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.

Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology.

OBJECTIVE: To determine the relative contribution of genetics and environment to essential tremor using a twin study method. METHODS: Twins with postural or kinetic tremor were identified by movement disorders specialists during the conduct of a study investigating PD in members of the National Academy of Sciences and National Research Council World War II Veteran Twins Registry. The diagnosis of essential tremor was made by consensus using established diagnostic criteria. RESULTS: A total of 196 twins had postural or kinetic tremor on examination. Of these, 137 had PD or had a twin with PD and were excluded from this study. Thirty-three others were excluded because of incomplete data for their twin. Sixteen twin pairs were identified in which at least one twin had essential tremor. Pairwise concordance in monozygotic twins was approximately two times that in dizygotic twins (0.60 monozygotic, 0.27 dizygotic). CONCLUSION: This pattern is consistent with a genetic cause of essential tremor. Because monozygotic concordance is not 100%, environmental factors may also play a role in the cause of the disease.

The long-term safety and efficacy of pramipexole in advanced Parkinson's disease.

Objective: To assess the long-term safety and efficacy of pramipexole in advanced Parkinson's disease over a four year time period.Methods: This study is an open-label extension trial of pramipexole for Parkinson's disease open to patients completing a double-blind placebo controlled safety and efficacy trial of this drug. Three hundred and six patients entered the trial. These patients had moderate to severe PD (stage II-IV Hoehn and Yahr during off time) and were experiencing motor fluctuations. Patients were titrated over a six week period and then entered a maintenance phase which lasted up to 50 months. Patients were evaluated every 3 months using the Unified Parkinson's Disease Rating Scale (UPDRS II, III and IV) and modified Schwab and England scale (S/E).Results: Sixty-four percent (197) of the 306 patients who entered this study completed it. Patients showed steady improvement over the 6 week ascending dose interval when pramipexole was reintroduced into the trial as the open-label study medication. Over the duration of the trial patients slowly returned to their baseline levels. This was true for all measures evaluated except for the UPDRS part IV. On UPDRS part IV patients remained below their baseline score which indicated an improvement for the duration of the study. Patterns similar to the overall scores were seen when the individual components of the UPDRS scale part II for "on" and "off" periods and part III were evaluated. However tremor during "on" periods showed improvement over baseline for the duration of the trial. The most common adverse events secondary to pramipexole occurring in greater than 10% of patients included dyskinesias, asymptomatic orthostatic hypotension, dizziness, insomnia, and hallucinations.Conclusion: Pramipexole was well tolerated for up to 4 years. Pramipexole treatment appeared to show continued efficacy in the treatment of Parkinson's disease for 3 years in this open-label descriptive study. After 3 years there was a gradual return to baseline motor states perhaps suggesting progression of Parkinson's disease.

An impairment in sniffing contributes to the olfactory impairment in Parkinson's disease.

Although the presence of an olfactory impairment in Parkinson's disease (PD) has been recognized for 25 years, its cause remains unclear. Here we suggest a contributing factor to this impairment, namely, that PD impairs active sniffing of odorants. We tested 10 men and 10 women with clinically typical PD, and 20 age- and gender-matched healthy controls, in four olfactory tasks: (i) the University of Pennsylvania smell identification test; (ii and iii) detection threshold tests for the odorants vanillin and propionic acid; and (iv) a two-alternative forced-choice detection paradigm during which sniff parameters (airflow peak rate, mean rate, volume, and duration) were recorded with a pneomatotachograph-coupled spirometer. An additional experiment tested the effect of intentionally increasing sniff vigor on olfactory performance in 20 additional patients. PD patients were significantly impaired in olfactory identification (P < 0.0001) and detection (P < 0.007). As predicted, PD patients were also significantly impaired at sniffing, demonstrating significantly reduced sniff airflow rate (P < 0.01) and volume (P < 0.002). Furthermore, a patient's ability to sniff predicted his or her performance on olfactory tasks, i.e., the more poorly patients sniffed, the worse their performance on olfaction tests (P < 0.009). Finally, increasing sniff vigor improved olfactory performance in those patients whose baseline performance had been poorest (P < 0.05). These findings implicate a sniffing impairment as a component of the olfactory impairment in PD and further depict sniffing as an important component of human olfaction.

Pattern of dopaminergic loss in the striatum of humans with MPTP induced parkinsonism.

OBJECTIVES: To examine the distribution of striatal dopaminergic function in humans with parkinsonism induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) to determine if there is a caudate-putamen gradient as is seen in idiopathic Parkinson's disease. METHODS: We scanned nine humans exposed to MPTP with parkinsonism ranging from minimal to severe using [(18)F]fluorodopa (FD) and high resolution PET. The results were compared with those of 10 patients with Parkinson's disease and six normal subjects. RESULTS: In the MPTP group there was an equal degree of reduction of dopaminergic function in the caudate and putamen. This was different from the greater putaminal than caudate loss in Parkinson's disease (p<0.001). CONCLUSIONS: Parkinson's disease is not caused by transient exposure to MPTP.

