1. N Engl J Med—左旋多巴治疗对帕金森病无疾病修饰作用（不能延缓疾病进展）

英文摘要：

BACKGROUND:

Levodopais the main treatment for symptoms of Parkinson's disease. Determining whetherlevodopa also has a disease-modifying effect could provide guidance as to whenin the course of the disease the treatment with this drug should be initiated.

METHODS:

In amulticenter, double-blind, placebo-controlled, delayed-start trial, we randomlyassigned patients with early Parkinson's disease to receive levodopa (100 mgthree times per day) in combination with carbidopa (25 mg three times per day)for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopain combination with carbidopa for 40 weeks (delayed-start group). The primaryoutcome was the between-group difference in the mean change from baseline toweek 80 in the total score on the Unified Parkinson's Disease Rating Scale(UPDRS; scores range from 0 to 176, with higher scores signifying more severedisease). Secondary analyses included the progression of symptoms, as measuredby the UPDRS score, between weeks 4 and 40 and the noninferiority of earlyinitiation of treatment to delayed initiation between weeks 44 and 80, with anoninferiority margin of 0.055 points per week.

RESULTS:

Atotal of 445 patients were randomly assigned: 222 to the early-start group and223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4points in the early-start group and 29.3±12.1 points in the delayed-startgroup. The change in UPDRS score from baseline to week 80 was -1.0±13.1 pointsand -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidenceinterval [CI], -1.5 to 3.5; P=0.44); this finding of no significantbetween-group difference at week 80 implies that levodopa had nodisease-modifying effect. Between weeks 4 and 40, the rate of progression ofsymptoms, as measured in UPDRS points per week, was 0.04±0.23 in theearly-start group and 0.06±0.34 in the delayed-start group (difference, -0.02;95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); thedifference in the rate of progression between weeks 44 and 80 did not meet thecriterion for noninferiority of early receipt of levodopa to delayed receipt.The rates of dyskinesia and levodopa-related fluctuations in motor response didnot differ significantly between the two groups.

CONCLUSIONS:

Amongpatients with early Parkinson's disease who were evaluated over the course of80 weeks, treatment with levodopa in combination with carbidopa had nodisease-modifying effect. (Funded by the Netherlands Organization for HealthResearch and Development and others; LEAP Current Controlled Trials number,ISRCTN30518857 .).

参考文献：

Verschuur et al (2019). Randomized Delayed-Start Trial ofLevodopa in Parkinson's Disease. N Engl J Med. 2019 Jan 24;380(4):315-324.

2. Lancet Neurol—无症状LRRK2和GBA突变携带者在出现DAT缺陷之前就可以出现轻微的运动和非运动体征

英文摘要：

BACKGROUND:

TheParkinson's Progression Markers Initiative (PPMI) is an ongoing observational,longitudinal cohort study of participants with Parkinson's disease, healthycontrols, and carriers of the most common Parkinson's disease-related geneticmutations, which aims to define biomarkers of Parkinson's disease diagnosis andprogression. All participants are assessed annually with a battery of motor andnon-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, andbiological variables. We aimed to examine whether non-manifesting carriers ofLRRK2 and GBA mutations have prodromal features of Parkinson's disease thatcorrelate with reduced DAT binding.

METHODS:

Thiscross-sectional analysis is based on assessments done at enrolment in thesubset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into thePPMI study from 33 participating sites worldwide. The primary objective was toexamine baseline clinical and DAT imaging characteristics in non-manifestingcarriers with GBA and LRRK2 mutations compared with healthy controls. DATdeficit was defined as less than 65% of putamen striatal binding ratio expectedfor the individual's age. We used t tests, χ2 tests, and Fisher's exact teststo compare baseline demographics across groups. An inverse probabilityweighting method was applied to control for potential confounders such as ageand sex. To account for multiple comparisons, we applied a family-wise errorrate to each set of analyses. This study is registered with ClinicalTrials.gov,number NCT01141023.

