The APP intracellular domain promotes LRRK2 expression to enable feed-forward neurodegenerative mechanisms in Parkinson's disease.

Gain-of-function mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are common in familial forms of Parkinson's disease (PD), which is characterized by progressive neurodegeneration that impairs motor and cognitive function. We previously demonstrated that LRRK2-mediated phosphorylation of ß-amyloid precursor protein (APP) triggers the production and nuclear translocation of the APP intracellular domain (AICD). Here, we connected LRRK2 to AICD in a feed-forward cycle that enhanced LRRK2-mediated neurotoxicity. In cooperation with the transcription factor FOXO3a, AICD promoted LRRK2 expression, thus increasing the abundance of LRRK2 that promotes AICD activation. APP deficiency in LRRK2G2019S mice suppressed LRRK2 expression, LRRK2-mediated mitochondrial dysfunction, α-synuclein accumulation, and tyrosine hydroxylase (TH) loss in the brain, phenotypes associated with toxicity and loss of dopaminergic neurons in PD. Conversely, AICD overexpression increased LRRK2 expression and LRRK2-mediated neurotoxicity in LRRK2G2019S mice. In LRRK2G2019S mice or cultured dopaminergic neurons from LRRK2G2019S patients, treatment with itanapraced reduced LRRK2 expression and was neuroprotective. Itanapraced showed similar effects in a neurotoxin-induced PD mouse model, suggesting that inhibiting the AICD may also have therapeutic benefits in idiopathic PD. Our findings reveal a therapeutically targetable, feed-forward mechanism through which AICD promotes LRRK2-mediated neurotoxicity in PD.

Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer's disease.

To date, the development of disease-modifying therapies for Alzheimer's disease (AD) has largely focused on the removal of amyloid beta Aß fragments from the CNS. Proteomic profiling of patient fluids may help identify novel therapeutic targets and biomarkers associated with AD pathology. Here, we applied the Olink™ ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 Aß- negative cognitively normal individuals (Aß- CN), 142 Aß-positive CN (Aß+ CN), 50 Aß- mild cognitive impairment (MCI) patients, 75 Aß+ MCI patients, and 161 Aß+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 Aß- CN, 23 Aß- + CN, 44 Aß- MCI and 53 Aß+ MCI. To compare protein concentrations in patients versus controls, we applied multiple linear regressions adjusting for age, gender, medications, smoking and mean subject-level protein concentration, and corrected findings for false discovery rate (FDR, q < 0.05). We identified, and replicated, altered levels of ten CSF proteins in Aß+ individuals, including CHIT1, SMOC2, MMP-10, LDLR, CD200, EIF4EBP1, ALCAM, RGMB, tPA and STAMBP (- 0.14 < d < 1.16; q < 0.05). We also identified and replicated alterations of six plasma proteins in Aß+ individuals OSM, MMP-9, HAGH, CD200, AXIN1, and uPA (- 0.77 < d < 1.28; q < 0.05). Multiple analytes associated with cognitive performance and cortical thickness (q < 0.05). Plasma biomarkers could distinguish AD dementia (AUC = 0.94, 95% CI = 0.87-0.98) and prodromal AD (AUC = 0.78, 95% CI = 0.68-0.87) from CN. These findings reemphasize the contributions of immune markers, phospholipids, angiogenic proteins and other biomarkers downstream of, and potentially orthogonal to, Aß- and tau in AD, and identify candidate biomarkers for earlier detection of neurodegeneration.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects.

PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which is a key aspartyl protease in the generation of amyloid-ß (Aß) peptides, thought to be critical for the cerebral degeneration observed in Alzheimer's disease. Two Phase I studies (NCT02509117, NCT02793232) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well tolerated at all doses given, and all treatment-related adverse events (AEs) were mild to moderate. PK parameters remained consistent across the PF-06751979 QD dosing regimens, and no notable food effects were observed. PD analysis showed that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Aß peptides in a dose-dependent manner, with the greatest reductions observed in subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF Aß1-40 and Aß1-42 observed at 24 h after Day 14 dose, respectively). A drug interaction study (NCT03126721) using midazolam indicated that there was no clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK of single-dose midazolam in healthy adults. Overall, these data suggest that PF-06751979 with daily dosing is favorable for further clinical development.

The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease: Perspectives from the Research Roundtable.

The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the "A, T, N System" (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Safety, Pharmacokinetics, and Biomarker Results of Subcutaneous Bapineuzumab in Patients with mild to moderate Alzheimer's disease.

BACKGROUND: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-ß (Aß1-40/1 -42) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD). OBJECTIVES: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated. METHODS: In this multicenter, double-blind study, 146 patients were randomized (1 : 1:1 : 1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET). RESULTS: Florbetapir PET SUVR decreased significantly (p = 0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups. CONCLUSION: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.

The roles of inflammation and immune mechanisms in Alzheimer's disease.

