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Peripheral artery disease (PAD) is associated with decreased physical function and increased mortality in the general population. We previously found that PAD is common in middle-aged women with and without HIV infection, but its association with functional decline is unclear. We examine the contribution of PAD to functional decline in the Women's Interagency HIV Study, controlling for traditional cardiovascular risk factors and HIV-related factors.Analysis included 1839 participants (72% with HIV) with measured ankle-brachial index (ABI) and 4 m gait speed. ABI values categorized PAD severity. Linear models with repeated measures estimated the association of PAD severity with log-transformed gait speed after controlling for demographic, behavioral, and metabolic risk factors, and HIV/hepatitis C virus status.Median age was 50 years and more than 70% were Black. Compared with normal ABI, there was a dose-response relationship between increasing PAD severity and slower gait speed in univariable analyses: 6% slower gait speed for low-normal ABI [95% confidence interval (CI): 4-9%], 10% for borderline PAD (95% CI: 6-13%), 14% for mild PAD (95% CI: 9-18%), and 16% for moderate-severe PAD (95% CI: 5-25%). PAD severity remained associated with slower gait speed in multivariable analyses. HIV/hepatitis C virus co-infection was independently associated with 9% (95% CI: 4-14%) slower gait speed compared with those with neither infection. Among women with HIV, neither CD4+ cell count nor HIV-RNA level was associated with gait speed.In middle-aged women with and without HIV infection, greater PAD severity is associated with progressively slower gait speed. Early detection of subclinical PAD may decrease the risk of lower extremity functional impairment and its long-term health consequences.

Background Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can quantify the functional integrity of the dopaminergic nerve terminals and has been suggested as an imaging modality to verify the clinical diagnosis of Parkinson’s disease (PD). Depending on the stage of progression, approximately 5–15% of participants clinically diagnosed with idiopathic PD have been observed in previous studies to have normal DaT-SPECT patterns. However, the utility of DaT-SPECT in enhancing early PD participant selection in a global, multicenter clinical trial of a potentially disease-modifying therapy is not well understood. Methods The SPARK clinical trial was a phase 2 trial of cinpanemab, a monoclonal antibody against alpha-synuclein, in participants with early PD. DaT-SPECT was performed at screening to select participants with DaT-SPECT patterns consistent with degenerative parkinsonism. Acquisition was harmonised across 82 sites. Images were reconstructed and qualitatively read at a central laboratory by blinded neuroradiologists for inclusion prior to automated quantitative analysis. Results In total, 482 unique participants were screened between January 2018 and May 2019; 3.8% (15/398) of imaged participants were excluded owing to negative DaT-SPECT findings (i.e., scans without evidence of dopaminergic deficit [SWEDD]). Conclusion A smaller proportion of SPARK participants were excluded owing to SWEDD status upon DaT-SPECT screening than has been reported in prior studies. Further research is needed to understand the reasons for the low SWEDD rate in this study and whether these results are generalisable to future studies. If supported, the radiation risks, imaging costs, and operational burden of DaT-SPECT for enrichment may be mitigated by clinical assessment and other study design aspects. Trial registration ClinicalTrials.gov identifier: NCT03318523. Date submitted: October 19, 2017. First Posted: October 24, 2017.

Introduction The prevalence of subtle cognitive decline in the early stages of Parkinson's Disease (PD) is common and is thought to be even greater in patients carrying genetic mutations in the GBA gene. Current cognitive tests often lack sensitivity to identify subtle impairments. Technological advancements may offer greater precision. We explored the utility of a digitized cognitive clock-drawing test to assess cognition in patients with PD compared to healthy controls (HC) and its sensitivity compared to that of standardized neuropsychological tests. Further, we investigated the existence of a cognitive profile based on genotype. Methods The study included 75 early stage PD patients (24 with GBA-PD, 23 LRRK2-PD, 28 idiopathic PD cases) and 59 HC. Participants underwent a cognitive assessment which included the Montreal Cognitive Assessment (MoCA), the Color Trails Test (CTT) and a digital clock drawing test (DCTclock). Results Patients with PD presented lower scores than HC on all cognitive tests. The DCTclock best discriminated PD from HC (AUC: 0.807) compared to the MoCA (0.590) and CTT (0.636 and 0.717 for CTT-1 and CTT-2 respectively). In-depth quantitative analysis of the DCTclock revealed that LRRK2-PD showed better performance than other PD sub-groups. Conclusion The use of quantitative digital cognitive assessment showed greater sensitivity in identifying subtle cognitive decline than the current standardized tests. Differences in cognitive profiles were observed based on genotype. The identification of early cognitive decline may improve the clinical management of PD patients and be useful for cognitive related clinical trials.

Background: Inflammation is an integral part of neurodegeneration including in Parkinson’s disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA-PD and LRRK2-PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. Objective: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. Methods: The following cytokines were assessed from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ. A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. Results: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK2-PD, 77 GBA-PD, 3 homozygote GBA-PD, 3 GBA-LRRK2-PD, 67 LRRK2-NMC, 105 GBA-NMC, 14 LRRK2-GBA-NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. Conclusion: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers.