FINDINGS:

BetweenJan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184GBA (96% N370S) non-manifesting carriers. Both groups were similar with respectto mean age, and about 60% were female. Of the 286 (73%) non-manifestingcarriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBAnon-manifesting carriers had a DAT deficit. Compared with healthy controls, bothLRRK2 and GBA non-manifesting carriers had significantly increased mean scoreson the Movement Disorders Society Unified Parkinson's Disease Rating Scale(total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA,p<0·0001 for both comparisons) and the Scale for Outcomes for PD - autonomicfunction (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for bothcomparisons). There was no difference in daytime sleepiness, anxiety,depression, impulsive-compulsive disorders, blood pressure, urate, and rapid eyemovement (REM) behaviour disorder scores. Hyposmia was significantly morecommon only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controlsvs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA butnot LRRK2 non-manifesting carriers showed increased DAT striatal binding ratioscompared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63]vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52];p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001).

INTERPRETATION:

Ourdata show evidence of subtle motor and non-motor signs of Parkinson's diseasein non-manifesting carriers compared with healthy controls that can precede DATdeficit. Longitudinal data will be essential to confirm these findings anddefine the trajectory and predictors for development of Parkinson's disease.

参考文献：

Simuniet al (2020). Clinical and dopamine transporter imaging characteristics ofnon-manifest LRRK2 and GBA mutation carriers in the Parkinson's ProgressionMarkers Initiative (PPMI): a cross-sectional study. Lancet Neurol. 2020Jan;19(1):71-80. doi: 10.1016/S1474-4422(19)30319-9. Epub 2019 Oct 31.

3.  Lancet Neurol—对于早期帕金森病患者，高强度的有氧运动有助于改善“关期”运动症状

英文摘要：

BACKGROUND:

High-intensityaerobic exercise might attenuate the symptoms of Parkinson's disease, buthigh-quality evidence is scarce. Moreover, long-term adherence remainschallenging. We aimed to evaluate the effectiveness of aerobicexercise-gamified and delivered at home, to promote adherence-on relievingmotor symptoms in patients with Parkinson's disease with mild disease severitywho were on common treatment regimes.

METHODS:

Inthis single-centre, double-blind, randomised controlled trial (Park-in-Shape),we recruited sedentary patients with Parkinson's disease from the outpatientclinic at Radboudumc, Nijmegen, Netherlands. Patients were made aware of thestudy either by their treating neurologist or via information in the waitingroom. Patients could also contact the study team via social media. We includedpatients aged 30-75 years with a Hoehn and Yahr stage of 2 or lower, who wereon stable dopaminergic medication. Patients were randomly assigned (in a 1:1ratio) to either aerobic exercise done on a stationary home-trainer (aerobicintervention group) or stretching (active control group) by means of aweb-based system with minimisation for sex and medication status (treated oruntreated) and permuted blocks of varying sizes of more than two (unknown tostudy personnel). Patients were only aware of the content of their assignedprogramme. Assessors were unaware of group assignments. Both interventions werehome based, requiring 30-45 min training three times per week for 6 months.Both groups received a motivational app and remote supervision. Home trainerswere enhanced with virtual reality software and real-life videos providing aso-called exergaming experience (ie, exercise enhanced by gamified elements).The primary outcome was the between-group difference in the Movement DisordersSociety-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor section at 6months, tested during the off state (≥12h after last dopaminergic medication). The analysis was done on an intention-to-treatbasis in patients who completed the follow-up assessment, regardless of whetherthey completed the assigned intervention. Patients reported adverse eventsdirectly to their coach and also after the 6-month visit retrospectively. Abetween-group difference of 3·5 points or more was deemed a-priori clinicallyrelevant. The study is concluded and registered with the Dutch Trial Registry,NTR4743.

FINDINGS:

BetweenFeb 2, 2015, and Oct 27, 2017, 139 patients were assessed for eligibility in person,of whom 130 were randomly assigned to either the aerobic intervention group(n=65) or the active control group (n=65). Data from 125 (96%) patients wereavailable for the primary analysis; five patients were lost to follow-up (fourin the intervention group; one in the control group). 20 patients (ten in eachgroup) did not complete their assigned programme. The off-state MDS-UPDRS motorscore revealed a between-group difference of 4·2 points (95% CI 1·6-6·9,p=0·0020) in favour of aerobic exercise (mean 1·3 points [SE 1·8] in theintervention group and 5·6 points [SE 1·9] for the control group). 11 patientshad potentially related adverse events (seven [11%] in the intervention group,four [6%] in the control group) and seven had unrelated serious adverse events(three in the intervention group [vestibilar disorder, vasovagal collapse, kneeinjury during gardening that required surgery; 6%], four in the control group[supraventricular tachycardia, hip fracture, fall related injury, severedyskinesias after suprathreshold dose levodopa in a patient with deep brainstimulation; 7%]).

