity and the pulse shape remains fixed.
In the third case the limit is strictly smaller than one. This case is also
related to the high frequency limit considered by Gavrila et al.Comment: 16 pages LateX, 2 figure
Adiabatic perturbation theory and geometry of periodically-driven systems
We give a systematic review of the adiabatic theorem and the leading non-adiabatic corrections in periodically-driven (Floquet) systems. These corrections have a two-fold origin: (i) conventional ones originating from the gradually changing Floquet Hamiltonian and (ii) corrections originating from changing the micro-motion operator. These corrections conspire to give a Hall-type linear response for non-stroboscopic (time-averaged) observables allowing one to measure the Berry curvature and the Chern number related to the Floquet Hamiltonian, thus extending these concepts to periodically-driven many-body systems. The non-zero Floquet Chern number allows one to realize a Thouless energy pump, where one can adiabatically add energy to the system in discrete units of the driving frequency. We discuss the validity of Floquet Adiabatic Perturbation Theory (FAPT) using five different models covering linear and non-linear few and many-particle systems. We argue that in interacting systems, even in the stable high-frequency regimes, FAPT breaks down at ultra slow ramp rates due to avoided crossings of photon resonances, not captured by the inverse-frequency expansion, leading to a counter-intuitive stronger heating at slower ramp rates. Nevertheless, large windows in the ramp rate are shown to exist for which the physics of interacting driven systems is well captured by FAPT.The authors would like to thank M. Aidelsburger, M. Atala, E. Dalla Torre, N. Goldman, M. Heyl, D. Huse, G. Jotzu, C. Kennedy, M. Lohse, T. Mori, L. Pollet, M. Rudner, A. Russomanno, and C. Schweizer for fruitful discussions. This work was supported by AFOSR FA9550-16-1-0334, NSF DMR-1506340, ARO W911NF1410540, and the Hungarian research grant OTKA Nos. K101244, K105149. M. K. was supported by Laboratory Directed Research and Development (LDRD) funding from Berkeley Lab, provided by the Director, Office of Science, of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. The authors are pleased to acknowledge that the computational work reported in this paper was performed on the Shared Computing Cluster which is administered by Boston University's Research Computing Services. The authors also acknowledge the Research Computing Services group for providing consulting support which has contributed to the results reported within this paper. The study of the driven non-integrable transverse-field Ising model was carried out using QuSpin [185] - an open-source state-of-the-art Python package for dynamics and exact diagonalization of quantum many body systems, available to download here. (FA9550-16-1-0334 - AFOSR; DMR-1506340 - NSF; W911NF1410540 - ARO; K101244 - Hungarian research grant OTKA; K105149 - Hungarian research grant OTKA; DE-AC02-05CH11231 - Laboratory Directed Research and Development (LDRD) funding from Berkeley Lab)https://arxiv.org/pdf/1606.02229.pd
Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts.
OBJECTIVE: To determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression. METHODS: We evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed. RESULTS: We confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69-6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04-20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16-1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19-2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (-0.72 [-1.21 to -0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27-1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21-1.03]). CONCLUSIONS: This study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.The Intramural Research Program the National Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinsonâs Researc
Differences in the Presentation and Progression of Parkinson's Disease by Sex.
BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1âyears. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17â719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.This study was supported by the Intramural Research Program the National
Institute on Aging (NIA, Z01-AG000949-02), Biogen Idec, and the Michael J Fox Foundation for Parkinsonâs Research
Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial
Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.
Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.
Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (nâ=â45) or placebo (nâ=â45) in a double-blind fashion at 34 Huntington Study Group sites.
Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.
Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Formâ physical functioning subscale score (SF-36), and the change in the Berg Balance Test.
Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was â2.5 units (95% CI, â3.7 to â1.3) (Pâ<â.001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (Pâ=â.002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (Pâ=â.002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (Pâ=â.03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, â0.3 to 2.3; Pâ=â.14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.
Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety
Association between metabolic syndrome and progression in Parkinson's disease
Background: Parkinson's disease (PD) and metabolic syndrome are separate entities that share common underlying pathophysiology. Management strategy for metabolic syndrome is clinically better characterized and finding a positive clinical correlation between the two could lead to a better understanding of Parkinson's disease progression and prognosis. Purpose: To explore the relationship between progression in PD and metabolic syndrome to characterize the underlying pathophysiology, which could then impact the clinical management of PD. Methods: Using modified NCEP (National Cholesterol Education Program) ATP III (Adult Treatment Plan) criteria, patients enrolled in STEADY-PD III (Safety, Tolerability, and Efficacy Assessment of Isradipine) were classified into one of three categories of metabolic syndrome and compared on PD progression over a period of 3 years. Results: Participants with metabolic syndrome showed a trend for more progression in terms of PD, as measured by the total Unified Parkinson's Disease Rating Scale (UPDRS), the motor EDL (Experiences of daily living) scores of the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and the Montreal Cognitive Assessment (MoCA). A significant trend for decline in MoCA was found in the group with metabolic syndrome (â0.78), compared with those without metabolic syndrome (0.14). Greater decline in MoCA signifies worse outcomes. Conclusion: The results demonstrate a trend in more clinical progression in PD in subjects with metabolic syndrome. However, results are limited by the sample size and the limited laboratory measurements available. We hope this study will encourage larger sample studies to explore this relationship further
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