Robust graft survival and normalized dopaminergic innervation do not obligate recovery in a <scp>P</scp>arkinson disease patient

Kordower, Jeffrey H.; Goetz, Christopher G.; Chu, Yaping; Halliday, Glenda M.; Nicholson, Daniel A.; Musial, Timothy F.; Marmion, David J.; Stoessl, A. Jon; Sossi, Vesna; Freeman, Thomas B.; Olanow, C. Warren

doi:10.1002/ana.24820

Cited by 78 publications

(77 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although simply providing dopamine to the striatum may have provided benefit in some cases, it may not always be sufficient. An illuminating analysis of the brain of a PD patient who had received a fetal mesencephalic implant showed that despite a substantial population of surviving neurons, and a virtually complete restoration of striatal dopaminergic innervation, there was no clinical benefit . One possible explanation for these observations is that ectopic placement of dopamine neurons in the striatum, even in the presence of abundant neurite outgrowth, does not restore system or circuit properties of endogenous SN dopamine neurons.…”

Section: New Axon Growth: Advantages and Disadvantagesmentioning

confidence: 99%

Induction of axon growth in the adult brain: A new approach to restoration in Parkinson's disease

Padmanabhan

Burke

2017

Movement Disorders

View full text Add to dashboard Cite

By the time patients with Parkinson's disease (PD) are first diagnosed, they have already suffered substantial and permanent loss of neurons and their axon projections. Although attention has been given to the possibility of making an earlier, premotor diagnosis of the disease, based on a variety of prodromal signs, such as olfactory dysfunction, constipation, and others, it is not yet possible to do so.1 Therefore, for the foreseeable future, there is a compelling need to develop neurorestorative approaches to the disease. Of the many neural systems, both central and peripheral, affected by PD, the best characterized, in terms of the extent of damage at the time of diagnosis by current motor criteria, is the nigrostriatal dopaminergic projection. In the classic literature and authoritative texts, estimates of 80% loss of striatal dopaminergic innervation at disease onset are often given 2,3 and estimates ranging from 50% to 70% have been proposed for loss of substantia nigra (SN) neurons.2-5 A review of more recent quantitative postmortem and imaging studies would suggest that these are overestimates. It is more likely that there is a 50% to 60% loss of striatal innervation and a 30% loss of neurons.6 These discrepancies notwithstanding, there is a consensus that substantial damage has occurred and that the axon projections bear the brunt of pathology at disease onset. The vulnerability of the axonal projection is especially highlighted in the study of Kordower and colleagues 7 who showed that by 4 years duration of the disease the dopaminergic innervation of the striatum is virtually gone. Thus in premotor and early PD it is the axons that take the brunt of injury and they therefore must merit our attention in approaches to restoration. Cell Replacement ApproachesUp until now, all efforts to provide restoration in PD have focused on cell replacement approaches. The first animal experiments were performed more than 40 years ago by placing solid tissue pieces into the striatum or ventricle 8,9 (see Barker and colleagues 10 for an excellent historic review). The rationale for this approach was to provide the striatum with cells that release dopamine and thereby alleviate the motor deficits. The efforts that have captured the most attention for human use have been implantation of fetal mesencephalic tissue and the development of stem cell approaches. These efforts have been the subject of a number of excellent recent reviews, and we would recommend them for greater detail. [10][11][12] Briefly, since the early days of implantation of whole-tissue fragments, the field of transplantation in the treatment of PD has come a very long way. Importantly, the ethical concerns related to the use of human embryonic tissue have been resolved by the discovery of induced pluripotent stem cells (iPSCs). In all likelihood, challenges at the cell biology level, including cell survival, loss of phenotype, and tumorigenesis, will be solvable. However, another set of challenges, not often discussed, will be those at the systems level...

show abstract

Section: New Axon Growth: Advantages and Disadvantagesmentioning

confidence: 99%

Induction of axon growth in the adult brain: A new approach to restoration in Parkinson's disease

Padmanabhan

Burke

2017

Movement Disorders

View full text Add to dashboard Cite

show abstract

“…Late‐onset individuals (age 70 and older) tend to have more severe motor deficits, a postural instability gait disorder, lower susceptibility to levodopa‐induced dyskinesias, and more rapid disease progression. Furthermore, evidence from both preclinical and clinical studies of cell transplantation indicate that despite implantation of immature DA neurons that are at a developmental stage optimal for neurite outgrowth and innervation, the environment of the aged brain inhibits functional reconstitution otherwise present in younger individuals . There are biological variables that could explain many of these features such as the difference in neuronal progenitor proliferation, integration, innervation, and function between young and aged individuals; however, this concept would need further empirical verification.…”

mentioning

confidence: 99%

Aging and Parkinson's disease: Different sides of the same coin?

2017

Self Cite

View full text Add to dashboard Cite

Despite abundant epidemiological evidence in support of aging as the primary risk factor for PD, biological correlates of a connection have been elusive. In this article, we address the following question: does aging represent biology accurately characterized as pre-PD? We present evidence from our work on midbrain dopamine neurons of aging nonhuman primates that demonstrates that markers of known correlates of dopamine neuron degeneration in PD, including impaired proteasome/lysosome function, oxidative/nitrative damage, and inflammation, all increase with advancing age and are exaggerated in the ventral tier substantia nigra dopamine neurons most vulnerable to degeneration in PD. Our findings support the view that aging-related changes in the dopamine system approach the biological threshold for parkinsonism, actively producing a vulnerable pre-parkinsonian state.

show abstract

“…These findings raise serious questions about the interpretation of striatal DAT SPECT and other presynaptic molecular imaging markers of nigrostriatal neurons and may explain the discord between such molecular imaging and clinical measures of progression in multiple clinical studies . Furthermore, longitudinal, long‐term studies of PD using molecular imaging biomarkers of presynaptic nigrostriatal neurons have greater risk of running into this discrepancy.…”

mentioning

confidence: 99%