INTERPRETATION:

Aerobicexercise can be done at home by patients with Parkinson's disease with milddisease severity and it attenuates off-state motor signs. Future studies shouldestablish long-term effectiveness and possible disease-modifying effects.

FUNDING:

NetherlandsOrganization for Health Research and Development.

参考文献：

Van et al (2019). Effectiveness of home-based andremotely supervised aerobic exercise in Parkinson's disease: a double-blind,randomised controlled trial. Lancet Neurol. 2019 Nov;18(11):998-1008.

4.  Lancet Neurol—五羟色胺能系统受损是A53TSNCA突变携带者的早期病理表型且和疾病负担相关

英文摘要：

Abstract

BACKGROUND:

Becauseof the highly penetrant gene mutation and clinical features consistent withidiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr(A53T; 209G→A)point mutation in the α-synuclein(SNCA) gene are an ideal population to study the premotor phase and evolutionof Parkinson's pathology. Given the known neurochemical changes in theserotonergic system and their association with symptoms of Parkinson's disease,we hypothesised that carriers of the A53T SNCA mutation might showabnormalities in the serotonergic neurotransmitter system before the diagnosisof Parkinson's disease, and that this pathology might be associated withmeasures of Parkinson's burden.

METHODS:

Inthis cross-sectional study, we recruited carriers of the A53T SNCA mutationfrom specialist Movement Disorders clinics in Athens, Greece, and Salerno,Italy, and a cohort of healthy controls with no personal or family history ofneurological or psychiatric disorders from London, UK (recruited via publicadvertisement) who were age matched to the A53T SNCA carriers. We alsorecruited one cohort of patients with idiopathic Parkinson's disease (cohort 1)from Movement Disorders clinics in London, UK, and retrieved data on a secondcohort of such patients (cohort 2; n=40) who had been scanned with a differentscanner. 7-day continuous recording of motor function was used to determine theParkinson's disease status of the A53T carriers. To assess whether serotonergicabnormalities were present, we used [11C]DASB PET non-displaceable binding toquantify serotonin transporter density. We constructed brain topographic mapsreflecting Braak stages 1-6 and used these as seed maps to calculate [11C]DASBnon-displaceable binding potential in our cohort of A53T SNCA carriers.Additionally, all participants underwent a battery of clinical assessments todetermine motor and non-motor symptoms and cognitive status, and [123I]FP-CITsingle-photon emission CT (SPECT) to assess striatal dopamine transporterbinding and MRI for volumetric analyses to assess whether pathology isassociated with measures of Parkinson's disease burden.

FINDINGS:

BetweenSept 1, 2016, and Sept 30, 2018, we recruited 14 A53T SNCA carriers, 25 healthycontrols, and 25 patients with idiopathic Parkinson's disease. Seven (50%) of14 A53T SCNA carriers were confirmed to have motor symptoms and confirmed tohave Parkinson's disease, and the absence of motor symptoms was confirmed inseven (50%) A53T SCNA carriers (ie, premotor), in whom [123I]FP-CIT SPECTconfirmed the absence of striatal dopaminergic deficits. Compared with healthycontrols, premotor A53T SNCA carriers showed loss of [11C]DASB non-displaceablebinding potential in the ventral (p<0·0001) and dorsal (p=0·0002) raphenuclei, caudate (p=0·00015), putamen (p=0·036), thalamus (p=0·00074),hypothalamus (p<0·0001), amygdala (p=0·0041), and brainstem (p=0·046); andin A53T SNCA carriers with Parkinson's disease this loss was extended to the hippocampus(p=0·0051), anterior (p=0·022) and posterior cingulate (p=0·036), insula(p=0·0051), frontal (p=0·0016), parietal (p=0·019), temporal (p<0·0001), andoccipital (p=0·0053) cortices. A53T SNCA carriers with Parkinson's diseaseshowed a loss of striatal [123I]FP-CIT-specific binding ratio compared withhealthy controls (p<0·0001). Premotor A53T SNCA carriers had loss of[11C]DASB non-displaceable binding potential in brain areas corresponding toBraak stages 1-3, whereas [11C]DASB non-displaceable binding potential waslargely preserved in areas corresponding to Braak stages 4-6. Except for oneparticipant who was diagnosed with Parkinson's disease in the past year, allA53T SNCA carriers with Parkinson's disease had decreases in [11C]DASBnon-displaceable binding potential in brain areas corresponding to Braak stages1-6. Decreases in [11C]DASB non-displaceable binding potential in the brainstemwere associated with increased Movement Disorder Score-Unified Parkinson'sDisease Rating Scale total scores in all A53T SNCA carriers (r -0·66, 95% CI-0·88 to -0·20; p=0·0099), idiopathic Parkinson's disease cohort 1 (r -0·66,-0·84 to -0·36; p=0·00031), and idiopathic Parkinson's disease cohort 2 (r-0·71, -0·84 to -0·52; p<0·0001).

