Marinesco bodies and substantia nigra neuron density in Parkinson's disease.

AIM: Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. METHODS: Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. RESULTS: Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles. CONCLUSIONS: While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes.

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.

Incidence of Parkinson disease in North America.

Parkinson disease (PD) is the second most common age-related neurodegenerative condition diagnosed in North America. We recently demonstrated, using multiple epidemiological data sources, that the prevalence of PD diagnoses was greater than previously reported and currently used for clinical, research, and policy decision-making. Prior PD incidence estimates have varied, for unclear reasons. There is a need for improved estimates of PD incidence, not only for care delivery planning and future policy but also for increasing our understanding of disease risk. The objective of this study was thus to investigate the incidence of Parkinson disease across five epidemiological cohorts in North America in a common year, 2012. The cohorts contained data on 6.7 million person-years of adults ages 45 and older, and 9.3 million person-years of adults ages 65 and older. Our estimates of age-sex-adjusted incidence of PD ranged from 108 to 212 per 100,000 among persons ages 65 and older, and from 47 to 77 per 100,00 among persons ages 45 and older. PD incidence increased with age and was higher among males. We also found persistent spatial clustering of incident PD diagnoses in the U.S. PD incidence estimates varied across our data sources, in part due to case ascertainment and diagnosis methods, but also possibly due to the influence of population factors (prevalence of genetic risk factors or protective markers) and geographic location (exposure to environmental toxins). Understanding the source of these variations will be important for health care policy, research, and care planning.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.

BACKGROUND AND PURPOSE: In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS: Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.

Prevalence of Parkinson's disease across North America.

Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health-care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood.

The role of environmental toxins in the etiology of Parkinson's disease.

The production by the pyridine MPTP of a parkinsonian syndrome strikingly similar to the 'idiopathic' disorder, and the paucity of evidence supporting a hereditary or infectious etiology for Parkinson's disease (PD), have stimulated a search for environmental chemicals resembling MPTP that might cause PD. In support of this, descriptive epidemiological studies have found higher prevalences of PD in highly industrialized countries. In North America and Europe, early onset PD appears to be associated with rural residence. Factors associated with this include vegetable farming, well water drinking, wood pulp, paper and steel industries. In China, living in industrialized urban areas increases the risk of developing PD. Preliminary epidemiological evidence supports the hypothesis that environmental chemicals may be related to the development of PD, but specific chemicals and their specific mechanism(s) have not been identified.

Nongenetic causes of Parkinson's disease.

Study of the nongenetic causes of Parkinson's disease (PD) was encouraged by discovery of a cluster of parkinsonism produced by neurotoxic pyridine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the 1980s. Since that time, epidemiologic investigations have suggested risk factors, though their results do not establish causality. Pesticide exposure has been associated with increased risk in many studies. Other proposed risks include rural residence and certain occupations. Cigarette smoking, use of coffee/caffeine, and non-steroidal antiinflammatory drugs (NSAIDs) all appear to lower risk of PD, while dietary lipid and milk consumption, high caloric intake, and head trauma may increase risk. The cause of PD is likely multifactorial. Underlying genetic susceptibility and combinations of risk and protective factors likely all contribute. The combined research effort by epidemiologists, geneticists, and basic scientists will be needed to clarify the cause(s) of PD.

Encephalopathy in chronic renal failure responsive to deferoxamine therapy. Another manifestation of aluminum neurotoxicity.

We describe a patient undergoing chronic hemodialysis who developed a neurologic syndrome consisting of seizures, progressive myoclonus, and mild dementia and who responded to chelation therapy with deferoxamine mesylate. Neither her serum nor bone aluminum concentrations indicated aluminum toxicity. However, the presence of a positive deferoxamine-infusion test was suggestive of an elevated body burden of aluminum. Treatment with deferoxamine resulted in marked clinical improvement in her neurologic status within two months. The utility of using the deferoxamine-infusion test rather than serum aluminum levels in evaluating aluminum toxicity in chronic renal failure is suggested.

Relationship of aluminum to neurocognitive dysfunction in chronic dialysis patients.

Aluminum has been proposed as the causative agent in dialysis encephalopathy syndrome. We prospectively assessed whether other, less severe, neuropsychologic abnormalities were also associated with aluminum. A total of 16 patients receiving chronic dialytic therapy were studied. The deferoxamine infusion test (DIT) was used to assess total body aluminum burden. Neurologic function was evaluated by quantitative measures of asterixis, myoclonus, motor strength, and sensation. Cognitive function was assessed by measures of dementia, memory, language, and depression. There were four patients with a positive DIT (greater than 125 micrograms/L increment in serum aluminum) that was associated with an increase in the number of neurologic abnormalities observed, as well as an increase in severity of myoclonus, asterixis, and lower extremity weakness. Patients with a positive DIT also showed significant impairment in memory; however, no differences were noted on tests of dementia, depression, or language. There was no significant correlation between sex, age, presence of diabetes, mode of dialysis, years of chronic renal failure, years of dialysis or years of aluminum ingestion and any neurologic or neurobehavioral measurement, serum aluminum level, or DIT. These changes may represent early aluminum-associated neurologic dysfunction.

Pharmacology of hallucinations induced by long-term drug therapy.

The authors studied 20 patients with Parkinson's disease and prominent hallucinations related to dopaminergic or anticholinergic therapy. The character of the hallucinations appeared distinct from the classic description of either acute anticholinergic or acute aminergic hallucinatory states. Manipulation of either kind of drug could precipitate or relieve hallucinations in a given patient, which suggests that the dopaminergic/cholinergic systems are reciprocally active in the pathophysiology of long-term drug-induced hallucinatory states in this population.

