Stig Rehncrona

Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation.

Two subjects with Parkinsons disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11–16 years) developed α-synuclein–positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinsons pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.

Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient

Synaptic dopamine release from embryonic nigral transplants has been monitored in the striatum of a patient with Parkinsons disease using [11C]-raclopride positron emission tomography to measure dopamine D2 receptor occupancy by the endogenous transmitter. In this patient, who had received a transplant in the right putamen 10 years earlier, grafts had restored both basal and drug-induced dopamine release to normal levels. This was associated with sustained, marked clinical benefit and normalized levels of dopamine storage in the grafted putamen. Despite an ongoing disease process, grafted neurons can thus continue for a decade to store and release dopamine and give rise to substantial symptomatic relief.

Brain Lactic Acidosis and Ischemic Cell Damage: 1. Biochemistry and Neurophysiology

This study explores the influence of severe lactic acidosis in the ischemic rat brain on postischemic recovery of the tissue energy state and neurophysiological parameters. Severe incomplete brain ischemia (cerebral blood flow below 5% of normal) was induced by bilateral carotid artery clamping combined with hypovolemic hypotension. We varied the production of lactate in the tissue by manipulating the blood glucose concentrations. A 30-min period of incomplete ischemia induced in food-deprived animals caused lactate to accumulate to 15–16 μmol g−1 in cortical tissue. Upon recirculation these animals showed: (1) a considerable recovery of the cortical energy state as evaluated from the tissue concentrations of phosphocreatine, ATP, ADP, and AMP; and (2) return of spontaneous electrocortical activity as well as of somatosensory evoked response (SER). In contrast, administration of glucose to food-deprived animals prior to ischemia caused an increase in tissue lactate concentration to about 35 μmol g−1. These animals did not recover energy balance in the tissue and neurophysiological functions did not return. In other experiments the production of lactate during 30 min of complete compression ischemia was increased from about 12 μmol g−1 (normoglycemic animals) to 20–30 μmol g−1 by preischemic hyperglycemia and. in separate animals, combined hypercapnia. The recovery of the cortical energy state upon recirculation was significantly poorer in hyperglycemic animals. It is concluded that a high degree of tissue lactic acidosis during brain ischemia impairs postischemic recovery and that different degrees of tissue lactic acidosis may explain why severe incomplete ischemia, in certain experimental models, is more deleterious than complete brain ischemia.

Brain Cortical Fatty Acids and Phospholipids During and Following Complete and Severe Incomplete Ischemia

Abstract: To explore the possibility that peroxtdative degradation of brain tissue lipid constituents is an important mechanism of irreversible ischemic damage, we measured cortical fatty acids and phospholipids during reversible brain ischemia in the rat. Neither complete nor severe incomplete ischemia (5 and 30 min) caused any measurable breakdown of total or individual fatty acids or phospholipids. Except for a small (and reversible) decrease of inositol plus serine phosphoglycerides in the early postischemic period following 30 min of incomplete ischemia, there were no significant losses of fatty acids or phospholipids during recirculation. Since peroxidation, induced in brain cortical tissue in vitro, characteristically involves degradation of polyenoic fatty acids (arachidonic and docosahexaenoic acids) and of ethanolamine phosphoglycerides, the present in vivo results fail to support the hypothesis that peroxidation of membrane lipids is of primary importance for ischemic brain cell damage. Both complete and severe incomplete ischemia caused a similar increase in the tissue content of free fatty acids (FFA). Thus the FFA pool increased by about 10 times during a 30‐min ischemic period, to constitute 1 ‐ 2% of the total fatty acid pool. Since there was a relatively larger increase in polyenoic FFA (especially in arachidonic acid) than in saturated FFA, the release of FFA may be the result of activation of a phospholipase A2 unbalanced by reesterification. Increased levels of FFA persisted during the initial recirculation period, but a gradual normalization occurred and the ischemic changes were essentially reversed at 30 min after restoration of circulation. The pathophysiological implications of the changes in FFA are discussed with respect to mitochondrial dysfunction, formation of cellular edema and prostaglandin‐mediated deterioration of postischemic circulation.