INTERPRETATION:

Thepresence of serotonergic pathology in premotor A53T SNCA carriers precededdevelopment of dopaminergic pathology and motor symptoms and was associatedwith disease burden, highlighting the potential early role of serotonergicpathology in the progression of Parkinson's disease. Our findings provideevidence that molecular imaging of serotonin transporters could be used tovisualise premotor pathology of Parkinson's disease in vivo. Future work mightestablish whether serotonin transporter imaging is suitable as an adjunctivetool for screening and monitoring progression for individuals at risk orpatients with Parkinson's disease to complement dopaminergic imaging, or as amarker of Parkinson's burden in clinical trials.

FUNDING:

LilySafra Hope Foundation and National Institute for Health Research (NIHR)Biomedical Research Centre at King's College London.

参考文献：

Wilson et al (2019). Serotonergic pathology and diseaseburden in the premotor and motor phase of A53T α-synuclein parkinsonism: across-sectional study. Lancet Neurol. 2019 Aug;18(8):748-759.

5. Lancet Neurol—口服吸入左旋多巴粉—CVT-301可以改善帕金森病患者“关期”运动症状

英文摘要：

BACKGROUND:

Patientswith Parkinson's disease chronically treated with levodopa commonly havedelayed or unpredictable onset of its benefits after oral intake. In thisstudy, we assessed the safety and efficacy of CVT-301, a self-administeredlevodopa oral inhalation powder, for the treatment of patients with Parkinson'sdisease during off periods.

METHODS:

Inthis randomised, double-blind, placebo-controlled, phase 3 trial, patients wererecruited at 65 sites in Canada, Poland, Spain, and the USA. Eligibleparticipants were patients with Parkinson's disease aged 30-85 years, who haddaily off periods of 2 h or longer and showed an improvement of 25% or greaterin the Unified Parkinson's Disease Rating Scale (UPDRS) motor score from off toon state after use of an oral levodopa plus a dopa-decarboxylase inhibitorcombination. Patients were assigned (1:1:1) with a computer-generatedrandomisation code, in fixed blocks of six, to either CVT-301 60 mg, CVT-301 84mg, or placebo. Spirometry results and modified Hoehn and Yahr disease stage atscreening were used for stratification of treatment groups. Patients, thesponsor, and site personnel were masked to treatment assignment. Each studydose consisted of two capsules administered with an inhaler. Patients wereinstructed to use the study drug as needed for off periods, and couldself-administer up to five doses per day. The primary endpoint was the changein UPDRS motor score from predose to 30 min postdose, assessed at week 12during an in-clinic off period, in the CVT-301 84 mg group compared with theplacebo group. Analysis was by intention to treat. Safety was assessed in allpatients who received at least one dose of experimental treatment. This trialis registered with ClinicalTrials.gov, number NCT02240030.