Contains fulltext : 238527.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is not clear how specific gait measures reflect disease severity across the disease spectrum in Parkinson's disease (PD). OBJECTIVE: To identify the gait and mobility measures that are most sensitive and reflective of PD motor stages and determine the optimal sensor location in each disease stage. METHODS: Cross-sectional wearable-sensor records were collected in 332 patients with PD (Hoehn and Yahr scale I-III) and 100 age-matched healthy controls. Sensors were adhered to the participant's lower back, bilateral ankles, and wrists. Study participants walked in a ~15-meter corridor for 1 minute under two walking conditions: (1) preferred, usual walking speed and (2) walking while engaging in a cognitive task (dual-task). A subgroup (n = 303, 67% PD) also performed the Timed Up and Go test. Multiple machine-learning feature selection and classification algorithms were applied to discriminate between controls and PD and between the different PD severity stages. RESULTS: High discriminatory values were found between motor disease stages with mean sensitivity in the range 72%-83%, specificity 69%-80%, and area under the curve (AUC) 0.76-0.90. Measures from upper-limb sensors best discriminated controls from early PD, turning measures obtained from the trunk sensor were prominent in mid-stage PD, and stride timing and regularity were discriminative in more advanced stages. CONCLUSIONS: Applying machine-learning to multiple, wearable-derived features reveals that different measures of gait and mobility are associated with and discriminate distinct stages of PD. These disparate feature sets can augment the objective monitoring of disease progression and may be useful for cohort selection and power analyses in clinical trials of PD. © 2021 International Parkinson and Movement Disorder Society.

The phenotype of Parkinson’s disease (PD) is variable with mutations in genes such as LRRK2 and GBA explaining part of this heterogeneity. Additional genetic and environmental factors contribute to disease variability. To assess the association between biochemical markers, PD severity and probability score for prodromal PD, among GBA and LRRK2 mutation carriers. Levels of uric acid, vitamin D, C-reactive protein, microalbumin/creatinine ratio (ACR), white blood count (WBC), hemoglobin, platelets, neutrophil/lymphocyte ratio and estimated glomerular filtration rate (eGFR) were assessed from patients with PD and non-manifesting carriers (NMC) of mutations in GBA and LRRK2, together with disease related questionnaires enabling the construction of the MDS prodromal probability score. A total of 241 patients with PD: 105 idiopathic PD (iPD), 49 LRRK2-PD and 87 GBA-PD and 412 non-manifesting subjects; 74 LRRK2-NMC, 118 GBA-NMC and 220 non-manifesting non-carriers (NMNC), participated in this study. No significant differences in biochemical measures were detected among patients with PD or non-manifesting carriers. Among GBA-PD patients, worse motor performance was associated with ACR (B = 4.68, 95% CI (1.779–7.559); p = 0.002). The probability score for prodromal PD among all non-manifesting participants was associated with eGFR; NMNC (B = − 0.531 95% CI (− 0.879 to − 0.182); p

Carcinoid crisis is a life-threatening manifestation of carcinoid syndrome characterized by profound autonomic instability in the setting of catecholamine release from stress, tumor manipulation, or anesthesia. Here, we present an unusual case of carcinoid crisis leading to acute systolic heart failure requiring mechanical circulatory support. (Level of Difficulty: Intermediate.), Graphical abstract

Author(s): Mollenhauer, Brit; Dakna, Mohammed; Kruse, Niels; Galasko, Douglas; Foroud, Tatiana; Zetterberg, Henrik; Schade, Sebastian; Gera, Roland G; Wang, Wenting; Gao, Feng; Frasier, Mark; Chahine, Lana M; Coffey, Christopher S; Singleton, Andrew B; Simuni, Tanya; Weintraub, Daniel; Seibyl, John; Toga, Arthur W; Tanner, Caroline M; Kieburtz, Karl; Marek, Kenneth; Siderowf, Andrew; Cedarbaum, Jesse M; Hutten, Samantha J; Trenkwalder, Claudia; Graham, Danielle | Abstract: BackgroundThe objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker.MethodsWe quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers.ResultsIn the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P l 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association.ConclusionsNeurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

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.

Objectives:HIV and hepatitis C virus (HCV) have been associated with cardiovascular disease (CVD), but it is unclear whether HIV and HCV are also associated with peripheral artery disease (PAD). We examined the association of HIV, HCV, and traditional CVD risk factors with PAD in the Women's Interag

As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson's Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.

Background Pathological and genetic evidence implicates toxic effects of aggregated α‐synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α‐synuclein is a promising strategy for delaying disease progression. Objective This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human‐derived monoclonal antibody that preferentially binds to aggregated α‐synuclein, in healthy volunteers and participants with Parkinson's disease. Methods A total of 48 healthy volunteers (age 40–65, 19 women) and 18 Parkinson's disease participants (age 47–75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single‐dose cohorts of BIIB054 (range 1–135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α‐synuclein complexes were measured in plasma. Results Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half‐life of BIIB054 was 28 to 35 days; the cerebrospinal fluid–to‐serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α‐synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α‐synuclein complex formation. Conclusions BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The Critical Path for Parkinson's (CPP) Imaging Biomarker and Modeling and Simulation working groups aimed to achieve qualification opinion by the European Medicines Agency (EMA) Committee for Medical Products for Human Use (CHMP) for the use of baseline dopamine transporter neuroimaging for patient selection in early Parkinson's disease clinical trials. This paper describes the regulatory science strategy to achieve this goal. CPP is an international consortium of three Parkinson's charities and nine pharmaceutical partners, coordinated by the Critical Path Institute.