Brain Lactic Acidosis and Ischemic Cell Damage: 2. Histopathology

The influence of severe tissue lactic acidosis during incomplete brain ischemia (30 min) on cortex morphology was studied in fasted rats. Production of lactate in the ischemic tissue was varied by preischemic infusions (i.v.) of either a saline or a glucose solution. The brains were fixed by perfusion with glutaraldehyde at 0, 5, or 90 min of recirculation. In saline-infused animals (tissue lactate about 15 μmol g−1), changes observed at 0 and 5 min of recirculation were strikingly discrete: slight condensation of nuclear chromatin. mild to moderate mitochondrial swelling, and only slight astrocyte edema. These changes had virtually disappeared after 90 min recirculation and. at this time. only discrete ribosomal changes were observed. In contrast. glucose-infused rats (tissue lactate about 35 μmol g−1) showed severe changes: marked clumping of nuclear chromatin and cell sap in all cells was already evident at 0 and 5 min recirculation, while mitochondrial swelling was mild to moderate. Although tissue fixation was inadequate at 90 min. the ultrastructural appearance indicated extensive damage. It is concluded that excessive tissue lactic acidosis during brain ischemia exaggerates structural alterations and leads to irreversible cellular damage. A tentative explanation is offered for the paucity (<0.2%) of condensed neurons with grossly swollen mitochondria. previously considered a hallmark of ischemic cell injury.

Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease†

We report the 5 to 6 year follow‐up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinsons disease (PD) patients. Thirty‐five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinsons Disease Rating Scale (UPDRS) assessed with a prospective cross‐over double‐blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off‐ and on‐medication states with and without stimulation, activities of daily living (ADL), anti‐PD medications, and dyskinesias. In double‐blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off‐stimulation, regardless of the sequence of stimulation. In open assessment, both STN‐ and GPi‐DBS significantly improved the off‐medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti‐PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long‐term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN‐DBS patients and fewer adverse events in the GPi‐DBS group.

Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts

Intrastriatal transplantation of dopaminergic neurones aims to repair the selective loss of nigrostriatal projections and the consequent dysfunction of striatocortical circuitries in Parkinsons disease (PD). Here, we have studied the effects of bilateral human embryonic dopaminergic grafts on the movement‐related activation of frontal cortical areas in 4 PD patients using H215O positron emission tomography and a joystick movement task. At 6.5 months after transplantation, mean striatal dopamine storage capacity as measured by 18F‐dopa positron emission tomography was already significantly elevated in these patients. This was associated with a modest clinical improvement on the Unified Parkinsons Disease Rating Scale, whereas the impaired cortical activation was unchanged. At 18 months after surgery, there was further significant clinical improvement in the absence of any additional increase in striatal 18F‐dopa uptake. Rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements had significantly improved, however. Our data suggest that the function of the graft goes beyond that of a simple dopamine delivery system and that functional integration of the grafted neurones within the host brain is necessary to produce substantial clinical recovery in PD. Ann Neurol 2000;48:689–695

Peroxidative Changes in Brain Cortical Fatty Acids and Phospholipids, as Characterized During Fe2+‐ and Ascorbic Acid‐Stimulated Lipid Peroxidation In Vitro

Abstract: The occurrence of peroxidative damage, as distinguished from anaerobic damage, to brain fatty acids and phospholipids was characterized in vitro. Fe2+ and ascorbic acid were used to stimulate peroxidation in cortical homogenates from rat brain incubated with or without oxygen. Lipid peroxidation was established in samples incubated with oxygen by increased diene conjugation, accumulation of thiobarbituric acid‐reactive material (TBAR) and of lipid‐soluble fluorescent products. No peroxidation occurred in samples incubated in the absence of oxygen (100% N2). Lipid peroxidation was characterized by a selective loss of arachidonic acid and docosahexaenoic acid and by degradation of ethanolamine phosphoglyceride, while choline phosphoglyceride did not change. During the course of peroxidation there were parallel increases in products of lipid peroxidation concomitant with the decrease in polyenoic fatty acids. The maximal changes in diene conjugation and TBAR occurred earlier than the maximal changes in fluorescent material and fatty acids. It is concluded that measurements of changes in brain fatty acid and phospholipid composition may be a useful tool to establishment of whether peroxidative damage is important in vivo in situations with a critically reduced oxygen supply. Estimation of lipid‐soluble fluorescence in vivo may also be useful, since it is considered to reflect the accumulation of stable end products of peroxidation.

Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments.

