Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Therapeutic efficacy of unilateral subthalamotomy in Parkinson's disease: results in 89 patients followed for up to 36 months.

BACKGROUND: Stereotactic thermocoagulative lesions of the subthalamic nucleus (STN) have been shown to induce significant motor improvement in patients with Parkinson's disease (PD). PATIENTS AND METHODS: 89 patients with PD were treated with unilateral subthalamotomy. 68 patients were available for evaluations after 12 months, 36 at 24 months and 25 at 36 months. RESULTS: The Unified Parkinson's Disease Rating Scale (UPDRS) motor scores improved significantly contralaterally to the lesion in the "off" and "on" states throughout the follow-up, except for the "on" state at the last evaluation. Axial features and signs ipsilateral to the lesion progressed steadily throughout the study. Levodopa daily doses were significantly reduced by 45%, 36% and 28% at 12, 24 and 36 months post-surgery. 14 patients (15%) developed postoperative hemichorea-ballism which required pallidotomy in eight. These 14 patients had significantly higher dyskinesia scores (levodopa induced) preoperatively than the entire cohort. CONCLUSION: Unilateral subthalamotomy was associated with significant and sustained motor benefit contralateral to the lesion. Further work is needed to ascertain what factors led to severe, persistent chorea-ballism in a subset of patients. Subthalamotomy may be considered an option in circumstances when deep brain stimulation is not viable.

Putamen: activity of single units during slow and rapid arm movements.

The activity of putamen neurons was studied in a monkey during the performance of both slow and rapid arm movements. More than half of all movement-related units discharged preferentially in relation to slow movements and less than 10 percent in relation to rapid movements. These findings indicate that at least a portion of the basal ganglia (the putamen) is primarily involved in the control of slow movements and are consistent with the hypothesis of Kornhuber that the primary motor function of the basal ganglia is to generate slow ("ramp") rather than rapid ("ballistic") movements.

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.

Although it is known that Parkinson's disease results from a loss of dopaminergic neurons in the substantia nigra, the resulting alterations in activity in the basal ganglia responsible for parkinsonian motor deficits are still poorly characterized. Recently, increased activity in the subthalamic nucleus has been implicated in the motor abnormalities. To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor. This result supports the postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease.

Alzheimer's disease: a disorder of cortical cholinergic innervation.

Great emphasis is being placed on identification of neurotransmitter systems involved in the symptomatic manifestations of neurological and psychiatric disorders. In the case of Alzheimer's disease, which now seems to be one of the most common causes of mental deterioration in the elderly, compelling evidence has been developed that acetylcholine-releasing neurons, whose cell bodies lie in the basal forebrain, selectively degenerate. These cholinergic neurons provide widespread innervation of the cerebral cortex and related structures and appear to play an important role in cognitive functions, especially memory. These advances reflect a close interaction between experimental and clinical neuroscientists in which information derived from basic neurobiology is rapidly utilized to analyze disorders of the human brain.

Primate models of movement disorders of basal ganglia origin.

Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorders (of which Parkinson's disease is the best-known example) at one extreme to the hyperkinetic disorders (exemplified by Huntington's disease and hemiballismus) at the other. Both extremes of this movement disorder spectrum can be accounted for by postulating specific disturbances within the basal ganglia-thalamocortical 'motor' circuit. In this paper, Mahlon DeLong describes the changes in neuronal activity in the motor circuit in animal models of hypo- and hyperkinetic disorders.

Functional and pathophysiological models of the basal ganglia.

Because of new data, anatomical and functional models of the basal ganglia in normal and pathological conditions (e.g. Parkinson's and Huntington's diseases) have recently come under greater scrutiny. An update of these models is clearly timely, taking into consideration not only changes in neuronal discharge rates, but also changes in the patterning and synchronization of neuronal discharge, the role of extrastriatal dopamine, and expanded intrinsic and input/output connections of these nuclei.

Basal ganglia discharge abnormalities in Parkinson's disease.

In the traditional model of the pathophysiology of parkinsonism, parkinsonian motor signs are viewed as the result of changes in discharge rates in the basal ganglia. However, not all experimental findings can be explained by rate changes alone, and changes in discharge patterns in these nuclei are increasingly emphasized as pathophysiologically important, including changes in burst discharges, in synchrony, and in oscillatory activity. This brief review highlights the pathophysiologic relevance of these rate and pattern changes in the pathophysiology of parkinsonism.

Bilateral subthalamotomy in Parkinson's disease: initial and long-term response.