The Alzheimer's Association's Research roundtable met in April 2015 to explore the role of neuroinflammatory mechanisms in the progression of Alzheimer's disease (AD). The ability of innate immune cells, particularly microglia and astrocytes, to mediate neuroinflammation in AD has been implicated as a significant contributor to disease pathogenesis. Adaptive immunity, which plays an important role in responding to injury and some diseases of the central nervous system, may contribute to neuroinflammation in AD as well. Communication between the central and peripheral immune systems may also be important in AD. An increased understanding of the physiology of the innate immune system may aid the identification of new therapeutic targets or mechanisms. The development of predictive animal models and translatable neuroinflammation biomarkers for AD would also facilitate the advancement of novel treatments for innate immunity. Important challenges impeding the advancement of new therapeutic agents and strategies to overcome them were discussed.

Amyloid-ß 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials.

OBJECTIVE: To evaluate the effects of bapineuzumab on brain ß-amyloid (Aß) burden using (11)C-Pittsburgh compound B ((11)C-PiB)-PET. METHODS: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aß monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aß over 71 weeks using an (11)C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. RESULTS: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in (11)C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = -0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = -0.068; p = 0.027; 1.0 mg/kg vs placebo δ = -0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results. CONCLUSIONS: The (11)C-PiB-PET imaging results demonstrated reduction of fibrillar Aß accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aß species were inadequately targeted.

An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-ß concentrations collected by lumbar puncture and indwelling lumbar catheter.

INTRODUCTION: Amyloid-ß (Aß) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aß fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aß variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aß concentrations over time. METHODS: Grouped analysis of CSF Aß levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aß concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aß40 and Aß42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aß concentrations over time. RESULTS: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aß40 and Aß42 as well as an Aß diurnal pattern in all of the sponsors' studies. In contrast, Aß concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aß40 and Aß42 concentrations during the first 6 hours of collection. CONCLUSIONS: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aß levels and keeping the frequency standardized between experimental groups. The Aß diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Aß concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aß over 24-48 hours, but factors affecting Aß concentration such as linear rise and diurnal variation need to be accounted for in planning study designs.

The influence of biological and technical factors on quantitative analysis of amyloid PET: Points to consider and recommendations for controlling variability in longitudinal data.

In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimer's and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course.

Depression in older patients with neurologic illness: causes, recognition, management.

Depression is common in the elderly, particularly in older persons with neurologic illness. Its etiology in this population is incompletely understood and likely to be multifactorial. Identifying depression in elderly patients with neurologic illness can be a challenge, as many of its features resemble symptoms of the underlying neurologic disease or of the aging process itself. Nevertheless, recognition and effective management of depression in this population is vital, since depression is a major source of excess morbidity and since treatment often results in improved quality of life for patients and their caregivers. Assessing for suidicality is a key diagnostic consideration in this population. Antidepressant medications, psychotherapy, and electroconvulsive therapy all can be effective in treating depression in elderly neurologic patients.

Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS).

CONTEXT: Goal-directed delivery of sedative and analgesic medications is recommended as standard care in intensive care units (ICUs) because of the impact these medications have on ventilator weaning and ICU length of stay, but few of the available sedation scales have been appropriately tested for reliability and validity. OBJECTIVE: To test the reliability and validity of the Richmond Agitation-Sedation Scale (RASS). DESIGN: Prospective cohort study. SETTING: Adult medical and coronary ICUs of a university-based medical center. PARTICIPANTS: Thirty-eight medical ICU patients enrolled for reliability testing (46% receiving mechanical ventilation) from July 21, 1999, to September 7, 1999, and an independent cohort of 275 patients receiving mechanical ventilation were enrolled for validity testing from February 1, 2000, to May 3, 2001. MAIN OUTCOME MEASURES: Interrater reliability of the RASS, Glasgow Coma Scale (GCS), and Ramsay Scale (RS); validity of the RASS correlated with reference standard ratings, assessments of content of consciousness, GCS scores, doses of sedatives and analgesics, and bispectral electroencephalography. RESULTS: In 290-paired observations by nurses, results of both the RASS and RS demonstrated excellent interrater reliability (weighted kappa, 0.91 and 0.94, respectively), which were both superior to the GCS (weighted kappa, 0.64; P<.001 for both comparisons). Criterion validity was tested in 411-paired observations in the first 96 patients of the validation cohort, in whom the RASS showed significant differences between levels of consciousness (P<.001 for all) and correctly identified fluctuations within patients over time (P<.001). In addition, 5 methods were used to test the construct validity of the RASS, including correlation with an attention screening examination (r = 0.78, P<.001), GCS scores (r = 0.91, P<.001), quantity of different psychoactive medication dosages 8 hours prior to assessment (eg, lorazepam: r = - 0.31, P<.001), successful extubation (P =.07), and bispectral electroencephalography (r = 0.63, P<.001). Face validity was demonstrated via a survey of 26 critical care nurses, which the results showed that 92% agreed or strongly agreed with the RASS scoring scheme, and 81% agreed or strongly agreed that the instrument provided a consensus for goal-directed delivery of medications. CONCLUSIONS: The RASS demonstrated excellent interrater reliability and criterion, construct, and face validity. This is the first sedation scale to be validated for its ability to detect changes in sedation status over consecutive days of ICU care, against constructs of level of consciousness and delirium, and correlated with the administered dose of sedative and analgesic medications.