Thalamic deep brain stimulation (DBS) is proven to suppress tremor in Parkinsons disease (PD) and essential tremor (ET). However, there are few reports on its long‐term efficacy. We studied the efficacy of DBS at 2 years and 6–7 years after electrode implantations in the ventrointermediate nucleus of the thalamus in 39 patients (20 PD, 19 ET) with severe tremor. Twenty‐five of the patients completed the study. Evaluations were done in a double‐blind manner with the Unified Parkinsons Disease Rating Scale (UPDRS) and Essential Tremor Rating Scale (ETRS). DBS decreased tremor sum scores in PD (P < 0.025) compared to the preoperative baseline (median, 7; Q25–75, 6–9) both at 2 years (median, 2; Q25–75, 2–3.5; n = 16) and at 6 to 7 years (median, 2.5; Q25–75, 0.5–3; n = 12). Stimulation on improved tremor sum as well as sub scores (P < 0.025) compared to stimulation off conditions. In ET, thalamic stimulation improved (P < 0.025) kinetic and positional tremor at both follow‐up periods (n = 18 and n = 13, respectively) with significant improvements (P < 0.025) in hand‐function tests. PD but not ET patients showed a general disease progression. Stimulation parameters were remarkably stable over time. We conclude that high‐frequency electric thalamic stimulation can efficiently suppress severe tremor in PD and ET more than 6 years after permanent implantation of brain electrodes.

Serotonergic Neurons Mediate Dyskinesia Side Effects in Parkinson's Patients with Neural Transplants

Two patients with Parkinson’s disease, successfully treated with fetal tissue transplants more than a decade ago, developed troublesome involuntary movements, which could be treated with a serotonin receptor agonist. The Two Faces of Fetal Grafts Before stem cells, there were fetal grafts. Pioneering treatments performed in the 1990s in patients with Parkinson’s disease proved that the diseased brain could be repaired, at least for a while. Two of these patients received grafts, one in the putamen and the other in both the caudate and the putamen, of fetal midbrain tissue. For several years, the patients showed mild improvement but eventually were able to function well with no drugs. Recently, however, both have started to experience abnormal uncontrolled movements, which Politis and colleagues have determined are a result of an overabundance of serotonin-using neurons that developed from the graft. A serotonin agonist eliminates these dyskinesias. Brain imaging exposed what was happening in these patients’ brains. When imaged by positron emission tomography, radioactive tracers that tag dopaminergic neurons and that bind to the dopamine receptor showed that the dopamine neurons that decay during Parkinson’s disease were restored by the grafts. Another scan with an agent that binds to the serotonin transporter showed an abnormality; there seemed to be more serotonin neurons than usual. This presented a conundrum because dyskinesias in Parkinson’s disease are thought to be a result of dopamine, not serotonin, stimulation. The authors hypothesized that the explanation lies in the ability of the serotonin neurons to switch to a different neurotransmitter—to adopt dopamine as a so-called false transmitter, releasing it to cause dyskinesias. If this were the case, then desensitizing these serotonin neurons, and so inhibiting their activity, would reduce the dyskinesias. They tested this idea by giving the patients low doses of a serotonin receptor agonist called buspirone. Both patients responded by a sudden and almost complete resolution of the troublesome abnormal movements, suggesting that the excess serotonergic neurons had in fact been pumping out dopamine, causing the dyskinesias. The patients described here are only two of a larger number who received fetal neural tissue implants years ago. In some patients, the grafted cells survived, possibly as a result of stem cells within the graft, and were able to replace the function of the diseased dopamine cells, forming connections with the existing brain cells. Exploration of the long-term consequences of such replacement tissue, such as the atypical movements and their inhibition reported here, is important in that it will inform future treatments with grafts that consist of cells from other sources, such as bioengineered or stem cells. Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson’s disease. The mechanisms underlying these dyskinesias are not well understood, and it is not known whether they are the same as in the dyskinesias induced by l-dopa treatment. Using in vivo brain imaging, we show excessive serotonergic innervation in the grafted striatum of two patients with Parkinson’s disease, who had exhibited major motor recovery after transplantation with dopamine-rich fetal mesencephalic tissue but had later developed off-medication dyskinesias. The dyskinesias were markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT1A) agonist, which dampens transmitter release from serotonergic neurons, indicating that the dyskinesias were caused by the serotonergic hyperinnervation. Our observations suggest strategies for avoiding and treating graft-induced dyskinesias that result from cell therapies for Parkinson’s disease with fetal tissue or stem cells.