BACKGROUND Objective diagnostic biomarkers are needed to support a clinical diagnosis. OBJECTIVES To analyze markers in various neurodegenerative disorders to identify diagnostic biomarker candidates for mainly α-synuclein (aSyn)-related disorders (ASRD) in serum and/or cerebrospinal fluid (CSF). METHODS Upon initial testing of commercially available kits or published protocols for the quantification of the candidate markers, assays for the following were selected: total and phosphorylated aSyn (pS129aSyn), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), tau protein (tau), ubiquitin C-terminal hydrolase L1 (UCHL-1), glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), soluble triggering receptor expressed on myeloid cells 2 (sTREM-2), and chitinase-3-like protein 1 (YKL-40). The cohort comprised participants with Parkinson's disease (PD, n = 151), multiple system atrophy (MSA, n = 17), dementia with Lewy bodies (DLB, n = 45), tau protein-related neurodegenerative disorders (n = 80, comprising patients with progressive supranuclear palsy (PSP, n = 38), corticobasal syndrome (CBS, n = 16), Alzheimer's disease (AD, n = 11), and frontotemporal degeneration/amyotrophic lateral sclerosis (FTD/ALS, n = 15), as well as healthy controls (HC, n = 20). Receiver operating curves (ROC) with area under the curves (AUC) are given for each marker. RESULTS CSF total aSyn was decreased. NfL, pNfH, UCHL-1, GFAP, S100B, and sTREM-2 were increased in patients with neurodegenerative disease versus HC (P

ObjectiveTo explore the utility of using patient reported emergence of new symptoms (ES) as an outcome measure during the early phase of the disease.MethodsWe analyzed data from MDS-UPDRS Part IB and Part II from the Safety, Tolerability, and Efficacy Assessment of Isradipine for PD (STEADY-PD3) study, with at least one annual follow-up over two years. We divided the sample into categories of follow-up visit (between 0 and 12-months, and 13 and 24-months) and the number of ES for each part of the scale between participants who started symptomatic treatment and those who did not (STx-yes/no). We assessed ES differences between participants STx in each follow-up visit using Mann-Whitney U test, and the Kaplan-Meier analyses.ResultsOf 331 participants observed for months 0 to 12, 288 (87%) developed ES, and 182 (55%) started STx. For Part IB, the median number of ES did not significantly differ between the STx groups (Z=-0.86, p = 0.39), while for Part 2, the number of ES was significantly higher for the STx-yes group (Z=-2.38, p=0.02). Of 148 participants who continued to be observed for months 13 to 24, 114 (77%) developed ES, and 62 (42%) started STx. For Part IB, the median number of ES did not significantly differ between the STx groups (Z=-0.33, p = 0.74), while for Part 2, the number of ES was significantly higher for the STx-yes group (Z=-2.25, p=0.02).ConclusionsAssessing ES among patient-reported experiences of daily living may provide a useful marker for tracking PD progression.

Background Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD). Objective To explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in the GBA and LRRK2 genes. Methods Participants were genotyped for the G2019S-LRRK2 and nine GBA mutations common in Ashkenazi Jews. Performance-based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected. Results One hundred and seventy PD patients (102 GBA-PD, 38 LRRK2-PD, and 30 idiopathic PD) and 221 non-manifesting carriers (NMC) (129 GBA-NMC, 45 LRRK2-NMC, 15 GBA-LRRK2-NMC, and 32 healthy controls) participated in this study. GCase activity was lower among GBA-PD (3.15 ± 0.85 μmol/L/h), GBA-NMC (3.23 ± 0.91 μmol/L/h), and GBA-LRRK2-NMC (3.20 ± 0.93 μmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype. Conclusions Low GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials’ failures to demonstrate disease-modifying benefit, and potential solutions. Methods The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. Results Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. Conclusions We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.