FINDINGS:

BetweenDec 4, 2014, and Aug 26, 2016, 351 patients were enrolled and randomly assignedto receive CVT-301 60 mg (115 patients), CVT-301 84 mg (120 patients), orplacebo (116 patients). Of these, 339 received the assigned study treatment(CVT-301 60 mg, n=113; CVT-301 84 mg, n=114; placebo, n=112) and 290 completedthe study (CVT-301 60 mg, n=96; CVT-301 84 mg, n=97; placebo, n=97). Theleast-squares mean difference in UPDRS motor score change from predose to 30min postdose was -5·91 (SE 1·50, 95% CI -8·86 to -2·96) for the placebo groupand -9·83 (1·51; -12·79 to -6·87) for the CVT-301 84 mg group (between-groupdifference -3·92 [-6·84 to -1·00]; p=0·0088). Treatments were safe and welltolerated. Severe adverse events were reported by 2 (2%) of 112 patients in theplacebo group, 7 (6%) of 113 in the CVT-301 60 mg group, and 5 (4%) of 114 inthe CVT-301 84 mg group, with no severe adverse event occurring in more thanone patient in any treatment group. 11 (3%) of 339 patients had 19 seriousadverse events (three [3%] of 112 patients in placebo, six [5%] of 113 inCVT-301 60 mg, and two [2%] of 114 in CVT-301 84 mg). Of these, hypotension andatrial fibrillation were assessed by investigators to be possibly related tothe study drug.

INTERPRETATION:

CVT-301can improve UPDRS motor scores of patients with Parkinson's disease duringin-clinic off periods, with few severe or serious adverse events. The long-termsafety and efficacy of CVT-301 need to be investigated in future studies.

FUNDING:

AcordaTherapeutics.

参考文献：

LeWitt et al (2019). Safety and efficacy of CVT-301(levodopa inhalation powder) on motor function during off periods in patientswith Parkinson's disease: a randomised, double-blind, placebo-controlled phase3 trial. Lancet Neurol. 2019 Feb;18(2):145-154.

6. Gut—炎症性肠病患者罹患帕金森病的风险显著增加

英文摘要：

Abstract

OBJECTIVE:

Intestinal inflammation has been suggested to play a role indevelopment of Parkinson's disease (PD) and multiple system atrophy (MSA). Totest the hypothesis that IBD is associated with risk of PD and MSA, weperformed a nationwide population-based cohort study.

DESIGN:

The cohort consisted of all individuals diagnosed with IBDin Denmark during 1977-2014 (n=76 477) and non-IBD individuals from the generalpopulation, who were comparable in terms of gender, age and vital status (n=7548 259). All cohort members were followed from IBD diagnosis/index date tooccurrence of PD and MSA (according to the Danish National Patient Register).

RESULTS:

Patients with IBD had a 22% increased risk of PD as comparedwith non-IBD individuals (HR=1.22; 95% CI 1.09 to 1.35). The increased risk waspresent independently of age at IBD diagnosis, gender or length of follow-up.The overall incidence of MSA was low in our study, and the regression analysissuggested a tendency towards higher risk of developing MSA in patients with IBDas compared with non-IBD individuals (HR=1.41; 95% CI 0.82 to 2.44). Estimateswere similar for women and men. The increased risk of parkinsonism was significantlyhigher among patients with UC (HR=1.35; 95% CI 1.20 to 1.52) and notsignificantly different among patients with Crohn's disease (HR=1.12; 95% CI0.89 to 1.40).

CONCLUSIONS:

This nationwide, unselected, cohort study shows asignificant association between IBD and later occurrence of PD, which isconsistent with recent basic scientific findings of a potential role of GIinflammation in development of parkinsonian disorders.

参考文献：

Villumsen et al (2019). Inflammatory bowel diseaseincreases the risk of Parkinson's disease: a Danish nationwide cohort study1977-2014. Gut. 2019 Jan;68(1):18-24.

7. Ann Neurol—帕金森病基因治疗研究再取突破：壳核注射携带AADC基因的腺病毒可改善帕金森病患者的临床症状

英文摘要：

Abstract

OBJECTIVE:

Tounderstand the safety, putaminal coverage, and enzyme expression ofadeno-associated viral vector serotype-2 encoding the complementary DNA for theenzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novelintraoperative monitoring to optimize delivery.