Quantification of dyskinesia in Parkinson's disease: validation of a novel instrumental method.

We used a rotation-sensitive movement monitor (RoMM) to quantify and characterize dyskinesia in Parkinson's disease (PD). Both upper limbs of 22 patients with dyskinetic PD were recorded and videotaped simultaneously. Three neurologists reviewed the video segments and rated severity of dyskinesia on a four-point scale; they also assessed any asymmetry of dyskinesia between the right and left side as well as the dyskinesia type (choreic, dystonic, or mixed). Mean and median clinical ratings for severity, asymmetry, and type of dyskinesia were compared with (1) the total power of the frequency power spectrum (FPS, degrees/second), (2) the percent difference of FPS values between the right and left side, and (3) the frequency (Hz) of the predominant peak, respectively. Intra- and interrater reliability was determined and a test-retest analysis was performed. FPS values showed a statistically significant correlation with the clinical ratings for dyskinesia severity. FPS difference between both sides was more sensitive than raters in detecting dyskinesia asymmetry. A predominant frequency peak of dyskinesia was obtained in all cases and ranged from 0.25-3.25 Hz. There was a significant trend for high-frequency dyskinesia to correlate with choreic type and for low-frequency dyskinesia to correlate with dystonic type. Test-retest analysis indicated a high reliability. We conclude that the RoMM is a valid, reliable, and sensitive method to quantify and characterize dyskinesia. Examples are provided suggesting that this instrument may prove useful for long-term assessment of dyskinetic patients and as a standardized tool for assessing dyskinesia in pharmaceutical or surgical trials for PD.

Autopsy-proven progressive supranuclear palsy in two siblings.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is generally considered to be nonfamilial. We report a brother and sister with clinical and pathologic findings characteristic of PSP. Both developed parkinsonism in the eighth decade of life and within 5 years exhibited severe postural instability, bradykinesia, rigidity, dystonia, dysarthria, dysphagia, urinary incontinence, pseudobulbar palsy, and supranuclear oculomotor dysfunction but no tremor. Neither responded to levodopa and/or carbidopa. Their mother and, possibly, maternal grandfather reportedly suffered from a parkinsonian syndrome. Essential tremor occurred in the siblings' father and in two of the brother's three children. Autopsy in the brother at age 81 years and sister at age 79 years revealed changes typical of PSP with atrophy and neurofibrillary tangles in the globus pallidus, subthalamic nucleus, and rostral tegmental brainstem. No Lewy bodies were present. These cases are the first pair of relatives reported with autopsy confirmation of PSP in both and raise the question of genetic predisposition to PSP.

Positron emission tomographic evidence for progression of human MPTP-induced dopaminergic lesions.

Transient exposure to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a syndrome resembling idiopathic parkinsonism (IP). While IP inevitably progresses, the long-term evolution of MPTP-parkinsonism is unknown. Fluorodopa positron emission tomography (FD-PET) is a reliable tool for assessing nigrostriatal dopaminergic function. We performed FD-PET and clinical assessments on two occasions, 7 years apart, on 10 human subjects exposed to MPTP (age at the first scan, 32.7 +/- 6.9 yr [mean +/- SD], and on 10 normal individuals (age, 53 +/- 16 yr). At the time of their first scan, 5 of the subjects exposed to MPTP were clinically normal and 5 had limited signs of parkinsonism; 5 had new clinical deficits 7 years later. In the subjects exposed to MPTP, the PET index [(striatal-occipital)/occipital ratio] dropped by 2.3% per year from 0.70 +/- 0.10 (mean +/- SD) to 0.58 +/- 0.10 (p < 0.001). This was significantly faster than normal aging (p < 0.01) and similar to the progression observed in IP (p = 0.06). The findings suggest that short-term exposure to MPTP leads to a protracted decline in nigrostriatal dopaminergic function more rapid than occurs in normal aging and similar to IP progression. This is the first evidence that transient exposure to a toxin can cause progressive nigral pathology. At present, the mechanism leading to this progression is unknown. Our findings support the hypothesis that some neurodegenerative disorders may result from transient exposure to an environmental agent.

Parkinsonism caused by petroleum waste ingestion.

A 20-year-old laborer developed moderate parkinsonism 1 week after accidentally ingesting a petroleum waste mixture. Parkinsonism persisted for 3 months and then began to improve, although subtle signs remained 29 months after exposure. 6-Fluorodopa-labeled positron emission tomography (6-FD PET) performed 3 months postexposure revealed a striatal dopamine rate constant level of 0.170 ml/striatum/min, nearly 3 SD below the mean for age-matched controls. However, subsequent PETs demonstrated 6-FD PET rate constants not significantly different than controls. Although the causative agent has not yet been identified, this case suggests that compounds capable of causing parkinsonism may exist in commonly used petroleum products.

Double-blind, placebo-controlled, crossover study of duodenal infusion of levodopa/carbidopa in Parkinson's disease patients with 'on-off' fluctuations.