International audience; BackgroundDevelopment of reliable and accurate imaging biomarkers of dopaminergic cell neurodegeneration is necessary to facilitate therapeutic drug trials in Parkinson's disease (PD). Neuromelanin‐sensitive MRI techniques have been effective in detecting neurodegeneration in the substantia nigra pars compacta (SNpc). The objective of the current study was to investigate longitudinal neuromelanin signal changes in the SNpc in PD patients.MethodsIn this prospective, longitudinal, observational case–control study, we included 140 PD patients and 64 healthy volunteers divided into 2 cohorts. Cohort I included 99 early PD patients (disease duration, 1.5 ± 1.0 years) and 41 healthy volunteers analyzed at baseline (V1), where 79 PD patients and 32 healthy volunteers were rescanned after 2.0 ± 0.2 years of follow‐up (V2). Cohort II included 41 progressing PD patients (disease duration, 9.3 ± 3.7 years) and 23 healthy volunteers at V1, where 30 PD patients were rescanned after 2.4 ± 0.5 years of follow‐up. Subjects were scanned at 3 T MRI using 3‐dimensional T1‐weighted and neuromelanin‐sensitive imaging. Regions of interest were delineated manually to calculate SN volumes, volumes corrected by total intracranial volume, signal‐to‐noise ratio, and contrast‐to‐noise ratio.ResultsResults showed (1) significant reduction in volume and volume corrected by total intracranial volume between visits, greater in progressing PD than nonsignificant changes in healthy volunteers; (2) no significant effects of visit for signal intensity (signal‐to‐noise ratio); (3) significant interaction in volume between group and visit; (4) greater volume corrected by total intracranial volume at baseline in female patients and greater decrease in volume and increase in the contrast‐to‐noise ratio in progressing female PD patients compared with male patients; and (5) correlations between neuromelanin SN changes and disease severity and duration.ConclusionsWe observed a progressive and measurable decrease in neuromelanin‐based SN signal and volume in PD, which might allow a direct noninvasive assessment of progression of SN loss and could represent a target biomarker for disease‐modifying treatments. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Introduction: Peripheral artery disease (PAD) is associated with decreased physical function and increased mortality in the general population. PAD is common in women with and at risk for HIV infection, but its association with functional decline is unclear. We examined the contribution of PAD to gait speed in the Women’s Interagency HIV Study, controlling for traditional cardiovascular risk factors and HIV-related factors. Methods: 1,839 participants (72% HIV+) with measured ankle-brachial index (ABI) and 4-meter gait speed were included in analysis. ABI scores were categorized as: Results: Median age was 50 years, >70% were Black. Figure 1 shows median gait speed by PAD group. In univariate analysis, compared to normal ABI, each category of PAD severity was associated with slower gait speed: 6% slower for low-normal (95% confidence interval [CI]:4%, 9%), 10% for borderline (95% CI:6%, 13%), 14% for mild (95% CI:9%, 18%), and 16% for moderate-severe (95% CI:5%, 25%). In multivariate analysis, PAD severity remained associated with 6% (95% CI:4%, 9%), 10% (95%CI:7%, 14%), 12% (95%CI:8%, 17%), and 11% (95%CI: -1%, 22%) slower gait speed, respectively. HIV/HCV coinfection reduced gait speed by 9% (95%CI:4%, 14%). Among HIV+ women, neither CD4 count nor HIV viral load was associated with gait speed. Conclusions: In middle-aged women with and at risk for HIV, greater PAD severity is associated with progressively slower gait speed. ABI measurement may be a simple and clinically useful tool for early assessment of functional declines.

Background: Cerebrospinal fluid (CSF) is essential for the medical workup of patients with neurological conditions and for disease-modifying clinical trials. Post- lumbar puncture (LP) headache is influenced by both operator and patient-related factors, including needle type and gauge, age, and gender. Objectives: We aimed to assess whether CSF volume measured based on pre-procedural brain MRI is associated with the risk of developing a post-LP headache. Methods: In total, n = 117 participants (n = 58 Parkinson's disease patients, and n = 59 healthy controls) underwent an LP and CSF collection. Of those, n = 89 underwent MRI scans prior to the LP procedure acquiring high-resolution 3D magnetization-prepared rapid gradient echo (MP-RAGE) T1-weighted images using a 3 T MR scanner. Clinical and behavioral assessments were performed for all participants, and CSF was assessed for content. The T1-weighted images were segmented producing gray matter, white matter, and CSF probability maps. Results: Thirteen participants (11.1%) experienced post-LP headache. They were younger (p = .033) and had lower CSF volumes (p = .040) compared to participants that did not develop a post LP headache. Conclusions: The results of this pilot study suggest that low CSF volumes might increase the risk for the occurrence of post-LP adverse events and should be taken into consideration when planning LP's.

In order toevaluate the influence of the metabolic syndrome (MS) (obesity, hypertension, elevated triglycerides, reduced levels of HDL cholesterol and glucose impairment) on the phenotype of LRRK2 and GBA Parkinson’s disease (PD), and on the prevalence of prodromal features among individuals at risk, we collected, laboratory test results, blood pressure, demographic, cognitive, motor, olfactory and affective information enabling the assessment of each component of MS and the construction of the MDS prodromal probability score. The number of metabolic components and their levels were compared between participants who were separated based on disease state and genetic status. One hundred and four idiopathic PD, 40 LRRK2-PD, 70 GBA-PD, 196 healthy non-carriers, 55 LRRK2-NMC and 97 GBA-NMC participated in this study. PD groups and non manifesting carriers (NMC) did not differ in the number of metabolic components (p = 0.101, p = 0.685, respectively). LRRK2-PD had higher levels of triglycerides (p = 0.015) and higher rates of prediabetes (p = 0.004), while LRRK2-NMC had higher triglyceride levels (p = 0.014). NMC with probability rates for prodromal PD above 50% had higher frequencies of hypertriglyceridemia and prediabetes (p LRRK2 carriers, MS does not seem to influence GBA and LRRK2-PD phenotype.

