Mitochondrial haplogroups and cognitive progression in Parkinson's disease.

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

The Hidden Burden of Disease and Treatment Experiences of Patients with Essential Tremor: A Retrospective Claims Data Analysis.

INTRODUCTION: Essential tremor (ET) affects approximately 7 million people in the USA, yet public recognition of the disease and its impact remain low. METHODS: A retrospective observational study examined US claims data from 2015 to 2019 using the Compile database. ET diagnoses were captured using longitudinal data from 2015 to 2019 and for the year 2019, with diagnosis estimates extrapolated to the general US population. Confirmed ET was identified by an ET diagnosis code with at least two relevant prescriptions or by two diagnosis codes for ET and unspecified tremor at least 90 days apart. Comorbidity and treatment use data were extracted, and medication compliance and 2-year treatment persistence were assessed as measures of treatment adherence. RESULTS: A total of 1,336,183 patients with ET diagnoses codes were identified from 2015 through 2019, corresponding to 2,226,971 projected US diagnoses. In 2019, 128,263 patients had a confirmed ET diagnosis, corresponding to 213,772 projected US confirmed diagnoses. Of these, 96% had at least one comorbidity, and 64% received at least one pharmacologic treatment. Propranolol (24%) and primidone (20%) comprised the most common ET prescriptions. Two-year medication discontinuation rates were approximately 40%. CONCLUSION: Our findings revealed that 1 million people were diagnosed and sought treatment for ET in the USA from 2015 to 2019. Projected population estimates of approximately 2 million people diagnosed suggest a further 1 million remain untreated. Our findings highlight the complexity of patient care in ET, complicated by delayed diagnoses, multiple comorbidities, and lack of effective and tolerable therapies that can mitigate treatment adherence limitations.

A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia.

Introduction: Friedreich ataxia (FRDA) is a recessive neurodegenerative disease characterized by progressive ataxia, dyscoordination, and loss of vision. The variable length of the pathogenic GAA triplet repeat expansion in the FXN gene in part explains the interindividual variability in the severity of disease. The GAA repeat expansion leads to epigenetic silencing of FXN; therefore, variability in properties of epigenetic effector proteins could also regulate the severity of FRDA. Methods: In an exploratory analysis, DNA from 88 individuals with FRDA was analyzed to determine if any of five non-synonymous SNPs in HDACs/SIRTs predicted FRDA disease severity. Results suggested the need for a full analysis at the rs352493 locus in SIRT6 (p.Asn46Ser). In a cohort of 569 subjects with FRDA, disease features were compared between subjects homozygous for the common thymine SIRT6 variant (TT) and those with the less common cytosine variant on one allele and thymine on the other (CT). The biochemical properties of both variants of SIRT6 were analyzed and compared. Results: Linear regression in the exploratory cohort suggested that an SNP (rs352493) in SIRT6 correlated with neurological severity in FRDA. The follow-up analysis in a larger cohort agreed with the initial result that the genotype of SIRT6 at the locus rs352493 predicted the severity of disease features of FRDA. Those in the CT SIRT6 group performed better on measures of neurological and visual function over time than those in the more common TT SIRT6 group. The Asn to Ser amino acid change resulting from the SNP in SIRT6 did not alter the expression or enzymatic activity of SIRT6 or frataxin, but iPSC-derived neurons from people with FRDA in the CT SIRT6 group showed whole transcriptome differences compared to those in the TT SIRT6 group. Conclusion: People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.

Translational Pharmacology of PRAX-944, a Novel T-Type Calcium Channel Blocker in Development for the Treatment of Essential Tremor.

