François J.G. Vingerhoets

Neuropathological Evidence of Graft Survival and Striatal Reinnervation after the Transplantation of Fetal Mesencephalic Tissue in a Patient with Parkinson's Disease

BACKGROUNDnTrials are under way to determine whether fetal nigral grafts can improve motor function in patients with Parkinsons disease. Some studies use fluorodopa uptake on positron-emission tomography (PET) as a marker of graft viability, but fluorodopa uptake does not distinguish between host and grafted neurons. There has been no direct evidence that grafts of fetal tissue can survive and innervate the striatum.nnnMETHODSnWe studied a 59-year-old man with advanced Parkinsons disease who received bilateral grafts of fetal ventral mesencephalic tissue in the postcommissural putamen. The tissue came from seven embryos between 6 1/2 and 9 weeks after conception. The patient died 18 months later from a massive pulmonary embolism. The brain was studied with the use of tyrosine hydroxylase immunohistochemical methods.nnnRESULTSnAfter transplantation, the patient had sustained improvement in motor function and a progressive increase in fluorodopa uptake in the putamen on PET scanning. On examination of the brain, each of the large grafts appeared to be viable. Each was integrated into the host striatum and contained dense clusters of dopaminergic neurons. Processes from these neurons had grown out of the grafts and provided extensive dopaminergic reinnervation to the striatum in a patch-matrix pattern. Ungrafted regions of the putamen showed sparse dopaminergic innervation. We could not identify any sprouting of host dopaminergic processes.nnnCONCLUSIONSnGrafts of fetal mesencephalic tissue can survive for a long period in the human brain and restore dopaminergic innervation to the striatum in patients with Parkinsons disease. In the patient we studied, clinical improvement and enhanced fluorodopa with uptake on PET scanning were associated the survival of the grafts and dopaminergic reinnervation of the striatum.

Manganese intoxication in the rhesus monkey A clinical, imaging, pathologic, and biochemical study

We gave three adult rhesus monkeys seven IV injections of manganese chloride at approximate 1-week intervals. We evaluated neurologic status by serial clinical examinations and performed a levodopa test if the animal developed features of basal ganglia dysfunction. After the animals were killed, we performed neuropathologic, neurochemical, and laser microprobe mass analysis (LAMMA) studies. Two of three animals developed a parkinsonian syndrome characterized by bradykinesia, rigidity, and facial grimacing suggestive of dystonia but not tremor. Neither animal responded to levodopa. Autopsy demonstrated gliosis primarily confined to the globus pallidus (GP) and the substantia nigra pars reticularis (SNr). We detected focal mineral deposits throughout the GP and SNr, particularly in a perivascular distribution. LAMMA studies noted that mineral deposits were primarily comprised of iron and aluminum. The severity of pathologic change correlated with the degree of clinical dysfunction. These studies demonstrate that, in contrast to Parkinsons disease (PD) and MPTP-induced parkinsonism, manganese primarily damages the GP and SNr and relatively spares the nigrostriatal dopaminergic system. Further, the results suggest that Mn-induced parkinsonism can be differentiated from PD and MPTP-induced parkinsonism by the clinical syndrome and response to levodopa. The accumulation of iron and aluminum suggests that iron/aluminum-induced oxidant stress may contribute to the damage associated with Mn toxicity. NEUROLOGY 1996,46 492-498

Deprenyl and the issue of neuroprotection.