The convergence of human molecular genetics and Lewy pathology of Parkinson's disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein (α-syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson's Research convened a group of leaders in the field of PD research from academia and industry, the Alpha-Synuclein Clinical Path Working Group. This group set out to develop recommendations on preclinical and clinical research that can de-risk the development of α-syn targeting therapies. This consensus white paper provides a translational framework, from the selection of animal models and associated end-points to decision-driving biomarkers as well as considerations for the design of clinical proof-of-concept studies. It also identifies current gaps in our biomarker toolkit and the status of the discovery and validation of α-syn-associated biomarkers that could help fill these gaps. Further, it highlights the importance of the emerging digital technology to supplement the capture and monitoring of clinical outcomes. Although the development of disease-modifying therapies targeting α-syn face profound challenges, we remain optimistic that meaningful strides will be made soon toward the identification and approval of disease-modifying therapeutics targeting α-syn.

A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis.

Background The development of therapeutic interventions for Parkinson disease (PD) is challenged by disease complexity and subjectivity of symptom evaluation. A Parkinson's Disease Related Pattern (PDRP) of glucose metabolism via fluorodeoxyglucose positron emission tomography (FDG-PET) has been reported to correlate with motor symptom scores and may aid the detection of disease-modifying therapeutic effects. Objectives We sought to independently evaluate the potential utility of the PDRP as a biomarker for clinical trials of early-stage PD. Methods Two machine learning approaches (Scaled Subprofile Model (SSM) and NPAIRS with Canonical Variates Analysis) were performed on FDG-PET scans from 17 healthy controls (HC) and 23 PD patients. The approaches were compared regarding discrimination of HC from PD and relationship to motor symptoms. Results Both classifiers discriminated HC from PD (p, Graphical abstract Unlabelled Image, Highlights • The Parkinson's disease-related pattern (PDRP) of glucose metabolic effects is demonstrated in an independent cohort of early stage PD patients. • The PDRP pattern of metabolic changes is robust to variations in image processing and choice of classification model. • Age-related metabolic changes show partial overlap with the PDRP, suggesting that age-adjustment is an important consideration. • The PDRP correlates with motor function as defined by Hoehn & Yahr stage and UPDRS score. • An additional data driven metabolic classifier highlights pattern aspects associated with early stage motor decline.

The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. The discovery of genetic variants causing and/or increasing the risk for PD has provided the field with a new arsenal of potential therapies ready to be tested in clinical trials. We highlight 3 of the genetic discoveries (α-synuclein, glucocerebrosidase, and leucine-rich repeat kinase) that have prompted new therapeutic approaches now entering the clinical stages. We are at an exciting juncture in the journey to developing disease-modifying treatments based on knowledge of PD genetics and pathology. This review focuses on therapeutic paradigms that are under clinical development and highlights a wide range of key outstanding questions in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Carbapenem-resistant Enterobacterales (CRE) are classified as either carbapenemase-producing CRE (CP-CRE) or non-carbapenemase-producing CRE (non-CP-CRE) based on their mechanism of carbapenem resistance. Few studies have compared outcomes associated with each type of infection. We attempted to determine if either CRE subset is associated with increased mortality. We performed a retrospective observational study to collect demographic, clinical and outcomes data to compare patients with CP-CRE and non-CP-CRE bacteremia. Of 146 cases analyzed, 88/146 (60%) were CP-CRE and 58/146 (40%) were non-CP-CRE. Patients with CP-CRE bacteremia were less likely to receive active empiric or targeted antibiotic therapy. Non-CP-CRE bacteremia was associated with a 2.4 times higher hazard of death at 30 days after bacteremia onset compared to CP-CRE (HR, 2.4; 95% CI, 1.2, 4.6). Patients with non-CP-CRE bacteremia had a higher hazard of death at 30 days after bacteremia onset compared to those with CP-CRE bacteremia.

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.We assessed the prevalence of sleep disturbances and nocturnal hypokinesia in early and advanced PD and their relation to nonmotor symptoms and dopaminergic medication.A total of 305 patients with PD with diverse disease severity (Hoehn and Yahr [HY] stage 1 = 47, HY stage 2 = 181, HY 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.Nocturnal lying time was similar among all groups (healthy controls, 7.5 ± 1.2 hours; HY stage 1, 7.3 ± 0.9 hours; HY stage 2, 7.2 ± 1.3 hours; HY 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.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.

BackgroundThe Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.MethodsThis cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FindingsBetween Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on 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

Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group., The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

ObjectiveTo assess neurofilament light chain (NfL), as a biomarker for Parkinson’s disease (PD).MethodsWe quantified NfL in (1) longitudinal CSF samples from PD, other cognate/neurodegenerative disorders (OND), and healthy controls (HC); (2) a cross-sectional cohort with paired CSF and serum samples from participants with PD, OND, and HC, and (3) a large longitudinal validation cohort with serum samples from PD, OND, HC, prodromal conditions, and mutation carriers.ResultsIn the longitudinal discovery cohort (1) NfL in CSF was highest in OND and higher in PD vs. HC across all visits (p; pConclusionsNfL levels in serum samples are increased in PD vs. HC, increase significantly over time, and correlate with clinical measures of PD severity. Although the specificity of NfL in PD is low and more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and possibly assess responsiveness to neuroprotective treatments. NfL as a biomarker of response to neuroprotective interventions remains to be determined.Funding sources for studyPPMI is sponsored by the Michael J. Fox Foundation for Parkinson’s Research (MJFF) and is co-funded by MJFF, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer and UCB. The funders had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript or in the decision to submit the manuscript for publication.Financial Disclosure/Conflict of Interest concerning the research related to the manuscriptBrit Mollenhauer, Douglas Galasko, Tatiana Foroud, Lana M. Chahine, Christopher S. Coffey, Andrew B. Singleton, Tanya Simuni, Daniel Weintraub, John Seibyl, Arthur W. Toga, and Caroline M. Tanner received funding from The Michael J. Fox Foundation for Parkinson’s Research.Mohammed Dakna, Tzu-Ying Liu, Henrik Zetterberg, Sebastian Schade, Roland G. Gera, Wenting Wang, Feng Gao, Niels Kruse, Mark Frasier, Jesse M. Cedarbaum, Samantha J. Hutten, Claudia Trenkwalder, and Danielle Graham report no disclosures.