BACKGROUND: Essential tremor is the most common movement disorder with clear unmet need. Mounting evidence indicates tremor is caused by increased neuronal burst firing and oscillations in cerebello-thalamo-cortical circuitry and may be dependent on T-type calcium channel activity. T-type calcium channels regulate sigma band electroencephalogram (EEG) power during non-rapid eye movement sleep, representing a potential biomarker of channel activity. PRAX-944 is a novel T-type calcium channel blocker in development for essential tremor. OBJECTIVES: Using a rat tremor model and sigma-band EEG power, we assessed pharmacodynamically-active doses of PRAX-944 and their translation into clinically tolerated doses in healthy participants, informing dose selection for future efficacy trials. METHODS: Harmaline-induced tremor and spontaneous locomotor activity were used to assess PRAX-944 efficacy and tolerability, respectively, in rats. Sigma-power was used as a translational biomarker of T-type calcium channel blockade in rats and, subsequently, in a phase 1 trial assessing pharmacologic activity and tolerability in healthy participants. RESULTS: In rats, PRAX-944 dose-dependently reduced tremor by 50% and 72% at 1 and 3 mg/kg doses, respectively, without locomotor side effects. These doses also reduced sigma-power by ~30% to 50% in rats. In healthy participants, sigma-power was similarly reduced by 34% to 50% at 10 to 100 mg, with no further reduction at 120 mg. All doses were well tolerated. CONCLUSIONS: In rats, PRAX-944 reduced sigma-power at concentrations that reduced tremor without locomotor side effects. In healthy participants, comparable reductions in sigma-power indicate that robust T-type calcium channel blockade was achieved at well-tolerated doses that may hold promise for reducing tremor in patients with essential tremor. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10-11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10-8) and WWOX (HR = 2.12, P = 2.37 × 10-8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.

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 3.1 years. 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 17 719 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.

Association of Dilated Perivascular Spaces and Disease Severity in Patients With Huntington Disease.

OBJECTIVE: To quantify the percent volume of dilated perivascular space (PVS) in the subcortical forebrain in patients with early Huntington disease (HD) and to explore the relationship between PVS and disease severity. METHODS: MRI scans were performed on 25 patients with HD and 23 healthy age-matched controls at Massachusetts General Hospital. The imaging data were analyzed with a novel algorithm to determine regional PVS volume. A fractional logistic regression analysis was used to quantify the association between regional percent PVS volume and (1) disease designation (HD or control) and (2) disease severity as assessed by normalized caudate volume. RESULTS: Patients with HD had the greatest percent volume of dilated PVS in the putamen (left putamen: odds ratio 2.06 [95% confidence interval (CI) 1.62-2.62], HD 3.27% [95% CI 2.83-3.78] vs controls 1.62% [95% CI 1.32-1.97], p fdr < 0.001; right putamen: odds ratio 1.66 [95% CI 1.33-2.08], HD 3.43% [95% CI 2.94-4.01] vs controls 2.09% [95% CI 1.79-2.45], p fdr < 0.001) and several subcortical white matter regions compared to controls. Dilated PVS increased with disease severity. CONCLUSIONS: The objective quantification of dilated PVS suggests that PVS burden is high, is associated with disease severity, and may affect the distribution and success of treatments administered either intrathecally such as antisense oligonucleotides or by intraparenchymal administration such as cell and gene therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that increased dilated PVS is associated with worse HD severity. The study is rated Class II because of the cross-sectional design.

Data-driven evolution of neurosurgical gene therapy delivery in Parkinson's disease.

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

Aromatic L-Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson's Disease.

BACKGROUND: As Parkinson's disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson's disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements. OBJECTIVES: This substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01 administration. METHODS: Participants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Unified Parkinson's Disease Rating Scale motor scores, finger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion. RESULTS: Of 15 PD-1101 patients, 13 participated in the substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, respectively, after VY-AADC01; finger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre-VY-AADC01 and 2 participants post-VY-AADC01 administration. CONCLUSIONS: VY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Health related quality of life in Friedreich Ataxia in a large heterogeneous cohort.