Deprenyl and the Issue of Neuroprotection F. Vingerhoets, MD, Neurodegenerative Disorders Centre, University Hospital, UBC Site, Purdy Pavilion, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5 (Canada) The Parkinson Disease Study Group (PDSG) recently published its findings concerning antioxidant drug therapy for early Parkinson’s disease [1] (idiopathic parkinsonism (IP)) as follow-up to an earlier report published in 1989 [2]. After almost 4 years of controversy [3, 4], the sole firm conclusion that could be drawn concerning the use of deprenyl, a monoamine oxidase (MAO) type B inhibitor was that it allowed the introduction of levodopa treatment to be postponed by somewhat less than 1 year. For this reason, the authors argue, deprenyl should be considered among the available therapeutic options for the initial treatment of early Parkinson’s disease. A discussion of when and how symptomatic treatment of early Parkinson’s disease should be carried out is beyond the scope of this editorial and has recently been addressed elsewhere [5]. Our discussion here will be restricted to the issue of neuroprotection as illustrated by the DATATOP experience. Few would argue against neuroprotection being a goal worth pursuing. However, for the concept to be meaningfully assessed a specific definition is required. On the cellular level, the definition of neuroprotection is relatively straightforward. Most would accept an agent as neuroprotective if it reduced the death rate in a population of cells. In this context, visual examination of cells surviving in culture, following a toxic stressor, would allow conclusions regarding the neuroprotective effect of an agent. In experiments where neuropathological studies can be performed serially, for example in an experimental group of animals, comments concerning cellular neuroprotection can likewise be made. In this context, experimental models can be constructed, based on knowledge of a given deleterious phenomenon, including its mechanisms and natural evolution, and potential neuroprotective influences proposed (e.g. MPTP-induced parkinsonism – oxidative stress/excitotoxicity – MAO inhibitors). Similarly, when the cause of a human disease is known, as in the case of Wilson’s disease or subacute combined degeneration of the cord, chelation and vitamin therapy may be regarded as providing a kind of neuroprotection. By contrast, in the distinctly human condition of IP, the mechanism and natural evolution of the disorder are not known or quantifi-ably defined. Furthermore, practical access to visualizing neuronal populations from the brains of living patients is impossible. Consequently, it is difficult to define neuroprotection in this context. This difficulty has been recognized by the PDSG. The DATATOP design [1,2, 6] is representative of the framework for several human neuroprotective studies and therefore worthy of further consideration. Information from three sources seems essential for establishing a convincing neuroprotective story: (1) An ongoing pathogenic mechanism must be identified. In IP, some evidence suggests a disturbance in oxidative pathways in the substantia nigra. This has been taken, in the DATATOP study, as indicating a primary role for free radical/oxidative stress in the development of parkinsonism [6]. However, others speak with equal conviction and evidence against the oxidative stress hypothesis [7]. Alternatively, or perhaps additionally, it has been postulated that continuous exposure to an environmental pro-toxin may contribute to the demise of nigral neuronal function [6]. However, to date no relevant protoxin has been identified in the environment. Furthermore, it has been shown that, at least in some other forms of parkinsonism, a transient exposure to a toxic agent such as manganese [8] or MPTP [9] may lead to a chronically pro-gresssive condition. One can only speculate as to whether the cause(s) of IP is (are) an event or process [10].

The presymptomatic period in a patient with idiopathic parkinsonism

A 68-year-old, normal female volunteer was scanned by positron emission tomography (PET) with [(18)F]6-L-fluorodopa (FD). Striatal FD uptake was in the high normal range. Subsequently, she developed parkinsonism 3.7 years after the scan. A repeat FD PET scan revealed a significant reduction of FD uptake by 20% over the 5.2 year interval. Our observations suggest a relatively short presymptomatic period with fast initial losses of nigral neurons in idiopathic parkinsonism.

An Aging Effect in Striatal Fluorodopa Uptake? Large versus Small Rois

To the Editor: We read with interest the paper by Eidelberg et ai. (1993), in which the authors state that they anaxad lyzed the scans according to our method. Unfortuxad nately, they did not. We used elliptical striatal regions of interest (ROIs) in our original paper and found a clear aging effect (Martin et aI., 1989). Eidelberg et ai. used rectangular ROIs in their attempt to replicate our method. The difference may be critical, as rectanxad gular ROIs would necessarily include more ventrixad cle, where there is no background activity, than elxad liptical ROIs; the error introduced by this may obxad scure any aging effect. Eidelberg et ai. concede in their article that their failure to demonstrate an efxad fect of age may be explained by excess variability. The issue is important, as the Eidelberg et ai. paper attempts to resolve disparate findings of an age rexad lationship in fluorodopa uptake using different ROIs (Martin et aI., 1989; Sawle et aI., 1990). We have recently shown in a new data set that using total striatal ROIs reveals an aging effect in fluorodopa uptake, while using small (8.8-mmxad diameter) ROIs does not (Vingerhoets et aI., 1994). These findings reconcile the differing conclusions of Martin et ai. (1989) (who used total striatal ROIs and found an age effect) and Sawle et ai. (1990) (who used small ROIs and did not). The difference between the methods does not relate just to the size of the ROIs; large ROIs measure the total striatal fluorodopa uptake, while small ROIs measure the concentration of fluorodopa uptake per milliliter of striatum. Eidelberg et ai. are confused by this point when they state that the total striatal ROI method is sensitive to the known age-related striatal atrophy (Murphy et aI., 1992). In fact, the opposite is true, because dopaminergic neurons make up a minimal part of the volume of the striatum. Any atrophy of the nondopaminergic elements would alter the conxad centration of fluorodopa uptake but not the total uptake, which is therefore the true measure of nixad grostriatal dopaminergic function. Eidelberg et ai. could have contributed to the disxad cussion by applying the methods of both Martin et ai. and Sawle et ai. to the same data set. U nfortuxad nately they did not replicate the methods, and