Diane D. Murphy

Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment.

Background: Current therapies for PD ameliorate symptoms in the early phases of disease but become less effective over time, as the underlying disease progresses. Therapies that slow the progression of PD are needed. However, there have been relatively few clinical trials aimed at demonstrating neuroprotection. The authors sought to identify potential neuroprotective agents for testing in clinical trials. Methods: First a broad array of compounds were identified by working with clinicians and researchers in academics and industry. Specific criteria were drafted for drug evaluation, including scientific rationale, blood–brain barrier penetration, safety and tolerability, and evidence of efficacy in animal models or humans. Agents were prioritized based on these criteria. Results: The authors identified 59 potential neuroprotective compounds, proposed by 42 clinicians and scientists from 13 countries. After systematic reviews using the specified criteria they found 12 compounds to be attractive candidates for further clinical trials in PD. Conclusions: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in PD.

Diagnostic criteria for psychosis in Parkinson's disease: Report of an NINDS, NIMH work group

There are no standardized diagnostic criteria for psychosis associated with Parkinsons disease (PDPsy). As part of an NIH sponsored workshop, we reviewed the existing literature on PDPsy to provide criteria that distinguish PDPsy from other causes of psychosis. Based on these data, we propose provisional criteria for PDPsy in the style of the Diagnostic and Statistical Manual of Mental Disorders IV‐TR. PDPsy has a well‐characterized temporal and clinical profile of hallucinations and delusions, which is different than the pattern seen in other psychotic disorders such as substance induced psychosis or schizophrenia. PDPsy is associated with a poor prognosis of chronic psychosis, nursing home placement, and death. Medications used to treat Parkinsons disease (PD) contribute to PDPsy but may not be sufficient or necessary contributors to PDPsy. PDPsy is associated with Lewy bodies pathology, imbalances of monoaminergic neurotransmitters, and visuospatial processing deficits. These findings suggest that PDPsy may result from progression of the disease process underlying PD, rather than a comorbid psychiatric disorder or drug intoxication. PDPsy is not adequately described by existing criteria for psychotic disorders. We established provisional diagnostic criteria that define a constellation of clinical features not shared by other psychotic syndromes. The criteria are inclusive and contain descriptions of the full range of characteristic symptoms, chronology of onset, duration of symptoms, exclusionary diagnoses, and associated features such as dementia. These criteria require validation and may be refined, but form a starting point for studies of the epidemiology and pathophysiology of PDPsy, and are a potential indication for therapy development.

Provisional diagnostic criteria for depression in Parkinson's disease: Report of an NINDS/NIMH Work Group

Mood disorders are the most common psychiatric problem associated with Parkinsons disease (PD), and have a negative impact on disability and quality of life. Accurate diagnosis of depressive disturbances in PD is critical and will facilitate the testing and use of new interventions; however, there are no clear diagnostic criteria for depressive disorders in PD. In their current form, strict Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are difficult to use in PD and require attribution of specific symptoms to PD itself or the depressive syndrome. Additionally, DSM criteria for major depression and dysthymia exclude perhaps half of PD patients with comorbid clinically significant depression. This review summarizes an NIH‐sponsored workshop and describes recommended changes to DSM diagnostic criteria for depression for use in PD. Participants also recommended: (1) an inclusive approach to symptom assessment to enhance reliability of ratings in PD and avoid the need to attribute symptoms to a particular cause; (2) the inclusion of subsyndromal depression in clinical research studies of depression of PD; (3) the specification of timing of assessments for PD patients with motor fluctuations; and (4) the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and intended to be defined further and validated but provide a common starting point for clinical research in PD‐associated depression.

Metal-catalyzed Oxidation of α-Synuclein HELPING TO DEFINE THE RELATIONSHIP BETWEEN OLIGOMERS, PROTOFIBRILS, AND FILAMENTS

Oxidative stress is implicated in a number of neuro-degenerative diseases and is associated with the selective loss of dopaminergic neurons of the substantia nigra in Parkinsons disease. The role of α-synuclein as a potential target of intracellular oxidants has been demonstrated by the identification of posttranslational modifications of synuclein within intracellular aggregates that accumulate in Parkinsons disease brains, as well as the ability of a number of oxidative insults to induce synuclein oligomerization. The relationship between these relatively small soluble oligomers, potentially neurotoxic synuclein protofibrils, and synuclein filaments remains unclear. We have found that metal-catalyzed oxidation of α-synuclein inhibited formation of synuclein filaments with a concomitant accumulation of β sheet-rich oligomers that may represent synuclein protofibrils. Similar results with a number of oxidative and enzymatic treatments suggest that the covalent association of synuclein into higher molecular mass oligomers/protofibrils represents an alternate pathway from filament formation and renders synuclein less prone to proteasomal degradation.

Degradative organelles containing mislocalized α- and β-synuclein proliferate in presenilin-1 null neurons

Presenilin-1 null mutation (PS1 −/−) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins. Stimulation of autophagy in control neurons produced a similar mislocalization of synucleins as genetic ablation of PS1. These effects were not the result of the loss of PS1 γ-secretase activity; however, dysregulation of calcium channels in PS1 −/− cells may be involved. Finally, colocalization of α-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD. Thus, aberrant accumulation of α- and β-synuclein in degradative organelles are novel features of PS1 −/− neurons, and similar events may promote the formation of α-synuclein inclusions associated with neurodegenerative diseases.

