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.

The effect of deprenyl (selegiline) on the natural history of Parkinson's disease.

The effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that produces the symptoms of Parkinson's disease, can be fully prevented in experimental animals by inhibiting monoamine oxidase B. On the basis of this observation, a double-blind, placebo-controlled study in patients with early Parkinson's disease was initiated to determine whether deprenyl (a selective monoamine oxidase B inhibitor) would delay the need for L-dopa therapy by slowing the progression of the disease. Fifty-four patients were randomly assigned to deprenyl (10 mg/day) or placebo treatment groups and followed until L-dopa therapy was indicated or until the patient had been in the study for 3 years. Analysis of Kaplan-Meier survival curves for each group showed that deprenyl delayed the need for L-dopa therapy; the average time until L-dopa was needed was 312.1 days for patients in the placebo group and 548.9 days for patients in the deprenyl group. Disease progression, as monitored by five different assessment scales, was slowed (by 40 to 83% per year) in the deprenyl group compared to placebo. Therefore, early deprenyl therapy delays the requirement for antiparkinsonian medication, possibly by slowing progression of the disease.

Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis.

Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.

Pargyline prevents MPTP-induced parkinsonism in primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin which produces permanent parkinsonism in human and nonhuman primates. Treatment of squirrel monkeys with pargyline, a monoamine oxidase (MAO) inhibitor, prevents both clinical and neuropathological evidence of the neurotoxic effects of MPTP. Pargyline also inhibits conversion of MPTP to 1-methyl-4-phenylpyridinium ion (MPP+), a metabolic step that occurs rapidly after administration of MPTP in animals not treated with pargyline. It is proposed that the conversion of MPTP to MPP+, possibly involving MAO, may be important for the neurotoxic effects of MPTP to take place, and MPTP itself may not be the neurotoxic agent.

GDNF induces a dystonia-like state in neonatal rats and stimulates dopamine and serotonin synthesis.

To test whether glial cell line-derived neurotrophic factor (GDNF) regulates the development of nigral dopaminergic neurons in vivo, neonatal rats received bilateral injections of GDNF into the striatum. Injections at postnatal day 2 induced a unique transient behavioral pattern characterized by forelimb hyperflexure, clawed toes of all limbs, and a kinked tail. Parallel to the behavioral changes, the levels of striatal and ventral mesencephalic dopamine and serotonin were increased from 60% to 100% with a proportional increase of principal metabolite levels. GDNF increased tyrosine hydroxylase activity in the ventral mesencephalon, but did not affect striatal activity of choline acetyltransferase and GABA uptake. GDNF failed to induce sprouting of dopaminergic neurites. Our findings suggest that during development striatal GDNF regulates the capacity of dopaminergic and of serotonergic neurons for neurotransmitter production and release.

Novel features in a patient homozygous for the L347P mutation in the PINK1 gene.

The purpose of this study was to assess the genotype-phenotype of PINK1 mutations. We genotyped eight known mutations in three clinic-based cohorts with Parkinsonism and found one homozygous p.L347P mutation in PINK1. Clinically, hypo-osmia and profound diurnal variation of symptoms were identified as novel features; fluorodopa positron emission tomography revealed striking decline in striatal fluorodopa uptake. We suggest that it may be possible to clinically separate this form of Parkinsonism from dopa-responsive dystonia and Parkin-related Parkinsonism. Furthermore, as this mutation has only been reported in Filipinos (two originated from Luzon island), our results support the hypothesis of a common founder.

Decreased susceptibility to oxidative stress underlies the resistance of specific dopaminergic cell populations to paraquat-induced degeneration.