We conducted an open label pilot study of the effect of bilateral subthalamotomy in 18 patients with advanced Parkinson's disease. In seven patients, the first subthalamotomy pre-dated the second by 12-24 months ('staged surgery'). Subsequently, a second group of 11 patients received bilateral subthalamotomy on the same day ('simultaneous surgery'). Patients were assessed according to the CAPIT (Core Assessment Program for Intracerebral Transplantation) protocol, a battery of timed motor tests and neuropsychological tests. Evaluations were performed in the 'off' and 'on' drug states before surgery and at 1 and 6 months and every year thereafter for a minimum of 3 years after bilateral subthalamotomy. Compared with baseline, bilateral subthalamotomy induced a significant (P < 0.001) reduction in the 'off' (49.5%) and 'on' (35.5%) Unified Parkinson's Disease Rating Scale (UPDRS) motor scores at the last assessment. A blind rating of videotape motor exams in the 'off' and 'on' medication states preoperatively and at 2 years postoperatively also revealed a significant improvement. All of the cardinal features of Parkinson's disease as well as activities of daily living (ADL) scores significantly improved (P < 0.01). Levodopa-induced dyskinesias were reduced by 50% (P < 0.01), and the mean daily levodopa dose was reduced by 47% at the time of the last evaluation compared with baseline (P < 0.0001). Dyskinesias occurred intraoperatively or in the immediate postoperative hours in 13 patients, but were generally mild and short lasting. Three patients developed severe generalized chorea that gradually resolved within the next 3-6 months. Three patients experienced severe and persistent postoperative dysarthria. In two, this coincided with the patients exhibiting large bilateral lesions also suffering from severe dyskinesias. No patient exhibited permanent cognitive impairment. The motor benefit has persisted for a follow-up of 3-6 years. This study indicates that bilateral subthalamotomy may induce a significant and long-lasting improvement of advanced Parkinson's disease, but the clinical outcome was variable. This variability may depend in large part on the precise location and volume of the lesions. Further refinement of the surgical procedure is mandatory.

Organization of striatopallidal, striatonigral, and nigrostriatal projections in the macaque.

The topographic organization of neostriatal connections was investigated by axonal transport of horseradish peroxidase, tritiated amino acids, or mixtures of both injected into the neostriatum of macaque monkeys. Striatal projections to pallidum and substantia nigra and the origin of projections to striatum from cerebral cortex and substantia nigra were examined. All striatal injections gave rise to projections to external and internal pallidum and to substantia nigra. Injections in caudate nucleus and in putamen both gave rise to substantial projections to pallidum and to substantia nigra, and the ratio of pallidal and nigral projections was generally similar. The striatopallidal projection showed prominent arborizations at right angles to the striatofugal pathway traversing the pallidum, forming in this manner terminal fields consisting of multiple bands or discs within a broad segment of the pallidum. Thus separate but neighboring regions of striatum appeared to have overlapping pallidal projection territories. In broad terms, rostral striatum projects to rostral pallidum, caudal striatum to caudal pallidum, and dorsal and ventral striatum, respectively, to dorsal and ventral pallidum. Inner (medial) and outer (lateral) putamen showed only subtle differences in pallidal projection patterns. The striatonigral projection from each injected area of striatum formed a longitudinal band extending over the entire length of the substantia nigra, with scattered, dense terminal fields occupying portions of pars compacta as well as pars reticularis. Rostral striatum projected to medial nigra and caudal striatum to lateral nigra. Terminal fields from ventral striatum were located somewhat more dorsally in the substantia nigra than those from dorsal striatum. Neighboring but separate regions of striatum appeared to have overlapping nigral projection territories, especially in caudal nigra. The nigrostriatal neurons projecting to an injected area of striatum generally were located in the same longitudinal band of the substantia nigra as the corresponding striatonigral projection. Labeled pars compacta neurons were often surrounded by a dense, labeled striatonigral terminal field, suggesting the existence of a striato-nigrostriatal loop. The rostromedial pars compacta contained labeled neuronal cell bodies in most cases, suggesting a widely divergent projection to striatum from this cell group. A slight tendency for preferential cell labeling rostrally in nigra with rostral striatal injection and caudally in nigra with caudal injections was noted. The preferred relationship of lateral nigra with caudal striatum and medial nigra with rostral striatum has implications for clinical expression of Parkinson's disease, which may vary with differential involvement of different nigral cell groups along the medial to lateral axis.(ABSTRACT TRUNCATED AT 400 WORDS)

Synaptic innervation of neurones in the internal pallidal segment by the subthalamic nucleus and the external pallidum in monkeys.