INTRODUCTION: This study assessed the Health Related Quality of Life (HRQOL) of individuals with Friedreich Ataxia (FRDA) through responses to HRQOL questionnaires. METHODS: The SF-36, a generic HRQOL instrument, and symptom specific scales examining vision, fatigue, pain and bladder function were administered to individuals with FRDA and analyzed by comparison with disease features. Multiple linear regression models were used to study independent effects of genetic severity and age. Assessments were performed at baseline then intermittently after that. RESULTS: Subjects were on average young adults. For the SF36, the subscale with the lowest HRQOL score was the physical function scale, while the emotional well-being score was the highest. The physical function scale correlated with age of onset, duration, and subject age. In assessment of symptom specific scales, bladder control scores (BLCS) correlated with duration and age, while impact of visual impairment scores (IVIS) correlated with duration. In linear regression models, the BLCS, Pain Effect Score, and IVIS scores were predicted by age and GAA length; modified fatigue impact scale scores were predicted only by GAA length. Physical function and role limitation scores declined over time. No change was seen over time in other SF-36 subscores. Symptom specific scales also worsened over time, most notably the IVIS and BLCS. CONCLUSION: The SF-36 and symptom specific scales capture dysfunction in FRDA in a manner that reflects disease status. HRQOL dysfunction was greatest on physically related scales; such scales correlated with disease duration, indicating that they worsen with progressing disease.

Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts.

BACKGROUND: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. OBJECTIVES: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. METHODS: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. RESULTS: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. CONCLUSIONS: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Measuring peripheral nerve involvement in Friedreich's ataxia.

OBJECTIVE: Experimental therapies under development for Friedreich's Ataxia (FRDA) require validated biomarkers. In-vivo reflectance confocal microscopy (RCM) of skin is a noninvasive way to quantify Meissner's corpuscle (MC) density and has emerged as a sensitive measure of sensory polyneuropathies. We conducted a prospective, cross-sectional study evaluating RCM of MCs and conventional peripheral nerve measures as candidate peripheral nerve markers in FRDA. METHODS: Sixteen individuals with FRDA and 16 age- and gender-matched controls underwent RCM of MC density and morphology, skin biopsies for epidermal nerve fiber density (ENFD), nerve conduction studies (NCS), and quantitative sensory testing (QST) including touch, vibration, and cooling thresholds. RESULTS: MC densities were measurable in all participants with FRDA, and were lower at digit V (hand), thenar eminence, and arch (foot) compared to controls. By contrast, sensory NCS showed floor effects and were obtainable in only 13% of FRDA participants. QST thresholds for touch, vibration, and cooling were higher at the hand and foot in FRDA than controls. Reductions in ENFDs were present in more severely affected individuals with FRDA (Friedreich's Ataxia Rating Scale (FARS) >60) compared to matched controls, although skin biopsies were not well tolerated in children. MC densities, ENFDs, and touch and vibration thresholds were associated with clinical disease severity (FARS and modified FARS) and duration since symptom onset. INTERPRETATION: MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.

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.

Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease.

OBJECTIVE: To understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery. METHODS: Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 µl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 µl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 µl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes. RESULTS: MRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life. INTERPRETATION: Novel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714.

Psychometric properties of the Friedreich Ataxia Rating Scale.

OBJECTIVE: To investigate the psychometric properties of the Friedreich Ataxia Rating Scale neurologic examination (FARSn) and its subscores, as well as the influence of the modifications resulting in the now widely used modified FARS (mFARS) examination. METHODS: Based on cross-sectional FARS data from the FA-Clinical Outcome Measures cohort, we conducted correlation-based psychometric analyses to investigate the interplay of items and subscores within the FARSn/mFARS constructs. RESULTS: The results provide support for both the FARSn and the mFARS constructs, as well as individually for their upper limb and lower limb coordination components. The omission of the peripheral nervous system subscore (D) and 2 items of the bulbar subscore (A) in the mFARS strengthens the overall construct compared with the complete FARS. CONCLUSIONS: A correlation-based psychometric analysis of the neurologic FARSn score justifies the overall validity of the scale. In addition, omission of items of limited functional significance as created in the mFARS improves the features of the measures. Such information is crucial to the ongoing application of the mFARS in natural history studies and clinical trials. Additional analyses of longitudinal changes will be necessary to fully ascertain its utility, especially in nonambulant patients.