Background Carbapenem-Resistant Enterobacteriales (CRE) bacteremia is associated with significant morbidity and mortality. CRE were assigned a threat level of “urgent” in the 2019 CDC report on antibiotic resistance in the United States. We attempted to identify predictors of 30-day mortality in patients with CRE bacteremia. Methods We performed a chart review of 146 patients with CRE bacteremia from January 2010 - July 2019. CRE was defined using the current CDC definition. Electronic medical records were reviewed to obtain clinical characteristics and outcomes including prior antibiotic use, comorbidities, prior location, treatment, hospital course, microbiological data and outcomes including in-hospital mortality. Results Of 146 patients included for analysis, the overall 30-day mortality rate was 36.3%. Patients admitted from a healthcare facility including outside hospitals, rehab, nursing homes, and LTACs had a 49.1% (29/59) 30-day mortality rate compared to 27.5% (24/87) for those admitted from home (RR=1.78, 95% CI 1.16–2.73, p=.0082). Patients with a Pitt bacteremia score ≥ 4 had a greater 30-day mortality rate (42.6%, 26/61) compared to those with a Pitt bacteremia score < 4 (17.6%, 15/85) (RR=2.92, 95% CI 1.40–4.16, p=.0015). Patients that received inactive empiric therapy had a 30-day mortality rate of 36% (36/100) compared to 36.9% (17/46) in those that received active empiric therapy (RR=.9741, 95% CI .6155-1.59, p=.9109). Patients with isolates determined to have a meropenem MIC ≥ 4 had a 30-day mortality rate of 40.2% (37/92) while those with an MIC < 4 had a 30-day mortality rate of 30.2% (16/53) (RR=1.33, 95% CI .8250–2.1513, p=.2408). A pulmonary source of bacteremia was associated with an increased risk of 30-day mortality (64.3%, 9/14) compared to all other sources of bacteremia (34.8%, 31/89) (RR=1.85, 95% CI 1.39–2.99, p=.0129). No other infection source was associated with an increased 30-day mortality rate. Conclusion Admission from a healthcare facility, Pitt bacteremia score ≥ 4, and pulmonary source of bacteremia were associated with increased risk of 30-day mortality. Interestingly, administration of active empiric therapy was not associated with a decreased mortality risk. Meropenem MIC was not predictive of 30-day mortality. Disclosures All Authors: No reported disclosures

Author(s): Chahine, Lana M; Siderowf, Andrew; Barnes, Janel; Seedorff, Nicholas; Caspell-Garcia, Chelsea; Simuni, Tanya; Coffey, Christopher S; Galasko, Douglas; Mollenhauer, Brit; Arnedo, Vanessa; Daegele, Nichole; Frasier, Mark; Tanner, Caroline; Kieburtz, Karl; Marek, Kenneth; The Parkinson’s Progression Markers Initiative | Abstract: BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding.

Aggregation of α-synuclein (α-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of α-syn pathology is believed to contribute to disease progression, immunotherapy with antibodies directed against α-syn is considered a promising therapeutic approach for slowing disease progression. Here we report the identification, binding characteristics, and efficacy in PD mouse models of the human-derived α-syn antibody BIIB054, which is currently under investigation in a Phase 2 clinical trial for PD. BIIB054 was generated by screening human memory B-cell libraries from healthy elderly individuals. Epitope mapping studies conducted using peptide scanning, X-ray crystallography, and mutagenesis show that BIIB054 binds to α-syn residues 1–10. BIIB054 is highly selective for aggregated forms of α-syn with at least an 800-fold higher apparent affinity for fibrillar versus monomeric recombinant α-syn and a strong preference for human PD brain tissue. BIIB054 discriminates between monomers and oligomeric/fibrillar forms of α-syn based on high avidity for aggregates, driven by weak monovalent affinity and fast binding kinetics. In efficacy studies in three different mouse models with intracerebrally inoculated preformed α-syn fibrils, BIIB054 treatment attenuated the spreading of α-syn pathology, rescued motor impairments, and reduced the loss of dopamine transporter density in dopaminergic terminals in striatum. The preclinical data reported here provide a compelling rationale for clinical development of BIIB054 for the treatment and prevention of PD.