In order to better understand the way by which the subthalamic nucleus interacts with the globus pallidus to control the output of the basal ganglia, we carried out a series of experiments to investigate the pattern of synaptic innervation of the pallidal neurones by the subthalamic terminals in the squirrel monkey. To address this problem we used the anterograde transport of biocytin. Following injections of biocytin in the subthalamic nucleus, rich plexuses of labelled fibres and varicosities formed bands that lay along the medullary lamina in both segments of the ipsilateral pallidum. At the electron microscopic level, two populations of biocytin-containing terminals were identified in the internal pallidum (GPi). A first group of small to medium-sized terminals (type 1; mean cross-sectional area +/- S.D. = 0.41 +/- 0.04 microns 2) contained round vesicles and formed asymmetric synapses with dendritic shafts (95%) of mixed sizes (maximum diameter ranging from 0.3 to 4.0 microns) and spine-like structures (5%). The second group of terminals (type 2) contained pleiomorphic vesicles, had a larger cross-sectional area (mean +/- S.D. = 0.9 +/- 0.4 micron 2) and formed symmetric synapses predominantly with perikarya (41%) and large dendrites (57%). In some cases, the two types of terminals converged at the level of single GPi neurones. Postembedding immunogold method revealed that the type 2 terminals displayed gamma-aminobutyric acid (GABA) immunoreactivity, whereas the type 1 terminals did not. In the external pallidum (GPe), injections in the subthalamic nucleus labelled both type 1 or type 2 terminals. However, the labelled type 2 boutons were much less abundant in GPe than in GPi. The presence of biocytin-labelled perikarya in GPe and the fact that the type 2 terminals displayed GABA immunoreactivity led us to suspect that these terminals were derived from axons of GPe neurones. In agreement with this hypothesis, injections of Phaseolus vulgaris-leucoagglutinin (PHA-L) in GPe labelled terminals in GPi that displayed the morphological features and a pattern of synaptic organization similar to the type 2 terminals. In conclusion, the results of our study demonstrate that the subthalamopallidal terminals form asymmetric synapses that are distributed along the dendritic tree of GPe and GPi neurones. In contrast, the GPe projection to GPi gives rise to large GABA-containing terminals that form symmetric synapses predominantly with the proximal region of pallidal neurones.(ABSTRACT TRUNCATED AT 400 WORDS)

Course of motor and associative pallidothalamic projections in monkeys.

As a result of the frequent performance of lesioning and electrical stimulation procedures targeting the globus pallidus internus (GPi) to treat medically intractable hypokinetic and hyperkinetic movement disorders, the course of the pallidothalamic projections originating, in particular, from the motor territory of GPi has important clinical relevancy. To assess the organization of pallidothalamic projections originating from motor and associative portions of GPi, small quantities of the anterograde/ retrograde tracer, biotinylated dextran amine (BDA) were injected into localized regions of the caudal GPi in squirrel monkeys. The localization to motor and associative territories in GPi was confirmed by examining the corresponding regions of retrograde labeling in the striatum and subthalamic nucleus (STN). The labeled pallidothalamic fibers projected principally medially across the inferior edge of the internal capsule. The fiber bundle ventral to the caudal GPi was mainly devoid of labeling. Fibers labeled along the medial and inferior borders of GPi at centrorostral levels were traceable to the medial edge of the injections. The densest fiber labeling at rostral levels was produced by those injections with the greatest extent of rostral labeling of neurons. In opposition to generally accepted schemes, the findings from this study suggest that the pallidothalamic fibers originating from the caudal portions of GPi, including the motor territory, do not course ventromedially to form the ansa lenticularis, but rather, travel predominately medially through the lenticular fasciculus en route to the thalamus. Thus, proposed surgical schemes to target fibers ventral to the caudal GPi or at the rostral pole of GPi appear to be misguided.

Stereotactic pallidotomy in the treatment of Parkinson disease: an expert opinion.