Gene therapy for neurological disorders: progress and prospects.

This corrects the article DOI: 10.1038/nrd.2018.110.

Gene therapy for neurological disorders: progress and prospects.

Adeno-associated viral (AAV) vectors are a rapidly emerging gene therapy platform for the treatment of neurological diseases. In preclinical studies, transgenes encoding therapeutic proteins, microRNAs, antibodies or gene-editing machinery have been successfully delivered to the central nervous system with natural or engineered viral capsids via various routes of administration. Importantly, initial clinical studies have demonstrated encouraging safety and efficacy in diseases such as Parkinson disease and spinal muscular atrophy, as well as durability of transgene expression. Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

Improved stratification of ALS clinical trials using predicted survival.

INTRODUCTION: In small trials, randomization can fail, leading to differences in patient characteristics across treatment arms, a risk that can be reduced by stratifying using key confounders. In ALS trials, riluzole use (RU) and bulbar onset (BO) have been used for stratification. We hypothesized that randomization could be improved by using a multifactorial prognostic score of predicted survival as a single stratifier. METHODS: We defined a randomization failure as a significant difference between treatment arms on a characteristic. We compared randomization failure rates when stratifying for RU and BO ("traditional stratification") to failure rates when stratifying for predicted survival using a predictive algorithm. We simulated virtual trials using the PRO-ACT database without application of a treatment effect to assess balance between cohorts. We performed 100 randomizations using each stratification method - traditional and algorithmic. We applied these stratification schemes to a randomization simulation with a treatment effect using survival as the endpoint and evaluated sample size and power. RESULTS: Stratification by predicted survival met with fewer failures than traditional stratification. Stratifying predicted survival into tertiles performed best. Stratification by predicted survival was validated with an external dataset, the placebo arm from the BENEFIT-ALS trial. Importantly, we demonstrated a substantial decrease in sample size required to reach statistical power. CONCLUSIONS: Stratifying randomization based on predicted survival using a machine learning algorithm is more likely to maintain balance between trial arms than traditional stratification methods. The methodology described here can translate to smaller, more efficient clinical trials for numerous neurological diseases.

Biomarkers for cognitive impairment in Lewy body disorders: Status and relevance for clinical trials.

Biomarkers have the potential to improve diagnosis and prognosis, and guide clinical treatment decisions. In research, biomarkers can be used for patient selection and as outcome measures in clinical trials. A range of biochemical and imaging biomarkers are relevant to patients with Lewy body disorders, including PD, PD dementia, and dementia with Lewy bodies. Dopaminergic imaging is used for differential diagnosis of parkinsonian disorders versus tremor disorders without dopamingeric deficits, and also to differentiate dementia with Lewy bodies from Alzheimer's disease. Markers of underlying Alzheimer's disease pathology have been applied to PD patients experiencing cognitive decline to determine the extent of mixed pathology in these cases. Assessment of alpha-synuclein species in spinal fluid is possible, and more specific assays attempt to identify alpha-synuclein aggregates or phosphorylated alpha-synuclein. While alpha-synuclein markers are intended to measure the pathology most central to PD dementia and dementia with Lewy bodies, convincing evidence of robust reliability and validity from multiple laboratories is lacking. Similarly, alpha-synuclein imaging by PET or single-photon emission computed tomography, while an important research goal, is not yet available. In addition to their uses in the clinic, biomarkers have natural uses in therapeutic trials that target cognitive and neuropsychiatric features of Lewy body disorders. The biomarkers most likely to be incorporated into trials are dopaminergic and amyloid imaging for the purpose of accurate patient selection, and possibly to demonstrate the utility of antiamyloid treatments in Lewy body disorders patients with mixed pathology. © 2018 International Parkinson and Movement Disorder Society.