Digital technology is transforming the development of drugs for Alzheimer's disease and was the topic of the Alzheimer's Association's Research Roundtable on its May 23-24, 2017 meeting. Research indicates that wearable devices and unobtrusive passive sensors that enable the collection of frequent or continuous, objective, and multidimensional data during daily activities may capture subtle changes in cognition and functional capacity long before the onset of dementia. The potential to exploit these technologies to improve clinical trials as both recruitment and retention tools as well as for potential end points was discussed. The implications for the collection and use of large amounts of data, lessons learned from other related disease areas, ethical concerns raised by these new technologies, and regulatory issues were also covered in the meeting. Finally, the challenges and opportunities of these new technologies for future use were discussed.

Recent indicators point to substantial increases in the number of young heroin users across much of the United States as well as across Washington State. This study characterizes this younger generation of heroin injectors in order to inform public health responses.A cross-sectional analysis was conducted using street-intercept surveys at King County, WA syringe exchange programs in 2013. Survey responses were restricted to heroin injectors (n=389) and then categorized by the participant's age (30 and ≥30) for a descriptive epidemiological analysis. A manual stepwise logistic regression tested the independent relationship of user characteristics with being under the age of 30.In regression analyses, adjusting for other characteristics, young adults were significantly (p0.05) more likely to: re-use syringes 2-4 times (OR=2.28 compared to those who used a syringe once), share syringes (OR=2.92), report they were "hooked on" prescription-type opioids prior to using heroin (OR=2.54), have had a sexual partner in the prior year (opposite sex OR=7.37, same sex OR=23.29, both genders OR=22.04), and report powder cocaine use in the prior 3 months (OR=2.49) compared to those ages 30 and older. Young adults were significantly less likely to report using pain medicines (OR=0.33), having an abscess in the prior year (OR=0.33) or having tested positive for hepatitis C (OR=0.22) than older adults adjusting for other variables.Younger heroin injectors engage in risky injection practices more than older heroin injectors. Along with other significant differences, these findings have implications for outreach programs and medical care for younger heroin injectors.

ELND005 (scyllo-inositol), an endogenous inositol stereoisomer, is being investigated as an oral treatment for Alzheimer's disease (AD). Pharmacokinetics of ELND005 in plasma, cerebrospinal fluid (CSF), and brain was characterized in healthy young subjects. Eight men received 2000 mg ELND005 every 12 hours for 10 days. Plasma and CSF samples were collected at predetermined time points; ELND005 and amyloid-beta (Aβ) fragments were measured by validated bioanalytical methods. Brain ELND005 levels, estimated by (1) H Magnetic Resonance Spectroscopy (MRS) scans were obtained from gray/white matter voxels at baseline and Day 8. ELND005 was well-tolerated during the study. During the apparent steady state, ELND005 plasma levels rapidly peaked at 39.8 µg/mL and decreased to an average trough concentration of 10.6 µg/mL at the end of the 12-hour dosing regimen. In contrast, CSF drug levels slowly peaked at 13.7 µg/mL and remained near the same level with average trough concentrations of 12.4 µg/mL. At Day 8, Brain ELND005 concentrations increased by 58-76% compared to baseline levels. The CSF concentrations achieved in this study were similar to those associated with efficacy in transgenic models of AD. No changes were detected in plasma and CSF levels of Aβ fragments.

An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer's disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit.

To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD).In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg. The primary end point was the change from baseline in central retinal/lesion thickness (CR/LT) at week-8. Secondary outcomes were the change from baseline BCVA, the change in CNV lesion size and area of leakage, and proportion of patients requiring repeat injection at 8 weeks.Mean percent decrease in CR/LT for the 4-mg and 0.15-mg groups was, respectively, 34.2 versus 13.3 at week 4 (P=0.0065), 23.8 versus 5.9 at week 6 (P=0.0380), and 25.2% versus 11.3% at week 8 (P=0.150). The 4-mg group gained a mean of 4.5 letters in BCVA (6/14 patients gaining ≥10 letters) versus 1.1 letters in 0.15-mg group (1/14 gaining ≥10 letters) at week 8. Fewer patients needed retreatment in the 4-mg group at week 8. No serious adverse event or ocular inflammation was reported in either group.Intravitreal aflibercept 4 mg had a safety profile similar to that of the very low dose 0.15 mg, and was well-tolerated. The 4-mg dose significantly reduced foveal thickening at weeks 4 and 6, significantly improved BCVA at weeks 6, and reduced the need for repeat injection after 8 weeks compared with intravitreal aflibercept 0.15 mg in neovascular AMD patients.

This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted.