The vulnerability of different dopaminergic cell populations to damage caused by the herbicide paraquat was assessed by stereological counts of tyrosine hydroxylase-positive and calbindin-D28k-immunoreactive neurons in A9 (substantia nigra pars compacta) and A10 (ventral tegmental area and other cell groups). In saline-treated control mice, tyrosine hydroxylase-immunoreactive neurons represented 80% and 45% of the total neuronal population in A9 and A10, respectively, and the number of calbindin-D28k-positive neurons was five times greater in A10 than A9. Sequential injections with paraquat resulted in a significant loss of dopaminergic neurons in A9. In contrast, tyrosine hydroxylase-positive cells in A10 were spared from paraquat-induced degeneration. Furthermore, expression of calbindin-D28k was consistently associated with neuronal resistance to the herbicide in both A9 and A10. Paraquat exposure also induced oxidative stress as indicated by an increase in the number of midbrain cells positive for 4-hydroxy-2-nonenal, a marker of lipid peroxidation. Co-localization studies revealed that calbindin-D28k immunoreactivity overlapped with tyrosine hydroxylase labeling and that, after paraquat administration, (i) the vast majority of midbrain 4-hydroxy-2-nonenal-immunoreactive cells were dopaminergic (tyrosine hydroxylase-immunoreactive), (ii) tyrosine hydroxylase/4-hydroxy-2-nonenal-positive neurons were much more prevalent in A9 than A10, and (iii) all calbindin-D28k-containing neurons were characterized by lack of lipid peroxidation (4-hydroxy-2-nonenal immunoreactivity). Results in this paraquat model emphasize that, despite sharing a similar dopaminergic phenotype, different groups of midbrain neurons vary dramatically in their vulnerability to injury. Data also indicate that these differences are attributable, at least in part, to a varying susceptibility of dopaminergic cell populations to oxidative stress.

Diffusion tensor imaging of tract involvement in children with pontine tumors.

BACKGROUND AND PURPOSE: Conventional MR imaging permits subcategorization of brain stem tumors by location and focality; however, assessment of white matter tract involvement by tumor is limited. Diffusion tensor imaging (DTI) is a promising method for visualizing white matter tract tumor involvement supratentorially. We investigated the ability of DTI to visualize and quantify white matter tract involvement in pontine tumors. METHODS AND MATERIALS: DTI data (echo-planar, 1.5T) were retrospectively analyzed in 7 patients with pontine tumors (6 diffuse, 1 focal), 4 patient controls, and 5 normal volunteers. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated from the diffusion tensor in 6 regions of interest: bilateral corticospinal tracts, transverse pontine fibers, and medial lemnisci. Relationships between FA and ADC values and results of the neurologic examinations were evaluated. RESULTS: The corticospinal tracts and transverse pontine fibers were affected more often than the medial lemnisci. The DTI parameters (FA and ADC) were significantly altered in all tracts of patients with pontine tumors (P < .05), compared with those values in the control groups. A marginally significant (P = .057) association was seen between the severity of cranial nerve deficit and decreased FA. CONCLUSION: DTI provided superior visualization and quantification of tumor involvement in motor, sensory, and transverse pontine tracts, compared with information provided by conventional MR imaging. Thus, DTI may be a sensitive measure of tract invasion. Further prospective studies are warranted to assess the ability of DTI to delineate tumor focality and improve risk stratification in children with pontine tumors.

Low-grade astrocytoma: a decade of experience at St. Jude Children's Research Hospital.

PURPOSE: To evaluate the impact of primary tumor site, age at diagnosis, extent of resection, and histology on progression-free survival (PFS) in pediatric low-grade astrocytoma. PATIENTS AND METHODS: Medical, pathologic, and imaging information were reviewed for 142 children (ages 2 months to 19 years) with low-grade astrocytoma treated between January 1984 and July 1994. Gross total resection (GTR) was attempted for cerebellar and cerebral hemisphere tumors, with biopsy or less aggressive resection used predominantly for tumors in other sites. Surgery was followed by observation in 107 cases, radiation therapy in 31, and chemotherapy in four. RESULTS: The overall survival rate was 90% +/- 3% (SE) at 4 years. PFS was significantly better for patients with cerebellar and cerebral hemisphere tumors (n = 75) than those with tumors in all other sites (P = .0006). Within the former group, there was no significant difference in PFS for patients in whom GTR was achieved versus those with incomplete resections (4-year estimates, 89% and 77%, respectively). Histology (juvenile pilocytic v astrocytoma not otherwise specified [NOS]) was not related to PFS in an analysis that controlled for tumor site and patient age. Patients younger than 5 years at diagnosis had a significantly poorer PFS than older children, regardless of histology (P < .03) or tumor site (P < .002). Treatment for progressive/recurrent disease was effective in a majority of patients, but appeared more successful in patients with hemispheric than thalamic or hypothalamic tumors. CONCLUSION: The overall survival in this series of pediatric low-grade astrocytomas is excellent. Age at diagnosis and tumor location, but not histology, had a significant impact on PFS. Efforts to improve treatment outcome should focus on young patients (< 5 years) and on those with central midline tumors. The majority of patients with completely resected hemispheric tumors were monitored without further therapy, which supports attempted GTR of cerebral and cerebellar hemisphere low-grade astrocytoma.

Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor.

PURPOSE: Leptomeningeal disease (LMD) significantly affects the prognosis and treatment of pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). Examination of CSF for malignant cells, detection of LMD on spinal magnetic resonance imaging (MRI), or both are the methods routinely used to diagnose LMD. A recent study suggested 100% correlation between CSF and MRI findings in children with medulloblastoma. To determine the validity of this hypothesis, we compared the rate of detection of LMD between concurrent lumbar CSF cytology and spinal MRI performed at diagnosis in patients with medulloblastoma or PNET. PATIENTS AND METHODS: As a part of diagnostic staging, 106 consecutive patients newly diagnosed with medulloblastoma or PNET were evaluated with concurrent lumbar CSF cytology and spinal MRI. CSF cytology was examined for the presence of malignant cells and spinal MRI was reviewed independently for the presence of LMD. RESULTS: Thirty-four patients (32%) were diagnosed with LMD based on CSF cytology, spinal MRI, or both. There were 21 discordant results. Nine patients (8.5%) with positive MRI had negative CSF cytology. Twelve patients (11.3%) with positive CSF cytology had negative MRIs. The exact 95% upper bounds on the proportion of patients with LMD whose disease would have gone undetected using either CSF cytology or MRI as the only diagnostic modality were calculated at 14.4% and 17.7%, respectively. CONCLUSION: With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET. Thus, both CSF cytology and spinal MRI should routinely be used to diagnose LMD in patients with medulloblastoma or PNET.

Preirradiation cisplatin and etoposide in the treatment of high-risk medulloblastoma and other malignant embryonal tumors of the central nervous system: a phase II study.

Medulloblastoma, pineoblastoma, and cerebral neuroblastoma are malignant embryonal tumors of the CNS that may demonstrate similar histologic features, a propensity for neuraxis dissemination and sensitivity to radiation therapy and, in certain cases, chemotherapy. To evaluate the activity of preirradiation chemotherapy in such tumors, 11 newly diagnosed children with measurable residual disease and characteristics indicative of poor prognosis were treated postoperatively with cisplatin (CDDP) and etoposide (VP-16). Responses graded on the basis of radiographic findings in areas of either macroscopic residual tumor or metastatic disease included two complete responses (CRs), eight partial responses (PRs), and one stable disease (SD). Acute and subacute toxicity consisted of high-frequency hearing loss in four patients, reversible signs and symptoms of increased intracranial pressure in two patients, and transient neutropenia. Seven of eight patients with high-risk medulloblastoma and two of two with pineoblastoma remain free of tumor progression following neuraxis irradiation at 8 to 48 months postdiagnosis (median, 18 months). CDDP and VP-16 is a highly active drug combination when given before irradiation in children with high-risk medulloblastoma and other malignant embryonal tumors of the CNS, producing objective responses in at least one site of measurable disease in 10 of 11 newly diagnosed patients, including all of five with gross neuraxis dissemination.

Enhanced striatal opioid receptor-mediated G-protein activation in L-DOPA-treated dyskinetic monkeys.