CREB Activation Mediates Plasticity in Cultured Hippocampal Neurons

Activation of cyclic AMP dependent kinase is believed to mediate slow onset, long-term potentiation (LTP) in central neurons. Cyclic- AMP activates a cascade of molecular events leading to phosphorylation of the nuclear cAMP responsive element binding protein (pCREB). Whereas a variety of stimuli lead to activation of CREB, the molecular processes downstream of CREB, which may be relevant to neuronal plasticity, are yet largely unknown. We have recently found that following exposure to estradiol, pCREB mediates the large increase in dendritic spine density in cultured rat hippocampal neurons. We now extend these observations to include other stimuli, such as bicuculline, that cause the formation of new dendritic spines. Such stimuli share with estradiol the same mechanism of action in that both require activity-dependent CREB phosphorylation. Our observations suggest that CREB phosphorylation is a necessary, but perhaps not sufficient, step in the process leading to the generation of new dendritic spines and perhaps to functional plasticity as well.

New directions for frontotemporal dementia drug discovery

This report summarizes the recommendations of the Frontotemporal Dementia (FTD) Working Group on FTD Drug Discovery that was part of an international FTD Workshop held on January 18 and 19, 2007, in Miami, Florida. The workshop was sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA) of the National Institutes of Health (NIH) and the Association for Frontotemporal Dementia (AFTD) with the express purpose of defining opportunities to improve the diagnosis and treatment of patients affected by a neurodegenerative disorder classified as one of the many variants of FTD. The recognition that almost all forms of FTD are due to TDP‐43 proteinopathies and tauopathies creates new opportunities for FTD drug discovery targeting pathways of TDP‐43 and tau‐mediated neurodegeneration.

The cell biology of α-synuclein

Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, marked by chronic progressive loss of neurons in the substantia nigra, thereby damaging purposeful control of movement. For decades, it was believed that PD was caused solely by environmental causes. However, the discovery of genetic factors involved in PD has revolutionized our attempts to understand the disease’s pathology. PD now appears to be more polygenetic than previously thought and is most likely caused by a complex interaction of genetic risks and environmental exposures. The first gene found to be mutated in PD encodes for the presynaptic protein α-synuclein, which is also a major component of Lewy bodies and Lewy neurites, the neuropathological hallmarks of the disease. While these findings provide a classic example of how rare genetic mutations in disease can point to important pathways in idiopathic disease pathologies, much of the study of α-synuclein has focused on understanding how this protein undergoes the transition from an unfolded monomer to amorphous aggregates or Lewy body-like filaments rather than addressing what its fundamental function might be. Since alterations in synuclein function may predispose to the disease pathology of PD, regardless of the presence of genetic mutations, a more thorough understanding of the cellular regulation and function of α-synuclein may be of crucial importance to our understanding of this degenerating disorder.

Culture models for the study of estradiol-induced synaptic plasticity.

Estrogen, which classically affects areas of the brain related to reproduction, has also been found to affect brain regions important in learning and memory. Additionally, it has been suggested that estrogen exerts protective effects against neurodegenerative diseases such as Alzheimers disease. Important mechanisms by which estrogen may confer protection are through the maintenance or modulation of existing synapses, or by the production of new ones. It has now been demonstrated that estrogen can increase synaptogenesis and spine production in the hippocampus, both in vivo as well as in primary hippocampal neurons in culture. The latter model system is the primary focus of this review. Synaptogenesis and spine production have been well characterized in developing and adult animals, and parallels between the synaptic morphology reflecting these processes can be readily observed in high-density primary hippocampal cultures. Moreover, in culture, estrogen induces a variety of ultrastructural modifications, many of which occur in vivo, that have been linked to various in vivo models of learning and memory. For these reasons, high-density hippocampal culture systems should be regarded as valuable tools with which to predict in vivo physiology, and may well be particularly useful for studies of the neuroprotective effects of estrogen.

Brain banking for neurodegenerative diseases.

Purpose of review Brain banking remains a necessity for the study of neurodegenerative diseases. While the characterization of pathology observed at autopsy confirms clinical diagnosis, the structure and contents of pathological hallmarks are the starting point from which disease pathogenesis may be elucidated. Traditional neuropathology has served to define, characterize, and diagnose neurodegenerative diseases, accompanied by clinical presentation. The pathological substrates are then studied for their role in how they cause dysfunction in disease, or how their accumulation is presumably damaging. Recent findings New genetic findings have revolutionized these studies and have prompted a reexamination of traditional pathological definitions of disease. Many familial genetic mutations have been found, encoding proteins such as synuclein, parkin, tau, and others, creating genetic ways to define neurodegenerative diseases. Many of these proteins are components of aggregates, thus the ability to label these proteins has revealed new pathological characteristics that must be standardized. More complicating is that many proteins genetically linked to clinically distinct diseases are involved in overlapping neuropathology of what now appears to be a spectrum of diseases: ‘synucleinopathies’, ‘tauopathies’, and so on. Moreover, as genetic discoveries fuel molecular experiments on brain tissue, banking methods must now accommodate these techniques. Lastly, DNA screening involves ethical issues beyond those which were previously considered with postmortem tissue banking. Summary As more proteins are linked to disease, more is revealed about the underlying causative mechanisms, exposing points for interventions. To achieve this end, characterization for neurodegenerative disease in the post genomic era must include genotype, phenotype and clinical characterization, and postmortem brain banking data which includes these.