METHODS:

Fifteensubjects (three cohorts of 5) with moderately advanced Parkinson's disease andmedically refractory motor fluctuations received VY-AADC01 bilaterallycoadministered with gadoteridol to the putamen using intraoperative magneticresonance imaging (MRI) guidance to visualize the anatomic spread of theinfusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 μlper putamen (total dose, ≤7.5 × 1011vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 μlper putamen (total dose, ≤1.5 × 1012vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 1012vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET)at baseline and 6 months postprocedure assessed enzyme activity; standardassessments measured clinical outcomes.

RESULTS:

MRI-guidedadministration of ascending VY-AADC01 doses resulted in putaminal coverage of21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showedcorresponding increases in enzyme activity assessed by PET of 13%, 56%, and79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%,respectively, at 6 months. At 12 months, there were dose-related improvementsin clinical outcomes, including increases in patient-reported ON-time withouttroublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life.

INTERPRETATION:

Novelintraoperative monitoring of administration facilitated targeted delivery ofVY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzymeexpression and clinical improvements were dose dependent. ClinicalTrials.govIdentifier: NCT01973543 Ann Neurol 2019;85:704-714.

参考文献：

Christine et al (2019). Magnetic resonance imaging-guidedphase 1 trial of putaminal AADC gene therapy for Parkinson's disease. AnnNeurol. 2019 May;85(5):704-714.

8.  Ann Neurol—脑脊液α-synRT-QuIC检测有助于鉴别α突触核蛋白病和非α突触核蛋白病

英文摘要：

Areliable biomarker is needed for accurate and early differentiation betweenParkinson disease and the various forms of atypical parkinsonism. We used anovel real-time quaking-induced conversion (RT-QuIC) assay to detectα-synuclein (α-syn) aggregates in cerebrospinal fluid (CSF) of 118 patientswith parkinsonism of uncertain clinical etiology and 52 controls. Diagnosticaccuracy to distinguish α-synucleinopathies from non-α-synucleinopathies andcontrols was 84% (sensitivity = 75%, specificity = 94%, area under thecurve = 0.84, 95% confidence interval = 0.78-0.91, p < 0.0001, positivepredictive value = 93%). CSF α-syn RT-QuIC could be a useful diagnostic tool tohelp clinicians differentiate α-synucleinopathies from other forms ofparkinsonism when the clinical picture is uncertain.

参考文献：

Van et al (2019). α-Synuclein real-time quaking-inducedconversion in the cerebrospinal fluid of uncertain cases of parkinsonism. AnnNeurol. 2019 May;85(5):777-781

9. Ann Neurol—血浆高尿酸水平是LRRK2突变携带者帕金森病抵抗的生物标志物

英文摘要：

OBJECTIVE:

LRRK2mutations, the most common genetic cause of Parkinson disease (PD), displayincomplete penetrance, indicating the importance of other genetic andenvironmental influences on disease pathogenesis in LRRK2 mutation carriers.The present study investigates whether urate, an antioxidant, Nrf2 activator,and inverse risk factor for idiopathic PD, is one such candidate biomarker ofPD risk modulation in pathogenic LRRK2 mutation carriers.

METHODS:

Bankedplasma samples or urate levels were obtained for 3 cohorts of age- andsex-matched subjects with and without a known LRRK2 mutation in PD andunaffected controls to conduct a pilot study of 192 subjects from the LRRK2Cohort Consortium (LCC) and 2 validation studies of 380 additional subjectsfrom the LCC and 922 subjects from the Parkinson's Progression MarkersInitiative. Urate levels were compared by multiple regression between subjectswith and without a PD diagnosis conditional on LRRK2 status, controlling forage and sex.

RESULTS:

NonmanifestingLRRK2 mutation carriers had significantly higher levels of urate than those whodeveloped PD in each of the 3 independent cohorts. A meta-analysis demonstratedan adjusted mean difference of 0.62 mg/dL (p < 0.001), with similar resultsfor separate assessments of women (p < 0.02) and men (p < 0.001). A2 mg/dL increment in urate concentration decreased the odds of having PD byapproximately 50% (odds ratio = 0.48, p = 0.004).

INTERPRETATION:

Thesefindings identify and substantiate urate as a biomarker of resistance to PDamong LRRK2 mutation carriers. Ann Neurol 2019;85:593-599.