The objective of this workshop was to provide recommendations on several issues involving pallidotomy for patients with medically intractable Parkinson disease to physicians, patients, and other health care providers. An international consortium of experts in neurology, neurosurgery, and neurophysiology who had extensive experience with pallidotomy were invited to the workshop. Participants were sent background materials from the scientific literature for review-based participant recommendations. A proposed agenda was circulated to all participants before the workshop, and the final agenda was based on their recommendations. Topics were introduced at the workshop by members of the organizing committee, followed by extensive group discussion. A draft of a consensus statement, based on the previous day's discussion, was circulated and further modifications were made. The final statement was agreed on by all members. The conclusions of the participants were: (1) Pallidotomy should be performed only at centers that have a team of physicians with substantial expertise and experience in the field. (2) Patients with disabling idiopathic Parkinson disease, without dementia, and who have exhausted medical therapy should be considered for pallidotomy. (3) All patients should be examined by means of standardized rating scales both preoperatively and postoperatively to ensure quality of care at each center. (4) Symptoms that respond best to pallidotomy include medication-induced dyskinesias, rigidity, and tremor, while balance, gait disorders, and hypophonia are generally less responsive to surgery. Benefits of pallidotomy appear to be long lasting. (5) Each institution's complication rate should be discussed before surgery.

Wilson's disease. Development of neurological disease after beginning penicillamine therapy.

Patients with neurological symptoms and signs of Wilson's disease have been frequently noted to have a worsening of their condition after beginning chelation therapy with D-penicillamine. Presymptomatic patients, however, are not expected to develop neurological manifestations once appropriate therapy is begun. We describe a patient who was seen with hepatic disease and no neurological symptoms who became neurologically incapacitated soon after beginning penicillamine therapy. This case identifies an unexpected complication of penicillamine therapy that should be watched for in the presymptomatic patient who is beginning therapy.

Complications of gamma knife surgery for Parkinson disease.

BACKGROUND: Many medical centers throughout the world offer radiosurgery with the gamma knife (GK) for pallidotomy and thalamotomy as a safe and effective alternative to radiofrequency ablative surgery and deep brain stimulation for Parkinson disease (PD). The reported incidence of significant complications varies considerably, and the long-term complication rate remains unknown. DESIGN: We describe 8 patients seen during an 8-month period referred for complications of GK surgery for PD. RESULTS: Of the 8 patients, 1 died as a result of complications, including dysphagia and aspiration pneumonia. Other complications included hemiplegia, homonymous visual field deficit, hand weakness, dysarthria, hypophonia, aphasia, arm and face numbness, and pseudobulbar laughter. In all patients, lesions were significantly off target. CONCLUSIONS: The 8 patients with PD seen in referral at our center for complications of GK surgery highlight a spectrum of potential problems associated with this procedure. These include lesion accuracy and size and the delayed development of neurological complications secondary to radiation necrosis. Gamma knife surgery may have a higher complication rate than has been previously appreciated due to delayed onset and underreporting. We believe that the risk-benefit ratio of the GK will require further scrutiny when considering pallidotomy or thalamotomy in patients with PD. Physicians using this technique should carefully follow up patients postoperatively for delayed complications, and fully inform patients of these potential risks.

Tactile spatial acuity and roughness discrimination: impairments due to aging and Parkinson's disease.

We used gratings of alternating ridges and grooves in a quantitative psychophysical investigation of tactile perception in patients with Parkinson's disease (PD) and age-matched normal controls. The groove width required for threshold discrimination of grating orientation was 25% higher in the control subjects compared to younger individuals studied previously (p = 0.004), indicating a small but significant decline in tactile spatial acuity with age. Relative to age-matched controls, patients with PD showed a twofold increase in the tactile spatial threshold (p = 3.07 x 10(-8), with somewhat greater impairment on the side more affected clinically (p = 0.03). Testing with the forearm prone, as compared to supine, produced a small improvement in the acuity of patients (p = 0.01) but not controls (p = 0.26). PD patients were also impaired in tactually discriminating grating roughness: their difference limens were over three times higher than those of controls (p = 5.74 x 10(-5)) for gratings differing in groove width, and over twice as high (p = 0.0003) for gratings differing in ridge width. We conclude that PD significantly impairs performance on these tactile tasks.

Pathophysiologic basis of surgery for Parkinson's disease.