Background The purpose of conducting this study was to identify areas of concordance and sources of variation for the published rates of prevalence and incidence associated with various definitions for mild cognitive impairment (MCI). Methods The study used systematic review of studies published in English since 1984. Studies were identified by searching MEDLINE and EMBASE databases. Population-based observational studies of incidence or prevalence of MCI and related terms were eligible for inclusion. Results A total of 3,705 citations were identified, and 42 were accepted for inclusion; 35 included data on prevalence and 13 on incidence. The following four terms predominated: age-associated memory impairment (AAMI); cognitive impairment no dementia (CIND); MCI; and amnestic MCI (aMCI). Within each term, the operational definition varied. Substantial variation was observed for both incidence (MCI: 21.5–71.3; aMCI: 8.5–25.9 per 1,000 person-years) and prevalence of each definition of cognitive impairment (AAMI 3.6%–38.4%; CIND 5.1%–35.9%; MCI 3%–42%; aMCI 0.5%–31.9%). CIND and MCI showed increasing prevalence among older age groups, whereas age-specific rates of aMCI were lower and without any apparent age relationship. Conclusions Prevalence and incidence estimates associated with MCI vary greatly both between definitions and within a definition across the 42 publications. These wide differences pose a significant challenge to our understanding of the social burden of this disease. Enhancement and standardization of operational definitions of the subtypes of cognitive impairment could improve estimates of disease burden and provide a mechanism to assist in the identification of individuals at risk for future Alzheimer's disease and other dementias.

Objective: This randomized, double-blind, placebo-controlled, dose-ranging phase 2 study explored safety, efficacy, and biomarker effects of ELND005 (an oral amyloid anti-aggregation agent) in mild to moderate Alzheimer disease (AD). Methods: A total of 353 patients were randomized to ELND005 (250, 1,000, or 2,000 mg) or placebo twice daily for 78 weeks. Coprimary endpoints were the Neuropsychological Test Battery (NTB) and Alzheimer9s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale. The primary analysis compared 250 mg (n =84) to placebo (n =82) after an imbalance of infections and deaths led to early discontinuation of the 2 higher dose groups. Results: The 250 mg dose demonstrated acceptable safety. The primary efficacy analysis at 78 weeks revealed no significant differences between the treatment groups on the NTB or ADCS-ADL. Brain ventricular volume showed a small but significant increase in the overall 250 mg group ( p =0.049). At the 250 mg dose, scyllo-inositol concentrations increased in CSF and brain and CSF Aβx-42 was decreased significantly compared to placebo ( p =0.009). Conclusions: Primary clinical efficacy outcomes were not significant. The safety and CSF biomarker results will guide selection of the optimal dose for future studies, which will target earlier stages of AD. Classification of evidence: Due to the small sample sizes, this Class II trial provides insufficient evidence to support or refute a benefit of ELND005.

Neuropsychiatric symptoms (NPS) are core features of Alzheimer's disease and related dementias. Once thought to emerge primarily in people with late-stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia-associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimer's Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimer's disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics.

Non-technical summary It is not well understood how all of the connections among neurons required for the brain to process information are established during development. It has recently become apparent that waves of spontaneous electrical activity spread across large groups of neurons during early brain development and that these waves of activity are crucial for correct development of brain circuitry. In this paper, we show that waves of spontaneous electrical activity propagate across the mouse cerebral cortex, beginning on the day before birth and continuing through the first 12 postnatal days. These waves are initiated at specific locations in the cortex, which do not change during the period of wave generation. Identity of the neurons that initiate the waves, however, does change during this time. This work indicates that even though spontaneous electrical activity occurs during a short contiguous period of development, the mechanisms underlying that activity change. Abstract Waves of spontaneous electrical activity propagate across many regions of the central nervous system during specific stages of early development. The patterns of wave propagation are critical in the activation of many activity-dependent developmental programs. It is not known how the mechanisms that initiate and propagate spontaneous waves operate during periods in which major changes in neuronal structure and function are taking place. We have recently reported that spontaneous waves of activity propagate across the neonatal mouse cerebral cortex and that these waves are initiated at pacemaker sites in the septal nucleus and ventral cortex. Here we show that spontaneous waves occur between embryonic day 18 (E18) and postnatal day 12 (P12), and that during that period they undergo major changes in transmitter dependence and propagation patterns. At early stages, spontaneous waves are largely GABA dependent and are mostly confined to the septum and ventral cortex. As development proceeds, wave initiation depends increasingly on AMPA-type glutamate receptors, and an ever increasing fraction of waves propagate into the dorsal cortex. The initiation sites and restricted propagation of waves at early stages are highly correlated with the position of GABAergic neurons in the cortex. The later switch to a glutamate-based mechanism allows propagation of waves into the dorsal cortex, and appears to be a compensatory mechanism that ensures continued wave generation even as GABA transmission becomes inhibitory.

Spontaneous waves of activity that propagate across large structures during specific developmental stages play central roles in CNS development. To understand the genesis and functions of these waves, it is critical to understand the spatial and temporal patterns of their propagation. We recently reported that spontaneous waves in the neonatal cerebral cortex originate from a ventrolateral pacemaker region. We have now analyzed a large number of spontaneous waves using calcium imaging over the entire area of coronal slices from E18-P1 mouse brains. In all waves, the first cortical region active is this ventrolateral pacemaker. In half of the waves, however, the cortical pacemaker activity is itself triggered by preceding activity in the septal nuclei. Most waves are restricted to the septum and/or ventral cortex, with only some invading the dorsal cortex or the contralateral hemisphere. Waves fail to propagate at very stereotyped locations at the boundary between ventral and dorsal cortex and at the dorsal midline. Waves that cross these boundaries pause at these same locations. Waves at these stages are blocked by both picrotoxin and CNQX, indicating that both GABAA and AMPA receptors are involved in spontaneous activity. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 679–692, 2010