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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.

We describe evidence supporting the hypothesis that α-synuclein has a prion-like role in Parkinson's disease and related α-synucleinopathies, and discuss how this novel thinking impacts the development of diagnostics and disease-modifying therapies.Observations that immature dopamine neurons grafted to Parkinson's disease patients can develop Lewy bodies triggered a surge of interest in the putative prion-like properties of α-synuclein. We recount results from experiments which confirm that misfolded α-synuclein can exhibit disease-propagating properties, and describe how they relate to the spreading of α-synuclein aggregates in α-synucleinopathies. We share insights into the underlying molecular mechanisms and their relevance to novel therapeutic targets. Finally, we discuss what the initial triggers of α-synuclein misfolding might be, where in the body the misfolding events might take place, and how this can instruct development of novel diagnostic tools. We speculate that differences in anatomical trigger sites and variability in α-synuclein fibril structure can contribute to clinical differences between α-synucleinopathies.The realization that α-synuclein pathology can propagate between brain regions in neurodegenerative diseases has deepened and expanded our understanding of potential pathogenic processes which can lead to the development of novel diagnostic tools as well as the identification of new therapeutic targets.

Numerous pathologic amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression in a prion-like fashion. Understanding the mechanism by which amyloid assemblies enter target cells and induce dysfunction is therefore key to understanding the progressive nature of diseases like Alzheimer's, Parkinson's, Huntington's, and chronic traumatic encephalopathy. In this study, we utilized an imaging-based assay to monitor the ability of amyloid assemblies to induce the rupture of intracellular vesicles following endocytosis, as well as to elucidate the cellular consequences of this damaging mechanism of invasion. We observe that induction of vesicle rupture is a conserved ability of fibrillar amyloid assemblies of alpha-synuclein, tau, and polyglutamine-rich huntingtin. Endocytic vesicle rupture potency is strongly influenced by strain conformation and is increased by assembly phosphorylation. Vesicles ruptured by alpha-synuclein can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro, and the same markers of vesicle rupture surround Lewy bodies in brain sections from Parkinson's patients. Finally, ruptured vesicles containing alpha-synuclein can be observed in the extracellular environment and can be seen trafficking from cell to cell. These data underscore the importance of endocytic vesicle rupture as a conserved mechanism of cellular invasion by multiple disease-associated amyloid protein assemblies, implicate this process in the formation of proteinaceous inclusions such as Lewy bodies, and suggest that this form of cellular damage can serve as both a driving force and a vector for amyloid protein release and subsequent transmission to neighboring cells.

HIV-1 proteins, including the transactivator of transcription (Tat), are believed to be involved in HIV-associated neurocognitive disorders by disrupting Ca²⁺ homeostasis, which leads to progressive dysregulation, damage, or death of neurons in the brain. We have found previously that bath-applied Tat abnormally increased Ca²⁺ influx through overactivated, voltage-sensitive L-type Ca²⁺ channels in pyramidal neurons within the rat medial prefrontal cortex (mPFC). However, it is unknown whether the Tat-induced Ca²⁺ dysregulation was mediated by increased activity and/or the number of the L-channels. This study tested the hypothesis that transient/early exposure to Tat in vivo promoted enduring L-channel dysregulation in the mPFC without neuron loss. Accordingly, rats were administered a single intracerebroventricular injection of recombinant Tat (80 μg/20 μl; diluted by cerebrospinal fluids to pathophysiological concentrations) or vehicle. Rats were killed 14 days after injection for immunohistochemical assessments of the mPFC, motor cortex, caudate-putamen, and nucleus accumbens. Stereological estimates for positively stained cells indicated a significant increase in the number of cells expressing the pore-forming Ca(v)1.2-α1c subunit of L-channels in the mPFC compared with other regions in Tat-treated or vehicle-treated rat brains. Optical density measurements showed a Tat-induced increase in glial fibrillary acidic protein expression, indicating astrogliosis in the cortical regions. There was no significant loss of neurons in any brain region investigated. These findings indicate that transient Tat exposure in vivo induced enduring L-channel dysregulation and astrogliosis in the mPFC without neuron loss. Such maladaptations may contribute toward dysregulated Ca²⁺ homeostasis and neuropathology in the PFC in the early stages of HIV infection.

OBJECTIVE: Parkinson's disease is characterized by profound motor deficits that result mainly as a consequence of degeneration of midbrain dopaminergic neurons. No current therapy slows or halts disease progression. Neurturin (NTN) and glial cell line-derived neurotrophic factor have potent neuroprotective and neurorestorative effects on dopaminergic neurons, but their use in treating Parkinson's disease has been limited by significant delivery obstacles. In this study, we examined the long-term expression, bioactivity, and safety/tolerability of CERE-120, an adeno-associated virus type 2 vector encoding human NTN, after bilateral stereotactic delivery to the striatum of nonhuman primates. METHODS: Twelve naive rhesus macaques received bilateral stereotactic injections of 1 of 2 CERE-120 doses or vehicle to the caudate and putamen. Neurological and clinical parameters were monitored for up to 1 year postadministration, after which animals were sacrificed for histological analyses. RESULTS: Dose-related NTN expression was observed at 1 year and was associated with enhanced tyrosine hydroxylase immunolabeling in the striatum, hypertrophy of tyrosine hydroxylase-positive cells in the substantia nigra, and induction of extracellular signal-regulated kinase signaling in the substantia nigra. Extensive, formal analyses, conducted in accordance with Good Laboratory Practice Regulations, across multiple time points revealed no evidence of clinical, neurological, or systemic toxicity. CONCLUSION: The present study provides evidence of long-term expression and bioactivity of NTN on the dopaminergic nigrostriatal system after bilateral stereotactic delivery of CERE-120 to the striatum. Furthermore, no evidence of any adverse effects for up to 1 year postadministration was observed. These findings reveal a wide safety margin for CERE-120 and collectively support the ongoing clinical testing of the efficacy and safety of CERE-120 in patients with Parkinson's disease.

OBJECTIVE As new clinical applications for deep brain stimulation (DBS) emerge and the number of patients with DBS systems continues to grow, lead technology will also advance. To direct improvement of these leads, improved understanding of the effects of the DBS electrodes and stimulation parameters on the surrounding brain parenchyma is necessary. We present a postmortem evaluation of a patient who had previously undergone bilateral DBS of the anterior thalamic nucleus. CLINICAL PRESENTATION A 21-year-old, right-handed man with a 2-year history of epilepsy secondary to encephalitis underwent bilateral DBS of the anterior nucleus of the thalamus. He died 8 months after surgery, and his death was classified as a sudden, unexpected, unexplained death as a result of epilepsy. INTERVENTION Microscopic examination and immunohistochemical analysis using glial fibrillary acidic protein, CD11b, CD45, and CD 68 were performed. The thalami of this patient were then compared with brain tissue obtained from a 45-year-old patient who died as a result of a myocardial infarction and had no history of neurological disease and no surgical intervention. There were no differences in the microscopic and histochemical evaluation of the thalami between patients, other than immediately around the electrode tract. Minimal tissue damage, mild astrocytosis, and mild inflammation surrounding the electrode termination site were observed. CONCLUSION We report the first postmortem examination after bilateral DBS of the anterior nucleus of the thalamus for epilepsy. A comparison with control tissue showed no significant difference other than mild inflammation along the lead track.