Autologous vs heterologous cell replacement strategies for Parkinson disease and other neurologic diseases.

Successful cell replacement strategies for brain repair depend on graft integration into the neural network, which is affected by the immune response to the grafted cells. Using Parkinson disease as an example, in this chapter, we consider the immune system interaction and its role in autologous vs heterologous graft survival and integration, as well as past and emerging strategies to overcome the immunologic response. We also reflect on the role of nonhuman primate research to assess novel approaches and consider the role of different stakeholders on advancing the most promising new approaches into the clinic.

Nigrostriatal tau pathology in parkinsonism and Parkinson's disease.

While Parkinson's disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinson's Disease Rating Scale III but were insufficient in degree to diagnose Parkinson's disease.

TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells.

Seeking progress in disease modification in Parkinson disease.

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.

Plasma Sphingomyelins in Late-Onset Alzheimer's Disease.

Background: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been found in mouse models of Alzheimer's disease (AD) and in AD patient plasma samples.

Objective: This study assesses fourteen plasma SM species in a late-onset AD (LOAD) patient cohort (n = 138).

Methods: Specimens from control, preclinical, and symptomatic subjects were analyzed using targeted mass-spectrometry-based metabolomic methods.

Author Correction: Plasma microRNA markers of upper limb recovery following human stroke.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effect of early-stage Alzheimer's disease on household financial outcomes.

Significant limitations and rapid declines in financial capacity are a hallmark of patients with early-stage Alzheimer's disease (AD). We use linked Health and Retirement Study and Medicare claims data spanning 1992-2014 to examine the effect of early-stage AD, from the start of first symptoms to diagnosis, on household financial outcomes. We estimate household fixed-effects models and examine continuous measures of liquid assets and net wealth, as well as dichotomous indicators for a large change in either outcome.

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease.

Objective: To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients.

Methods: Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 μL/hemisphere) at escalating doses: 9 × 10 vg (n = 6); 3 × 10 vg (n = 6); and 9 × 10 vg (n = 1). Intraoperative MRI monitored infusion distribution.

Fetal Bovine Serum-Derived Extracellular Vesicles Persist within Vesicle-Depleted Culture Media.

It is known that culture media (CM) promotes cellular growth, adhesion, and protects explanted primary brain cells from in vitro stresses. The fetal bovine serum (FBS) supplement used in most CM, however, contains significant quantities of extracellular vesicles (EVs) that confound quantitative and qualitative analyses from the EVs produced by the cultured cells. We quantitatively tested the ability of common FBS EV-depletion protocols to remove exogenous EVs from FBS-supplemented CM and evaluated the influence such methods have on primary astrocyte culture growth and viability.

Plasma metabolomic biomarkers accurately classify acute mild traumatic brain injury from controls.

Past and recent attempts at devising objective biomarkers for traumatic brain injury (TBI) in both blood and cerebrospinal fluid have focused on abundance measures of time-dependent proteins. Similar independent determinants would be most welcome in diagnosing the most common form of TBI, mild TBI (mTBI), which remains difficult to define and confirm based solely on clinical criteria. There are currently no consensus diagnostic measures that objectively define individuals as having sustained an acute mTBI.

Precision pharmacology for Alzheimer's disease.

The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment.

Systems healthcare: a holistic paradigm for tomorrow.

Systems healthcare is a holistic approach to health premised on systems biology and medicine. The approach integrates data from molecules, cells, organs, the individual, families, communities, and the natural and man-made environment. Both extrinsic and intrinsic influences constantly challenge the biological networks associated with wellness.

Metabolomic biomarkers of pancreatic cancer: a meta-analysis study.

Pancreatic cancer (PC) is an aggressive disease with high mortality rates, however, there is no blood test for early detection and diagnosis of this disease. Several research groups have reported on metabolomics based clinical investigations to identify biomarkers of PC, however there is a lack of a centralized metabolite biomarker repository that can be used for meta-analysis and biomarker validation. Furthermore, since the incidence of PC is associated with metabolic syndrome and Type 2 diabetes mellitus (T2DM), there is a need to uncouple these common metabolic dysregulations that may otherwise diminish the clinical utility of metabolomic biosignatures.

Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson's Disease.

Parkinson's disease (PD) is a chronic and progressive disorder characterized neuropathologically by loss of dopamine neurons in the substantia nigra, intracellular proteinaceous inclusions, reduction of dopaminergic terminals in the striatum, and increased neuroinflammatory cells. The consequent reduction of dopamine in the basal ganglia results in the classical parkinsonian motor phenotype. A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in PD pathogenesis.

Personality and Performance in Specific Neurocognitive Domains Among Older Persons.

Objective: Certain Big 5 personality dimensions have been repeatedly linked to global measures of cognitive function and outcome categories. We examined whether the Big 5 or their specific components showed differential evidence of associations with specific neurocognitive domains.

Methods: Participants were 179 older adults (70+) from a broader study on cognitive aging.

What success can teach us about failure: the plasma metabolome of older adults with superior memory and lessons for Alzheimer's disease.

As the world population ages, primary prevention of age-related cognitive decline and disability will become increasingly important. Prevention strategies are often developed from an understanding of disease pathobiology, but models of biological success may provide additional useful insights. Here, we studied 224 older adults, some with superior memory performance (n = 41), some with normal memory performance (n = 109), and some with mild cognitive impairment or Alzheimer's disease (AD; n = 74) to understand metabolomic differences which might inform future interventions to promote cognitive health.