参考文献：

Baksh et al (2019). Higher urate in LRRK2 mutationcarriers resistant to Parkinson disease. Ann Neurol. 2019 Apr;85(4):593-599.

10. Ann Neurol—脑血管风险因子可显著增加帕金森病的发生风险

英文摘要：

OBJECTIVE:

Todetermine whether cerebrovascular risk factors are associated with subsequentdiagnoses of Parkinson disease, and whether these associations are similar inmagnitude to those with subsequent diagnoses of Alzheimer disease.

METHODS:

Thiswas a retrospective cohort study using claims data from a 5% random sample ofMedicare beneficiaries from 2008 to 2015. The exposures were stroke, atrialfibrillation, coronary disease, hyperlipidemia, hypertension, sleep apnea,diabetes mellitus, heart failure, peripheral vascular disease, chronic kidneydisease, chronic obstructive pulmonary disease, valvular heart disease, tobaccouse, and alcohol abuse. The primary outcome was a new diagnosis of idiopathicParkinson disease. The secondary outcome was a new diagnosis of Alzheimerdisease. Marginal structural Cox models adjusting for time-dependentconfounding were used to characterize the association between exposures andoutcomes. We also evaluated the association between cerebrovascular riskfactors and subsequent renal colic (negative control).

RESULTS:

Among1,035,536 Medicare beneficiaries followed for a mean of 5.2 years, 15,531(1.5%) participants were diagnosed with Parkinson disease and 81,974 (7.9%)were diagnosed with Alzheimer disease. Most evaluated cerebrovascular riskfactors, including prior stroke (hazard ratio = 1.55; 95% confidence interval =1.39-1.72), were associated with the subsequent diagnosis of Parkinson disease.The magnitudes of these associations were similar, but attenuated, to theassociations between cerebrovascular risk factors and Alzheimer disease.Confirming the validity of our analytical model, most cerebrovascular riskfactors were not associated with the subsequent diagnosis of renal colic.

INTERPRETATION:

Cerebrovascularrisk factors are associated with Parkinson disease, an effect comparable totheir association with Alzheimer disease.

参考文献：

Kummer et al (2019). Associations between cerebrovascularrisk factors and parkinson disease. Ann Neurol. 2019 Oct;86(4):572-581.

2019年十大研究进展名录

1. 年终盘点：2019年帕金森病十大基础研究进展

2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症（ALS）十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破

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20个神经科学领域的突破可能获得诺贝尔奖

1. 意识研究：意识的本质、组成、运行机制及其物质载体；不同意识层次的操控和干预，意识障碍性疾病的治疗。

2. 学习和记忆的机制及其调控：记忆的形成和消退机制，记忆的人为移植和记忆的人为消除等；

3. 痴呆研究：阿尔茨海默病的机制和治疗研究，血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。

4. 睡眠和睡眠障碍的机制和干预研究。

5. 情绪研究：喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。

6. 计算和逻辑推理的神经科学基础研究。

7. 语言的神经科学基础研究。

8. 视觉图像形成和运用的神经科学基础研究。

9. 创造力、想象力和艺术文学创造的神经基础研究。

10. 痛觉的神经科学基础及其干预研究

11. 性行为研究：性行为的神经科学基础研究和性行为的调控和干预。

12. 脑和脊髓损伤的机制及其干预研究，包括脑卒中、脊髓损伤机制研究，神经干细胞移植研究，新型神经修复技术，神经康复技术。

13. 精神类疾病的机制和干预研究：自闭症、精分、抑郁症、智能障碍、药物成瘾等；

14. 运动神经元病等神经变性病机制研究及其干预。

15. 衰老的机制和永生研究，包括大脑衰老的机制和寿命延长研究。

16. 神经系统遗传病的机制研究及基因治疗。

17. 神经操纵和调控技术：光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。

18. 脑组织兼容性电子微芯片及脑机互动装置研究，包括脑机接口、神经刺激芯片、记忆存储芯片，意识存储芯片，人脑非语言互动装置等。

19. 半人半机器人的设计、完善和修复技术：包括任何机械肢体的人类移植，大脑移植入机器体内等。

20. 新型大脑成像和神经元活动记录技术：高分辨率成像技术、大型电极微阵列技术等。