Long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease leads to dyskinesias in the majority of patients. The underlying molecular mechanisms for L-DOPA-induced dyskinesias (LIDs) are currently unclear. However, the findings that there are alterations in opioid peptide mRNA and protein expression and that opioid ligands modulate dyskinesias suggest that the opioid system may be involved. To further understand its role in dyskinesias, we mapped opioid receptor-stimulated G-protein activation using [35S]guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) autoradiography in the basal ganglia of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned squirrel monkeys administered water or L-DOPA. Subtype-selective opioid receptor G-protein coupling was investigated using the mu-opioid agonist [D-Ala, N-Me-Phe, Gly-ol]-enkephalin, delta-agonist SNC80 and kappa-agonist U50488H. Our data show that mu-opioid receptor-mediated G-protein activation is significantly enhanced in the basal ganglia and cortex of L-DOPA-treated dyskinetic monkeys, whereas delta- and kappa-receptor-induced increases were limited to only a few regions. A similar pattern of enhancement was observed in both MPTP-lesioned and unlesioned animals with LIDs suggesting the effect was not simply due to a compromised nigrostriatal system. Opioid receptor G-protein coupling was not enhanced in non-dyskinetic L-DOPA-treated animals, or lesioned monkeys not given L-DOPA. The increases in opioid-stimulated [35S]GTPgammaS binding are directly correlated with dyskinesias. The present data demonstrate an enhanced subtype-selective opioid-receptor G-protein coupling in the basal ganglia of monkeys with LIDs. The positive correlation with LIDs suggests this may represent an intracellular signaling mechanism underlying these movement abnormalities.

Amphotericin B-induced myelopathy.

Two patients with coccidioidal meningitis experienced transient neurologic deficits shortly after receiving intrathecal injections of amphotericin B. Continuation of treatment eventually led to a severe flaccid paraparesis with a thoracic sensory level in one patient, and a partial Brown-Séquard's syndrome in the other. Myelography was normal in both, with no evidence of arachnoiditis. Autopsy findings in the first patient showed a focal area of necrosis in the left half of the spinal cord consistent with the patient's clinical findings during life. The distribution of the lesion corresponded to the area supplied by a central sulcal artery. Amphotericin B may exert a direct toxic effect on the spinal cord or its vascular supply when given intrathecally.

MPTP-induced parkinsonism as a model for Parkinson's disease.

It is now well recognized that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce a syndrome in human and non-human primates similar to Parkinson's disease. This highly selective neurotoxin, which affects specific catecholaminergic nuclei in the brainstem, has provided an important new tool for the study of Parkinson's disease. In this article we review several specific areas related to current research on MPTP, including the question of disease progression, issues regarding the validity of the animal model induced by MPTP, the role of aging in regard to its neurotoxicity and Parkinson's disease, and new therapeutic strategies that have evolved from basic research with the compound. We conclude that both clinical and basic research stemming from the discovery of MPTP have provided valuable insights regarding both the cause and treatment of Parkinson's disease.

MPTP-induced parkinsonism in human and non-human primates--clinical and experimental aspects.

In this review, we describe the discovery of a new neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPTP, which appears to be highly selective for the substantia nigra of human and non-human primates. This compound appears to produce a "pure" parkinsonian state more consistently than most, if not all previously described neurotoxins. Identification of its unique properties has already led to the development of an animal model for Parkinson's disease in the monkey. In this paper we review the history of the compound, and describe its clinical effects in man and monkeys. Experiments are reviewed which suggest that the "4-5" double bond in the nitrogen-containing ring is key for this compound to exert its toxic effects, probably serving as a starting point for oxidation of MPTP to its quaternary amine, 1-methyl-4-phenylpyridinium ion (MPP+). MPTP appears to be rapidly converted to the latter compound in all tissues studied to date, including brain. We believe that this newly recognized nigrotoxin holds promise as a tool for the study of Parkinson's disease and the nigrostriatal dopaminergic system of the brain.

Nigrostriatal monoamine oxidase A and B in aging squirrel monkeys and C57BL/6 mice.

