Peter Hagell

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.

Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity

BACKGROUND Depressive disorders are associated with immune system alterations that can be detected in the blood. Cytokine concentrations in cerebrospinal fluid (CSF) and their relationship to aspects of suicidality have previously not been investigated. METHODS We measured interleukin-1beta, interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-alpha (TNF-alpha) in CSF and plasma of suicide attempters (n = 63) and healthy control subjects (n = 47). Patients were classified according to diagnosis and violent or nonviolent suicide attempt. We evaluated suicidal ideation and depressive symptoms using the Suicide Assessment Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We also analyzed the relation between cytokines and monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF, as well as the integrity of the blood-brain barrier as reflected by the CSF:serum albumin ratio. RESULTS IL-6 in CSF was significantly higher in suicide attempters than in healthy control subjects. Patients who performed violent suicide attempts displayed the highest IL-6. Furthermore, there was a significant positive correlation between MADRS scores and CSF IL-6 levels in all patients. IL-6 and TNF-alpha correlated significantly with 5-HIAA and HVA in CSF, but not with MHPG. Cytokine levels in plasma and CSF were not associated, and patients with increased blood-brain barrier permeability did not exhibit elevated cytokine levels. CONCLUSIONS We propose a role for CSF IL-6 in the symptomatology of suicidal behavior, possibly through mechanisms involving alterations of dopamine and serotonin metabolism.

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

Clinical observations after neural transplantation in Parkinson's disease

Publisher Summary This chapter discusses critical analysis of the clinical findings in Parkinsons disease (PD) patients grafted with embryonic mesencephalic tissue. The emphasis is on the magnitude, pattern and time course of clinical recovery and the relation between the graft-induced symptomatic relief and the restoration of striatal dopaminergic neurotransmission. In addition, the chapter discusses some methodological issues and different strategies to improve the functional recovery following neural transplantation. The clinical observations after neural transplantation clearly documents that cell replacement has the potential to become a novel and effective therapeutic strategy for large numbers of patients with PD. However, neural transplantation currently remains an experimental approach and can only be applied to small groups of patients. The urgent problem is to develop the new sources of dopaminergic cells that are available in large amounts and suitable for transplantation in humans. It is conceivable that these cells, to give rise to maximal symptomatic relief, must exhibit several of the properties characteristic of human embryonic mesencephalic dopamine neurons, such as formation of specialized synaptic contacts with host neurons, regulated dopamine release, and functional integration into the patients brain.

Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow up

OBJECTIVES Despite the recent introduction of new peroral drugs as well as neurosurgical methods for Parkinson’s disease, treatment of late stage parkinsonian patients remains difficult and many patients become severely handicapped because of fluctuations in their motor status. Injections and infusions of apomorphine has been suggested as an alternative in the treatment of these patients, but the number of studies describing the effects of such a treatment over longer time periods is still limited. The objective was to investigate the therapeutic response and range of side effects during long term treatment with apomorphine in advanced Parkinson’s disease. METHODS Forty nine patients (30 men, 19 women; age range 42–80 years) with Parkinson’s disease were treated for 3 to 66 months with intermittent subcutaneous injections or continuous infusions of apomorphine. RESULTS Most of the patients experienced a long term symptomatic improvement. The time spent in “off” was significantly reduced from 50 to 29.5% with injections and from 50 to 25% with infusions of apomorphine. The quality of the remaining “off” periods was improved with infusion treatment, but was relatively unaffected by apomorphine injections. The overall frequency and intensity of dyskinesias did not change. The therapeutic effects of apomorphine were stable over time. The most common side effect was local inflammation at the subcutaneous infusion site, whereas the most severe were psychiatric side effects occurring in 44% of the infusion and 12% of the injection treated patients. CONCLUSION Subcutaneous apomorphine is a highly effective treatment which can substantially improve the symptomatology in patients with advanced stage Parkinson’s disease over a prolonged period of time.

Resource Use and Costs in a Swedish Cohort of Patients with Parkinson's Disease

We estimated resource use and costs in patients with Parkinsons disease (PD), thereby providing baseline data for future economic evaluations of therapeutic interventions. Data were collected from medical records of a South Swedish cohort of 127 PD patients during 1 year (1996) and a mailed questionnaire inquiring about cost‐related consequences and resource use in 1996 and in 2000. Annual costs were calculated based on prevalence and expressed in SEK (monetary value of the year 2000). Direct health care costs averaged approximately SEK 29,000 (≈USD 2,900; EUR 3,200) per patient per year, of which drugs were the most costly component. Nonmedical direct costs were higher than direct health care costs, averaging approximately SEK 43,000 (≈USD 4,300; EUR 4,800) per patient per year, and costs due to lost production were approximately SEK 52,000 (≈USD 5,200; EUR 5,800) per patient per year. The mean total annual cost for PD in our sample approximated SEK 124,000 (≈USD 12,400; EUR 13,800) per patient. These findings are roughly within the same range as estimates from other countries and show that PD causes a considerable societal burden. In addition to other outcomes, evaluations of the economic implications of new therapeutic interventions are highly warranted. In this perspective, the present study provides valuable baseline data.

