Temporal dynamics of neurovascular unit changes following blood-brain barrier opening in the putamen of non-human primates.

Low-intensity focused ultrasound (LIFU) combined with intravenously circulating microbubbles has recently emerged as a novel approach for increasing delivery through the blood-brain barrier (BBB). This technique safely and transiently enables therapeutic agents to overcome the BBB, which typically poses a significant obstacle for treatment of brain disorders. However, the full impact of LIFU on the entire neurovascular unit (NVU), as well as the mechanisms and factors involved in restoring BBB integrity still require further elucidation.

Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson's disease model.

The differential vulnerability of dopaminergic neurons of the substantia nigra pars compacta (SNc) is a critical and unresolved question in Parkinson´s disease. Studies in mice show diverse susceptibility of subpopulations of nigral dopaminergic neurons to various toxic agents. In the primate midbrain, the molecular phenotypes of dopaminergic neurons and their differential vulnerability are poorly characterized.

Neurovascular and immune factors of vulnerability of substantia nigra dopaminergic neurons in non-human primates.

Dopaminergic neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease (PD), while those in the dorsal tier and ventral tegmental area are relatively spared. The factors determining why these neurons are more vulnerable than others are still unrevealed. Neuroinflammation and immune cell infiltration have been demonstrated to be a key feature of neurodegeneration in PD.

Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain.

Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs).

BBB opening with focused ultrasound in nonhuman primates and Parkinson's disease patients: Targeted AAV vector delivery and PET imaging.

Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson's disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals.

Brain injections of glial cytoplasmic inclusions induce a multiple system atrophy-like pathology.

Synucleinopathies encompass several neurodegenerative diseases, which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. These diseases are characterized by the deposit of α-synuclein aggregates in intracellular inclusions in neurons and glial cells. Unlike Parkinson's disease and dementia with Lewy bodies, where aggregates are predominantly neuronal, multiple system atrophy is associated with α-synuclein cytoplasmic inclusions in oligodendrocytes.

Neuron types in the primate striatum: Stereological analysis of projection neurons and interneurons in control and parkinsonian monkeys.

Aims: The striatum is mainly composed of projection neurons. It also contains interneurons, which modulate and control striatal output. The aim of the present study was to assess the percentages of projection neurons and interneuron populations in the striatum of control monkeys and of parkinsonian monkeys.

Lack of Parkinsonian Pathology and Neurodegeneration in Mice After Long-Term Injections of a Proteasome Inhibitor in Olfactory Bulb and Amygdala.

Proteinaceous inclusions, called Lewy bodies (LBs), are used as a pathological hallmark for Parkinson's disease (PD). Recent studies suggested a prion-like spreading mechanism for α-synucleinopathy where early neuropathological deposits occur, among others, in the olfactory bulb (OB) and amygdala. LBs contain insoluble α-synuclein and many other ubiquitinated proteins, suggesting a role of protein degradation system failure in PD pathogenesis.

Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates.

In Parkinson's disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via the vagus nerve, to the CNS. Here, we compare, in baboon monkeys, the pathological consequences of either intrastriatal or enteric injection of α-synuclein-containing Lewy body extracts from patients with Parkinson's disease. This study shows that patient-derived α-synuclein aggregates are able to induce nigrostriatal lesions and enteric nervous system pathology after either enteric or striatal injection in a non-human primate model.

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification.

A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease-modifying therapy for PD.

Advances in Parkinson's Disease: 200 Years Later.

When James Parkinson described the classical symptoms of the disease he could hardly foresee the evolution of our understanding over the next two hundred years. Nowadays, Parkinson's disease is considered a complex multifactorial disease in which genetic factors, either causative or susceptibility variants, unknown environmental cues, and the potential interaction of both could ultimately trigger the pathology. Noteworthy advances have been made in different fields from the clinical phenotype to the decoding of some potential neuropathological features, among which are the fields of genetics, drug discovery or biomaterials for drug delivery, which, though recent in origin, have evolved swiftly to become the basis of research into the disease today.

Novel models for Parkinson's disease and their impact on future drug discovery.

Parkinson's disease is a progressive neurodegenerative disease that affects millions of elderly individuals worldwide. Despite intensive efforts dedicated to find a better treatment, the pathogenesis of Parkinson's Disease remains unknown. In search for a better therapy for the disease, several new in vivo and in vitro models of Parkinson´s disease have been developed in recent times.

Compensatory mechanisms in Parkinson's disease: Circuits adaptations and role in disease modification.

The motor features of Parkinson's disease (PD) are well known to manifest only when striatal dopaminergic deficit reaches 60-70%. Thus, PD has a long pre-symptomatic and pre-motor evolution during which compensatory mechanisms take place to delay the clinical onset of disabling manifestations. Classic compensatory mechanisms have been attributed to changes and adjustments in the nigro-striatal system, such as increased neuronal activity in the substantia nigra pars compacta and enhanced dopamine synthesis and release in the striatum.

The use of nonhuman primate models to understand processes in Parkinson's disease.

Research with animal models has led to critical health advances that have saved or improved the lives of millions of human beings. Specifically, nonhuman primate's genetic and anatomo-physiological similarities to humans are especially important for understanding processes like Parkinson's disease, which only occur in humans. Unambiguously, the unique contribution made by nonhuman primate research to our understanding of Parkinson's disease is widely recognized.

Oxidative stress and Parkinson's disease.

Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity.