Exploring the effects of deep brain stimulation and vision on tremor in Parkinson's disease - benefits from objective methods.

BACKGROUND: Tremor is a cardinal symptom of Parkinson's disease (PD) that may cause severe disability. As such, objective methods to determine the exact characteristics of the tremor may improve the evaluation of therapy. This methodology study aims to validate the utility of two objective technical methods of recording Parkinsonian tremor and evaluate their ability to determine the effects of Deep Brain Stimulation (DBS) of the subthalamic nucleus and of vision. METHODS: We studied 10 patients with idiopathic PD, who were responsive to L-Dopa and had more than 1 year use of bilateral subthalamic nucleus stimulation. The patients did not have to display visible tremor to be included in the study. Tremor was recorded with two objective methods, a force platform and a 3 dimensional (3D) motion capture system that tracked movements in four key proximal sections of the body (knee, hip, shoulder and head). They were assessed after an overnight withdrawal of anti-PD medications with DBS ON and OFF and with eyes open and closed during unperturbed and perturbed stance with randomized calf vibration, using a randomized test order design. RESULTS: Tremor was detected with the Unified Parkinson's Disease Rating Scale (UPDRS) in 6 of 10 patients but only distally (hands and feet) with DBS OFF. With the force platform and the 3D motion capture system, tremor was detected in 6 of 10 and 7 of 10 patients respectively, mostly in DBS OFF but also with DBS ON in some patients. The 3D motion capture system revealed that more than one body section was usually affected by tremor and that the tremor amplitude was non-uniform, but the frequency almost identical, across sites. DBS reduced tremor amplitude non-uniformly across the body. Visual input mostly reduced tremor amplitude with DBS ON. CONCLUSIONS: Technical recording methods offer objective and sensitive detection of tremor that provide detailed characteristics such as peak amplitude, frequency and distribution pattern, and thus, provide information that can guide the optimization of treatments. Both methods detected the effects of DBS and visual input but the 3D motion system was more versatile in that it could detail the presence and properties of tremor at individual body sections.

Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain.

Clinical trials using cells derived from embryonic ventral mesencephalon have shown that transplanted dopaminergic neurons can survive and function in the long term, as demonstrated by in vivo brain imaging using (18)F-fluorodopa and (11)C-raclopride positron emission tomography. Here we report the postmortem analysis of a patient with Parkinson's disease who 24 y earlier underwent unilateral transplantation of embryonic dopaminergic neurons in the putamen and subsequently exhibited major motor improvement and recovery of striatal dopaminergic function. Histopathological analysis showed that a dense, near-normal graft-derived dopaminergic reinnervation of the putamen can be maintained for a quarter of a century despite severe host brain pathology and with no evidence of immune response. In addition, ubiquitin- and α-synuclein-positive inclusions were seen, some with the appearance of typical Lewy bodies, in 11-12% of the grafted dopaminergic neurons, reflecting the spread of pathology from the host brain to the transplants. Because the clinical benefits induced by transplantation in this patient were gradually lost after 14 y posttransplantation, our findings provide the first reported evidence, to our knowledge, that even a viable dopaminergic graft giving rise to extensive striatal reinnervation may lose its efficacy if widespread degenerative changes develop in the host brain.

Subthalamic deep brain stimulation improves smooth pursuit and saccade performance in patients with Parkinson's disease.

BACKGROUND: Deep brain stimulation (DBS) in the subthalamic nucleus (STN) significantly reduces symptoms of Parkinson's disease (PD) such as bradykinesia, tremor and rigidity. It also reduces the need for anti-PD medication, and thereby potential side-effects of L-Dopa. Although DBS in the STN is a highly effective therapeutic intervention in PD, its mechanism and effects on oculomotor eye movement control and particularly smooth pursuit eye movements have to date rarely been investigated. Furthermore, previous reports provide conflicting information. The aim was to investigate how DBS in STN affected oculomotor performance in persons with PD using novel analysis techniques. METHODS: Twenty-five patients were eligible (22 males, 3 females) according to the clinical inclusion criteria: idiopathic PD responsive to L-Dopa and having had bilateral STN stimulation for at least one year to ensure stable DBS treatment. Fifteen patients were excluded due to the strict inclusion criteria applied to avoid interacting and confounding factors when determining the effects of DBS applied alone without PD medication. One patient declined participation. Nine PD patients (median age 63, range 59-69 years) were assessed after having their PD medications withdrawn overnight. They were examined with DBS ON and OFF, with the ON/OFF order individually randomized. RESULTS: DBS ON increased smooth pursuit velocity accuracy (p < 0.001) and smooth pursuit gain (p = 0.005), especially for faster smooth pursuits (p = 0.034). DBS ON generally increased saccade amplitude accuracy (p = 0.007) and tended to increase peak saccade velocity also (p = 0.087), specifically both saccade velocity and amplitude accuracy for the 20 and 40 degree saccades (p < 0.05). Smooth pursuit latency tended to be longer (p = 0.090) approaching normal with DBS ON. Saccade latency was unaffected. CONCLUSIONS: STN stimulation from DBS alone significantly improved both smooth pursuit and saccade performance in patients with PD. The STN stimulation enhancement found for oculomotor performance suggests clear positive implications for patients' ability to perform tasks that rely on visual motor control and visual feedback. The new oculomotor analysis methods provide a sensitive vehicle to detect subtle pathological modifications from PD and the functional enhancements produced by STN stimulation from DBS alone.

Spectral analysis of body movement during deep brain stimulation in Parkinson's disease.

BACKGROUND: The characteristics of Parkinson's disease (PD) include postural instability and resting tremor. However, reductions of tremor amplitude do not always improve postural stability. RESEARCH QUESTION: What is the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on spectral analysis of body movement in patients with PD when tested without anti-PD medication? The effect of visual cues was also studied. METHODS: Ten patients with PD (mean age 64.3 years, range 59-69 years) and 17 control participants (mean age 71.2 years, range 65-79 years) were recruited. Spectral power following a period of quiet stance (35 s) was analysed in three different spectral power bands (0-4 Hz, 4-7 Hz and 7-25 Hz). Motion markers were secured to the head, shoulder, hip, and knee, which recorded movements in two directions, the anteroposterior and lateral. RESULTS: DBS STN significantly changed the spectral distribution pattern across the body in the anteroposterior (p = 0.029) and lateral directions (p ≤ 0.003). DBS predominantly reduced spectral power at the head (p ≤ 0.037) and shoulder (p ≤ 0.031) in the lateral direction. The spectral power of the lower and upper body in patients with PD, with DBS ON, were more similar to the control group, than to DBS OFF. Visual cues mainly reduced spectral power in the anteroposterior direction at the shoulder (p ≤ 0.041) in controls and in patients with PD with DBS ON. SIGNIFICANCE: There is an altered postural strategy in patients with PD with DBS ON as shown by an altered spectral power distribution pattern across body segments and a reduction of spectral power in the lateral direction at the head and shoulder. A reduction of spectral power in controls and in patients with PD with DBS ON suggests that visual cues are able to reduce spectral power to some extent, but not with DBS OFF where postural sway and power are larger.

Strategic alterations of posture are delayed in Parkinson's disease patients during deep brain stimulation.

Parkinson's disease (PD) is characterized by rigidity, akinesia, postural instability and tremor. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces tremor but the effects on postural instability are inconsistent. Another component of postural control is the postural strategy, traditionally referred to as the ankle or hip strategy, which is determined by the coupling between the joint motions of the body. We aimed to determine whether DBS STN and vision (eyes open vs. eyes closed) affect the postural strategy in PD in quiet stance or during balance perturbations. Linear motion was recorded from the knee, hip, shoulder and head in 10 patients with idiopathic PD with DBS STN (after withdrawal of other anti-PD medication), 25 younger adult controls and 17 older adult controls. Correlation analyses were performed on anterior-posterior linear motion data to determine the coupling between the four positions measured. All participants were asked to stand for a 30 s period of quiet stance and a 200 s period of calf vibration. The 200 s vibration period was subdivided into four 50 s periods to study adaptation between the first vibration period (30-80 s) and the last vibration period (180-230 s). Movement was recorded in patients with PD with DBS ON and DBS OFF, and all participants were investigated with eyes closed and eyes open. DBS settings were randomized and double-blindly programmed. Patients with PD had greater coupling of the body compared to old and young controls during balance perturbations (p ≤ 0.046). Controls adopted a strategy with greater flexibility, particularly using the knee as a point of pivot, whereas patients with PD adopted an ankle strategy, i.e., they used the ankle as the point of pivot. There was higher flexibility in patients with PD with DBS ON and eyes open compared to DBS OFF and eyes closed (p ≤ 0.011). During balance perturbations, controls quickly adopted a new strategy that they retained throughout the test, but patients with PD were slower to adapt. Patients with PD further increased the coupling between segmental movement during balance perturbations with DBS ON but retained a high level of coupling with DBS OFF throughout balance perturbations. The ankle strategy during balance perturbations in patients with PD was most evident with DBS OFF and eyes closed. The increased coupling with balance perturbations implies a mechanism to reduce complexity at a cost of exerting more energy. Strategic alterations of posture were altered by DBS in patients with PD and were delayed. Our findings therefore show that DBS does not fully compensate for disease-related effects on posture.

Deep brain stimulation in the subthalamic nuclei alters postural alignment and adaptation in Parkinson's disease.

Parkinson's disease (PD) can produce postural abnormalities of the standing body position such as kyphosis. We investigated the effects of PD, deep brain stimulation (DBS) in the subthalamic nucleus (STN), vision and adaptation on body position in a well-defined group of patients with PD in quiet standing and during balance perturbations. Ten patients with PD and 25 young and 17 old control participants were recruited. Body position was measured with 3D motion tracking of the ankle, knee, hip, shoulder and head. By taking the ankle as reference, we mapped the position of the joints during quiet standing and balance perturbations through repeated calf muscle vibration. We did this to explore the effect of PD, DBS in the STN, and vision on the motor learning process of adaptation in response to the repeated stimulus. We found that patients with PD adopt a different body position with DBS ON vs. DBS OFF, to young and old controls, and with eyes open vs. eyes closed. There was an altered body position in PD with greater flexion of the head, shoulder and knee (p≤0.042) and a posterior position of the hip with DBS OFF (p≤0.014). With DBS ON, body position was brought more in line with the position taken by control participants but there was still evidence of greater flexion at the head, shoulder and knee. The amplitude of movement during the vibration period decreased in controls at all measured sites with eyes open and closed (except at the head in old controls with eyes open) showing adaptation which contrasted the weaker adaptive responses in patients with PD. Our findings suggest that alterations of posture and greater forward leaning with repeated calf vibration, are independent from reduced movement amplitude changes. DBS in the STN can significantly improve body position in PD although the effects are not completely reversed. Patients with PD maintain adaptive capabilities by leaning further forward and reducing movement amplitude despite their kyphotic posture.

Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease.

We previously reported the occurrence of Lewy bodies in grafted human fetal mesencephalic neurons in two patients with Parkinson's disease. Here, we have used immunohistochemistry and electron microscopy to characterize the development of Lewy bodies in one of these cases. This patient was operated in putamen on both sides at 12 or 16 years before death, respectively. We demonstrate that 2% of the 12-year-old and 5% of the 16-year-old grafted, presumed dopaminergic neurons contained Lewy bodies immunoreactive for alpha-synuclein. Based on morphological analysis, two forms of alpha-synuclein-positive aggregates were distinguished in the grafts, the first a classical and compact Lewy body, the other a loose meshwork aggregate. Lewy bodies in the grafts stained positively for ubiquitin and thioflavin-S, and contained characteristic alpha-synuclein immunoreactive electron dense fibrillar structures on electron microscopy. Our data indicate that Lewy bodies develop gradually in transplanted dopaminergic neurons in a fashion similar to that in dopaminergic neurons in the host substantia nigra.

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 Parkinson's 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 Parkinson's 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.

Effects of Deep Brain Stimulation on Postural Control in Parkinson's Disease.

The standard approach to the evaluation of tremor in medical practice is subjective scoring. The objective of this study was to show that signal processing of physiological data, that are known to be altered by tremor in Parkinson's disease (PD), can quantify the postural dynamics and the effects of DBS. We measured postural control and its capacity to adapt to balance perturbations with a force platform and perturbed balance by altering visual feedback and using pseudo-random binary sequence perturbations (PRBS) of different durations. Our signal processing involved converting the postural control data into spectral power with Fast-Fourier Transformation across a wide bandwidth and then subdividing this into three bands (0-4 Hz, 4-7 Hz and 7-25 Hz). We quantified the amount of power in each bandwidth. From 25 eligible participants, 10 PD participants (9 males, mean age 63.8 years) fulfilled the inclusion criteria; idiopathic PD responsive to l-Dopa; >1 year use of bilateral STN stimulation. Seventeen controls (9 males, mean age 71.2 years) were studied for comparison. Participants with PD were assessed after overnight withdrawal of anti-PD medications. Postural control was measured with a force platform during quiet stance (35 s) and during PRBS calf muscle vibration that perturbed stance (200 s). Tests were performed with eyes open and eyes closed and with DBS ON and DBS OFF. The balance perturbation period was divided into five sequential 35-s periods to assess the subject's ability to address postural imbalance using adaptation. The signal processing analyses revealed that DBS did not significantly change the dynamics of postural control in the 0-4 Hz spectral power but the device reduced the use of spectral power >4 Hz; a finding that was present in both anteroposterior and lateral directions, during vibration, and more so in eyes open tests. Visual feedback, which usually improves postural stability, was less effective in participants with PD with DBS OFF across all postural sway frequencies during quiet stance and during balance perturbations. The expected adaptation of postural control was found in healthy participants between the first and last balance perturbation period. However, adaptation was almost abolished across all spectral frequencies in both the anteroposterior and lateral directions, with both eyes open and eyes closed and DBS ON and OFF in participants with PD. To conclude, this study revealed that DBS altered the spectral frequency dynamics of postural control in participants through a reduction of the power used >4 Hz. Moreover, DBS tended to increase the stabilizing effect of vision across all spectral bands. However, the signal processing analyses also revealed that DBS was not able to restore adaptive motor control abilities in PD.

Long-term effects of pallidal or subthalamic deep brain stimulation on quality of life in Parkinson's disease.

We assessed the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) or internal pallidum (GPi-DBS) on health-related quality of life (HrQoL) in patients with advanced Parkinson's disease participating in a previously reported multicenter trial. Sickness Impact Profile (SIP) questionnaires were available for analysis in a subgroup of n = 20/20 patients with GPi-DBS and n = 45/49 patients with STN-DBS at baseline, 6 and 36 months. The SIP provides a physical dimension and a psychosocial dimension sum score and 12 category scores: Alertness/Intellectual Behavior (AIB), Ambulation (A), Body Care and Movement (BCM), Communication (C), Eating (E), Emotional Behavior (EB), Home Management (HM), Mobility (M), Recreation and Pastimes (RP), Sleep and Rest (SR), Social Interaction (SI), and Work (W). Motor functioning was assessed by means of the Unified Parkinson's Disease Rating Scale and diaries. At 6 months significant improvements in off-period motor symptoms and activities of daily living were paralleled by significant reductions in the total, physical, and psychosocial SIP score in both treatment groups. At 3 years, sustained improvements were observed in the physical dimension score, BCM, E, M, RP after STN-DBS and M, SI after GPi-DBS. All other SIP subscores approached baseline values, but were still the same or better (except C) whereas motor functioning remained stable after 36 months. STN-DBS and GPi-DBS led to significant early improvements in HrQoL. Despite sustained motor improvements many of these initial benefits were lost after 3 years. This may reflect either progression of the disease or adaptive changes in the subjective perception of health-related wellbeing over time.

The effects of high frequency subthalamic stimulation on balance performance and fear of falling in patients with Parkinson's disease.

BACKGROUND: Balance impairment is one of the most distressing symptoms in Parkinson's disease (PD) even with pharmacological treatment (levodopa). A complementary treatment is high frequency stimulation in the subthalamic nucleus (STN). Whether STN stimulation improves postural control is under debate. The aim of this study was to explore the effects of STN stimulation alone on balance performance as assessed with clinical performance tests, subjective ratings of fear of falling and posturography. METHODS: Ten patients (median age 66, range 59-69 years) with bilateral STN stimulation for a minimum of one year, had their anti-PD medications withdrawn overnight. Assessments were done both with the STN stimulation turned OFF and ON (start randomized). In both test conditions, the following were assessed: motor symptoms (descriptive purposes), clinical performance tests, fear of falling ratings, and posturography with and without vibratory proprioceptive disturbance. RESULTS: STN stimulation alone significantly (p = 0.002) increased the scores of the Berg balance scale, and the median increase was 6 points. The results of all timed performance tests, except for sharpened Romberg, were significantly (p or= 0.109) in torque variance values when comparing the two test situations. This applied both during quiet stance and during the periods with vibratory stimulation, and it was irrespective of visual input and sway direction. CONCLUSION: In this sample, STN stimulation alone significantly improved the results of the clinical performance tests that mimic activities in daily living. This improvement was further supported by the patients' ratings of fear of falling, which were less severe with the STN stimulation turned ON. Posturography could not be performed by three out of the ten patients when the stimulation was turned OFF. The posturography results of the seven patients with complete data showed no significant differences due to STN stimulation.

Multicenter study on deep brain stimulation in Parkinson's disease: an independent assessment of reported adverse events at 4 years.

Ongoing adverse events (AEs) at 4-years postsurgery in 69 patients with advanced Parkinson's disease (PD) who received deep brain stimulation (DBS) of the subthalamic nucleus (STN) (n = 49) or the internal globus pallidus (GPi) (n = 20), in the framework of a subset of eight centers of a multicenter study, were analyzed by an independent ad hoc committee. At baseline, the patients' age, sex, disease duration, and clinical condition were virtually identical, as was the duration of follow-up. There were 64 AEs reported in 53% of STN DBS patients and eight AEs reported in 35% of GPi DBS patients. Most of the AEs were not deemed severe and were reported to be present "both with and without stimulation." The majority of the AEs affected patients' cognitive, psychiatric and behavioral status, as well as speech, gait, and balance, and most of these AEs occurred in STN DBS patients. When comparing patients who exhibited AEs with those who did not, it was found that in the STN DBS group, the patients with AEs had a longer disease duration, as well as more gait disorders and psychiatric disturbances at baseline.

Dyskinesias following neural transplantation in Parkinson's disease.

Severe dyskinesias during the 'off' phases (periods of increased Parkinson's disease (PD) disability) have been observed following intrastriatal transplantation of human embryonic mesencephalic tissue. Here we retrospectively analyzed 14 patients who were followed for up to 11 years after grafting, and found that dyskinesias (abnormal involuntary movements and postures) increased during postoperative off phases, but were generally of mild to moderate severity. Dyskinesia severity was not related to the magnitude of graft-derived dopaminergic re-innervation, as judged by (18)F-labeled 6-L-fluorodopa (FD) positron emission tomography (PET), indicating that off-phase dyskinesias probably did not result from excessive growth of grafted dopaminergic neurons.

Fulfilment of patients' goals after thalamic deep brain stimulation: a follow-up study.

Deep brain stimulation (DBS) in the ventrolateral thalamus (VIM) is shown to reduce tremor in essential tremor (ET) and Parkinson's disease (PD). Our aim was to evaluate the results of VIM DBS from the patients' perspective. Sixteen consecutively included patients (8 ET and 8 PD) described their own outcome goals preoperatively and evaluated the fulfillment 1, 6 and 12 months postoperatively. We conclude that the patients could do specific activities that are of importance to them such as eating, drinking and socializing, and perceived either partial or total fulfillment of their goals.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 µg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

Women pioneers in basal ganglia surgery.

BACKGROUND: Stereotactic functional neurosurgery on basal ganglia has a long history and the pioneers are mostly men. We aimed at finding out if there were women who have contributed pioneering work in this field. METHODS: The literature was searched to identify women who have been first to publish innovative papers related to human basal ganglia surgery. RESULTS: Six women fulfilling our criteria were found: Marion Smith, a British neuropathologist, made unique observations on stereotactic lesions of basal ganglia and thalamus on autopsied brains, and the lesions' relation to the reported clinical outcome. Natalia Bechtereva, a Russian neurophysiologist, pioneered the technique of therapeutic chronic deep brain stimulation to treat various brain disorders, including Parkinson's disease (PD). Denise Albe-Fessard, a French neurophysiologist, pioneered the technique of microelectrode recording (MER) in stereotactic functional neurosurgery. Gunvor Kullberg, a Swedish neurosurgeon, contributed in early CT imaging as well as early functional imaging of stereotactic lesions in PD and psychiatric patients. Hilda Molina, a Cuban neurosurgeon, established the Centro Internacional de Restauración Neurológica (CIREN) and pioneered there MER-guided transplant surgery in PD patients. Veerle Vandewalle, a Belgian neurosurgeon, pioneered in 1999 deep brain stimulation (DBS) for Tourette Syndrome. CONCLUSION: Although men constitute the great majority of neurosurgeons, neurologists and other neuro-specialists who have made groundbreaking contributions in basal ganglia surgery, there are women who have made equally important and unique contributions to the field. The principal two techniques used today in functional stereotactic neurosurgery, MER and DBS, have once upon a time been pioneered by women.

Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports.

IMPORTANCE: Recent advances in stem cell technologies have rekindled an interest in the use of cell replacement strategies for patients with Parkinson disease. This study reports the very long-term clinical outcomes of fetal cell transplantation in 2 patients with Parkinson disease. Such long-term follow-up data can usefully inform on the potential efficacy of this approach, as well as the design of trials for its further evaluation. OBSERVATIONS: Two patients received intrastriatal grafts of human fetal ventral mesencephalic tissue, rich in dopaminergic neuroblasts, as restorative treatment for their Parkinson disease. To evaluate the very long-term efficacy of the grafts, clinical assessments were performed 18 and 15 years posttransplantation. Motor improvements gained gradually over the first postoperative years were sustained up to 18 years posttransplantation, while both patients have discontinued, and remained free of any, pharmacological dopaminergic therapy. CONCLUSIONS AND RELEVANCE: The results from these 2 cases indicate that dopaminergic cell transplantation can offer very long-term symptomatic relief in patients with Parkinson disease and provide proof-of-concept support for future clinical trials using fetal or stem cell therapies.

First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation.

The c.4309A>C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.

Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants.

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-HT(1A)) 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.