Clinical rating of dyskinesias in Parkinson's disease: use and reliability of a new rating scale

Drug‐induced dyskinesias (DID) manifested as hyperkinetic and/or dystonic movements or postures are common problems in Parkinsons disease (PD). Novel therapeutic interventions may offer possibilities to counteract these common adverse effects of an otherwise necessary treatment. To be able to evaluate the effects of such interventions on DID, reliable and relevant clinical assessment tools are needed. We tested the inter‐ and intrarater reliability of a new clinical dyskinesia rating scale consisting of separate ratings of different body parts, including lateralization and separate ratings of dystonia and hyperkinesias. Interrater reliability was tested both with and without a defined scoring code and clarification of the dystonia section. The nondefined version was also tested for intrarater reliability. Thirteen raters independently reviewed 23 videotape sequences showing PD patients performing standardized motor tests. Inter‐ and intrarater agreement was significant in all evaluations, and no differences were detected when comparing ratings performed with the defined and nondefined version of the scale. The rationale for, and the role and use of, the present scale are addressed.

Towards an understanding of fatigue in Parkinson disease

Objectives: To gain an improved understanding of fatigue in Parkinson disease (PD) by exploring possible predictors among a wide range of motor and non-motor aspects of PD. Methods: 118 consecutive PD patients (54% men; mean age 64 years) were assessed regarding fatigue, demographics and a range of non-motor and motor symptoms. Variables significantly associated with fatigue scores in bivariate analyses were used in multiple regression analyses with fatigue as the dependent variable. Results: Fatigue was associated with increasing Hoehn & Yahr stages, specifically the transition from stages I–II to stages III–V. Regression analysis identified five significant independent variables explaining 48% of the variance in fatigue scores: anxiety, depression, lack of motivation, Unified PD Rating Scale (UPDRS) motor score and pain. Gender, age, body mass index, PD duration, motor fluctuations, dyskinesias, symptomatic orthostatism, thought disorder, cognition, drug treatment, sleep quality and daytime sleepiness were not significantly associated with fatigue scores. When considering individual motor symptom clusters instead of the UPDRS motor score, only axial/postural/gait impairment was associated with fatigue. Conclusions: This study found fatigue to be primarily associated with symptoms of depression and anxiety, and with compromised motivation, parkinsonism (particularly axial/postural/gait impairment) and pain. These results are in agreement with findings in other disorders and imply that fatigue should be considered a separate PD entity differing from, for example, excessive daytime sleepiness. Fatigue may have a distinguished neurobiological background, possibly related to neuroinflammatory mechanisms. This implies that novel treatment options, including anti-inflammatory therapies, could be effective.

Measurement properties and hierarchical item structure of the Epworth Sleepiness Scale in Parkinson's disease.

The aim of this work was to evaluate the measurement properties and hierarchical item structure of the Epworth Sleepiness Scale (ESS) in patients with Parkinsons disease (PD). Data were taken from a cross‐sectional study regarding fatigue and sleep‐related aspects of PD. One hundred and eighteen consecutive patients with neurologist‐diagnosed PD without significant co‐morbidities (54% men; mean age, 64 years; mean PD duration, 8.4 years) from four Swedish neurological outpatient clinics participated. The ESS displayed good data quality with few missing items (0–2.5%): good reliability (Cronbachs alpha, 0.84), marginal floor and no ceiling effects (1.7% and 0% respectively), and differentiated between those reporting problems staying awake during the past month and those who did not. Item–total correlations, factor and Rasch analyses indicated that items tap a single underlying construct. Rasch analysis supported basic rating scale assumptions and demonstrated an item hierarchy similar to that previously found in patients with other sleep disorders. Gaps in the levels of sleep propensity covered by ESS items and their response options were identified at the higher and lower ends of the underlying sleepiness continuum. This study provides an evidence base for using the ESS in PD by demonstrating good psychometric properties and a stable hierarchical item structure. However, addition of new items and use of Rasch scoring has potential to further enhance the clinical usefulness of the ESS.