Dopamine depletion induces a series of changes in the basal ganglia motor circuit that underlie the origin of the cardinal features of Parkinson's disease. It has now been established that hyperactivity of the subthalamic nucleus (STN) is an essential feature of the parkinsonian state. This leads to increased excitatory driving onto the globus pallidum internum (GPi) and substantia nigra reticulata (SNr) which, in turn, overinhibits the motor projections to the thalamus and brainstem. The STN and GPi have become the preferred targets for surgery to treat PD. In keeping with the classic pathophysiologic model, physiologic and neuroimaging studies in patients have shown that lesioning or functional blockades (by deep brain stimulation, or DBS) of these nuclei increased cortical activation, in parallel with clinical improvements of bradykinesia. Neuronal recording during surgery has also shown tremor-related activity in both the STN and GPi. However, the pathophysiologic model of the basal ganglia needs further refinement to provide a more detailed explanation of the origin of both tremor and rigidity in Parkinson's disease and to explain the antidyskinetic effect of surgery of the GPi and STN.

Cognitive impairments in advanced PD without dementia.

OBJECTIVE: To determine the nature and frequency of cognitive impairments in nondemented patients with advanced PD and their relationship to other variables potentially predictive of neuropsychological performance. METHODS: The neuropsychological performance of nondemented, nondepressed patients with idiopathic PD (n = 61) was quantified with respect to clinically available normative data. The relationship of neuropsychological measures to motor symptoms, age, years of education, disease duration, age at disease onset, disease deterioration rate, and dopaminergic therapy was assessed. RESULTS: Impairment was most frequent on measures sensitive to frontal lobe function (67% on Wisconsin Card Sorting Test number of categories, 30% on letter fluency, 30% on verbal learning). Poorer performance on multiple neuropsychological measures was related to greater overall motor abnormality (total Unified Parkinson's Disease Rating Scale score), increased bradykinesia on medication, older age, longer disease duration, and reduced education. CONCLUSIONS: Even in the absence of dementia or depression, patients with advanced PD are likely to show clinically significant impairments on neuropsychological measures sensitive to changes in dorsolateral prefrontal regions participating in cognitive basal ganglia-thalamocortical circuits.

Visual fields in patients with posterior GPi pallidotomy.

The objective of this study was to describe the incidence and types of visual field defects after posterior globus pallidus internus (GPi) pallidotomy for Parkinson's disease. The creation of the pallidotomy lesion carries a risk of damaging neighboring structures such as the optic tract. The reported frequency of visual field defects in patients after pallidotomy varies from 0 to 40%. Goldmann visual field testing was performed on 40 patients who underwent microelectrode-guided posterior GPi pallidotomy. The optic tract was identified during the procedure by listening during microelectrode recording for the evoked responses to light flashes and by assessing stimulation-induced subjective responses. After the first 18 patients, lesioning thresholds were increased from 0.5 to > or =1.0 mA so that the lesion was placed more distant from the optic tract. The location of individual lesions was determined on postsurgical MRI. Three patients (7.5%) had visual field defects likely related to the pallidotomy. These were contralateral homonymous superior quadrantanopias, associated in two patients with small paracentral scotomas. The incidence of visual field defects with the early technique was 11% (2/18) and decreased to 4.5% (1/22) after thresholds for lesioning were increased. Except for the location of the lesion relative to the optic tract (more ventral, adjacent to or extending into the optic tract), no other variable correlated with a post-pallidotomy visual field defect. Microelectrode-guided GPi pallidotomy is a relatively safe procedure as regards visual function even when the optic tract is used as a guide for lesion placement.

Neuropsychological and psychiatric sequelae of pallidotomy for PD: clinical trial findings.

OBJECTIVE: To evaluate the neuropsychological and psychiatric sequelae of unilateral posterior pallidotomy for treatment of PD. METHODS: Patients with idiopathic PD completed baseline and 3- and 6-month assessments after random assignment to an immediate surgery (n = 17) or medical management (n = 16) group. RESULTS: Compared with the medical management group, the immediate surgery group with single lesions centered on the posterior internal pallidum showed superior naming and response inhibition, better verbal recall at 6 months, but greater distractibility, a tendency toward lower phonemic fluency, and a transient (3 months' only) semantic fluency deficit. The group with left lesions had more neuropsychological deficits than the group with right lesions or the medical management group, although these occurred mainly at 3 (but not 6) months. At 6 months, the patients with left lesions showed better verbal memory retention than the patients with right lesions. On most measures, the pattern of individual clinical change did not differ as a function of surgery or lesion laterality, with the exception of a higher frequency of decline in phonemic fluency in the patients with left lesions at 6 months. Although psychiatric status did not change overall, a history of depression tended to increase the risk of a depressive episode following surgery. CONCLUSIONS: Well-targeted, uncomplicated, unilateral pallidotomy does not produce overall neuropsychological or psychiatric change, although there are subtle changes on specific measures sensitive to frontal lobe function.