Pergolide in Parkinson's disease.

Twenty-two patients received pergolide mesylate for Parkinson's disease for one year. Improvement was maximal at six months, but average functional scores were still better at 12 months than at pretreatment evaluation. On-off fluctuations were reduced in severity, and two of 18 patients experienced full resolution. Pergolide is an effective and safe ongoing medication for Parkinson's disease.

Fluphenazine and multifocal tic disorders.

In a five-year study, 21 patients with multiple tic disorder intolerant of haloperidol therapy were treated with fluphenazine hydrochloride. Sixteen of these patients had fewer side effects with fluphenazine and had either equivalent (five patients) or better (11 patients) tic control. Fluphenazine can be an effective treatment for multiple tics in patients with dose-limiting side effects related to haloperidol.

A pure parkinsonian syndrome following acute carbon monoxide intoxication.

A 50-year-old woman with carbon monoxide (CO)-induced parkinsonism was found to have bilateral lucencies of the globus pallidus on computed tomographic (CT) scan consistent with old necrotic lesions. She showed no clinical response to levodopa therapy, although she did improve with anticholinergic therapy. It is suggested that the parkinsonism in this patient is due to the pallidal lesions demonstrated on CT scan, and that such pallidal-related parkinsonism may not respond to dopaminergic therapy.

Autologous transplantation of adrenal medulla in Parkinson's disease. 18-month results.

Eighteen of 19 patients who underwent autologous adrenal medullary transplantation to the right caudate nucleus have been followed up for 18 months. During the course of this study, a statistically significant improvement was noted in percent "on" time, percent "on" time without dyskinesia, activity of daily living (ADL) scores during the "on" stages, and ADL, motor, and Schwab-England scores during the "off" stages. Benefits tended to be maximal at 6 months and to gradually lessen thereafter, although statistically significant improvement in comparison with baseline was still present at 18 months for ADL, motor, and Hoehn-Yahr scores during the "off" stages. Almost all parameters had deteriorated by 18 months compared with 12 months, including those remaining significantly improved in comparison with baseline. These patterns were similar for each of the three participating centers. Complications were largely restricted to the perioperative period.

Abnormal liver enzyme-mediated metabolism in Parkinson's disease: a second look.

If toxicant exposure contributes to the cause of Parkinson's disease, poor function of detoxifying enzymes could increase vulnerability for Parkinson's disease. Although no hepatic enzyme system has been shown universally to be dysfunctional in Parkinson's disease patients, several have been suggested to be dysfunctional in subgroups, such as those with young age at disease onset. Specific enzymes implicated include several P450 enzymes, most notably P450 IID6, and cysteine dioxygenase. If hepatic enzyme abnormalities contribute to the development of Parkinson's disease, molecular genetic techniques may allow the development of screening tests to identify at-risk subjects in order to intervene with protective therapies.

Autonomic dysfunction in Parkinson's disease.

We studied autonomic functions in 31 chronically treated patients with Parkinson's disease. They were tested twice: before a dose of medication and after medication. Before a dose of medication, when motor disability was maximal ("off"), patients had higher resting pulse rate, greater orthostatic fall in blood pressure, and decreased responses to Valsalva and cold pressor stimuli than their spouse-controls. To a heat stimulus, sweating was increased in the head and neck, and skin temperatures were cooler. After medication when function was optimal ("on"), the cardiovascular reflex abnormalities remained but were no worse. Skin temperature alterations and sweating abnormalities resolved.

Progression of Parkinson's disease without levodopa.

We studied 100 consecutive patients with Parkinson's disease (PD) who were not receiving levodopa and followed them until symptoms advanced and levodopa was given. Eighty-three patients eventually received levodopa; 50% started within 36 months after a mean duration of symptoms of 48 months. Patients starting on levodopa showed significant progression of their disease compared with their baseline examination. These data have direct applicability to the design and implementation of future protocols aimed at preventing disease progression of PD.

Dysphagia after botulinum toxin injections for spasmodic torticollis: clinical and radiologic findings.

We prospectively evaluated the frequency, severity, and radiologic features of swallowing abnormalities following Botox treatment of spasmodic torticollis. We performed both clinical and radiologic evaluations of swallowing before and following Botox in 18 consecutive cervical dystonia patients receiving their first Botox treatment. Before Botox, 11% of the patients had clinical symptoms of dysphagia and 22% had radiologic signs of a peristaltic abnormality. After Botox, the signs and symptoms of dysphagia in these patients did not change, but an additional 33% developed new dysphagic symptoms and 50% of the patients developed new peristaltic abnormalities by radiologic studies. Complaints of swallowing difficulty were always associated with abnormal radiologic findings. Neither the total Botox dose nor Botox into particular muscles differed between those with dysphagia and those without.

Primary writing tremor: a selective action tremor.

Progressive difficulty in handwriting due to jerking movements precipitated by the act of writing beginning between the ages of 8 to 54 is reported in six patients. There was no rest tremor, but three had mild postural tremor. Specific muscle activity (especially pronation of the wrist or abduction of the fingers) elicited the tremors that persisted as long as the evocative posture or muscle activity was maintained. None had a family history of tremors, but two had a history suggestive of hypoxia at birth. Unlike benign essential tremor, the movements did not respond to propranolol HCl, but most patients were benefited both acutely and chronically by centrally active anticholinergic agents.