In this study we assessed the two forms of monoamine oxidase (MAO) in the caudate, putamen, and substantia nigra of young (4-year-old), intermediate-aged (11-year-old), and aged (20-year-old) squirrel monkeys and in the striata of young (2-month-old) and older (10-month-old) C57Bl/6 mice. MAO A and B activities were determined by measuring the rate of oxidation of the specific substrates phenethylamine and serotonin. In squirrel monkey, the vast majority of MAO activity was MAO B with activity of this isoform 10 times greater than of MAO A, while in mice the activity of the two forms was approximately equivalent. Although mice demonstrated nearly twofold selective increases in striatal MAO B between 2 and 10 months of age, neither MAO B nor A showed statistically significant changes with age in squirrel monkeys. These results document the marked differences between nonhuman primates and rodents with respect to the relative activities and the effects of age on MAO A and B, and indicate that increased MAO is not an inevitable feature of aging.

Evolution of nerve fiber degeneration in the striatum in the MPTP-treated squirrel monkey.

We have examined the ultrastructure of the striatum in squirrel monkeys 1-5 d after a single sc injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 2.5 mg/kg. One untreated monkey served as control. We expected to find a dense degeneration of the dopamine terminals, but found instead that the main abnormality consisted of a focal vacuolation of the tissue, perhaps related to the striosome/matrix mosaic of the neostriatum. The vacuolation involved not only terminals, but also other parts of the neuropil. The severity of the destructive process increased from d 1-5. We conclude that MPP+, the toxic metabolite of MPTP, may gain access to the neuropil, either before or after its active uptake into and subsequent destruction of the dopamine terminals. In the present study, abnormalities were observed simultaneously in the striatum and substantia nigra as early as 24 h after MPTP administration. It is, however, possible that the time-course might differ between the two locations with even shorter time intervals or changes in dosage of MPTP.

Localization of nicotinic receptor subunit mRNAs in monkey brain by in situ hybridization.

Nicotinic receptors are implicated in memory, learning, locomotor activity, and addiction. Identification of the specific receptor subtypes that mediate these behaviors is essential for understanding their role in central nervous system (CNS) function. Although expression of nicotinic receptor transcript has been studied in rodent brain, their localization in the monkey CNS, which may be a better model for the human brain, is not yet known. We therefore investigated the distribution of alpha4, alpha6, alpha7, beta2, beta3, and beta4 receptors subunit mRNAs in the monkey brain by using in situ hybridization. alpha4 and alpha7 mRNAs were very widely expressed, with a substantial degree of overlap in their distribution, except for the reticular nucleus of the thalamus in which alpha7 mRNA was much more prominently expressed. beta2 and beta4 mRNA were also widely distributed, although beta4 was more prominently localized in thalamic nuclei than beta2. The distribution of alpha6 and beta3 mRNA was very distinct from that of the other transcripts, being restricted to catecholaminergic nuclei, the cerebellum, and a few other areas. Although there were similarities in distribution of the nicotinic receptor subunit mRNAs in monkey and rodent brain, there were prominent differences in areas such as the caudate, putamen, locus coeruleus, medial habenula, and cerebellum. In fact, the distribution of alpha4 and alpha7 mRNAs in the monkey caudate and putamen was more similar to that reported in the human than rodent brain. These findings have implications for the development of drug therapies for neurological disorders, such as Alzheimer's and Parkinson's disease, in which nicotinic receptors are decreased.

Disulfiram-induced encephalopathy.

Two patients with disulfiram-(Antabuse-)induced encephalopathy exhibited paranoid ideas, disorientation, impaired memory, ataxia, dysarthria, snout and grasp reflexes, and abnormal electroencephalograms. The first patient developed symptoms on two occasions, each time after disulfiram administration. The second patient experienced a generalized seizure followed by fulminant psychosis three weeks after starting disulfiram therapy. Spinal fluid examination in the latter patient revealed a low homovanillic acid (HVA) level. Since disulfiram inhibits dopamine oxidation, disulfiram-induced encephalopathy may be related to excess dopaminergic activity in the central nervous system.

Infantile hemifacial spasm.

A 6-week-old infant had recurrent contractions of the facial musculature on the left side, which continued throughout early childhood. Surgical exploration at 5 1/2 years of age revealed a ganglioneuroma of the fourth ventricle. Hemifacial spasm (HFS) in infancy and childhood suggests the possibility of serious intracranial pathologic findings.