Ten patients with Parkinson's disease suffering severe motor fluctuations completed a double-blind, placebo-controlled, crossover trial of duodenal infusion of levodopa/carbidopa to determine if this technique improved the duration of functional time by reducing plasma levodopa level variability. With infusion, seven patients experienced increased functional "on" hours and decreased number of "off" episodes; however, two patients were slightly worse and one patient experienced no benefit. All 10 patients had significantly decreased variability in levodopa levels permitting better titration of levodopa dosage to individual requirements. Five patients continued to use infusion 12 to 20 months after completion of this study. Selected patients with Parkinson's disease who experience severe motor fluctuations may benefit from duodenal infusion with an improved and prolonged response to medication.

Oral levodopa/carbidopa solution versus tablets in Parkinson's patients with severe fluctuations: a pilot study.

Four patients with Parkinson's disease, optimally treated with levodopa/carbidopa (LD/CD) tablets but experiencing severe motor fluctuations, underwent an open trial of a levodopa/carbidopa/ascorbic acid solution (LCAS) orally at timed intervals. LCAS reduced bradykinesia, decreased dysfunctional dyskinesia, and increased functional "on" time when compared with previous LD/CD tablet therapy. Oral LCAS allowed better titration of levodopa dosage and offered a more predictable response than LD/CD tablets. Preparation and oral consumption of LCAS was easy and inexpensive. LCAS may be a practical alternative for patients whose motor fluctuations fail to respond to optimal therapy with LD/CD tablets.

Protective and preventive therapeutic strategies: monoamine oxidase inhibitors.

There is convincing evidence that monotherapy with 10 mg of selegiline daily substantially delays parkinsonian disability, although whether this delay is due to a symptomatic or protective mechanism remains a matter of debate. Evidence against a symptomatic effect is that the wash-out evaluation in two double-blind, placebo-controlled studies failed to detect clinical decline 1 month after discontinuing selegiline. Yet it can be argued that 1 month was not long enough to eliminate the biologic effect of the drug. Thus further studies are required to answer this question definitively. Nonetheless, because selegiline delays the requirement for levodopa therapy and appears to be relatively safe when used as monotherapy, it seems reasonable to recommend this drug as initial treatment when Parkinson's disease is first diagnosed. There is little doubt that future therapeutic and diagnostic strategies for Parkinson's disease and other neurodegenerative diseases will be profoundly influenced if this drug is unequivocally demonstrated to slow progression of Parkinson's disease. Such a finding would be a potent argument for developing biomarkers of preclinical disease because early intervention with such protective therapy might even halt the disease before symptoms develop.

Tremor in MPTP-induced parkinsonism.

We assessed clinical and electrophysiologic characteristics of tremor in patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Four of seven patients with moderate to severe MPTP-induced parkinsonism exhibited a tremor indistinguishable from the characteristic rest tremor of Parkinson's disease (PD). The pathology induced by MPTP in one human case is confined to the substantia nigra, but in nonhuman primates, the locus ceruleus or the ventral tegmental area can also be affected. These findings suggest that the pathophysiology of rest tremor in PD might result from damage to either the substantia nigra alone or in combination with damage to one or more of these other regions.

Preclinical detection of motor and nonmotor manifestations.

The advent of possible protective therapies for Parkinson's disease has created a need for methods of diagnosing the disease before the clinical features become fully evident. As a number of motor and nonmotor manifestations of the disease emerge months to years before a diagnosis can be made, a battery of clinical tests might be sufficient to identify individuals at an earlier stage than is currently possible using the standard history and physical examination. A list of questions regarding possible risk factors, specific symptoms, and observations of family members could be combined in a self-administered questionnaire that might identify individuals with a high probability of early, but otherwise undiagnosable, Parkinson's disease. Identification of subtle motor features is another possible screening method. For example, handwriting and speech are commonly affected prior to diagnosis; thus, automated analysis of these motor actions might also provide detection of incipient disease.

Preclinical Parkinson's disease: detection of motor and nonmotor manifestations.

The advent of possible protective therapies for Parkinson's disease has created a need for methods of diagnosing the disease before the clinical features become fully evident. As a number of motor and nonmotor manifestations of the disease emerge months to years before a diagnosis can be made, a battery of clinical tests might be sufficient to identify individuals at an earlier stage than is currently possible using the standard history and physical examination. A list of questions regarding possible risk factors, specific symptoms, and observations of family members could be combined in a self-administered questionnaire that might identify individuals with a high probability of early, but otherwise undiagnosable, Parkinson's disease. Identification of subtle motor features is another possible screening method. For example, handwriting and speech are commonly affected prior to diagnosis; thus, automated analysis of these motor actions might also provide detection of incipient disease.

The MPTP model: versatile contributions to the treatment of idiopathic Parkinson's disease.

In human and subhuman primates, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces irreversible clinical, biochemical and neuropathological alterations highly reminiscent of those observed in Parkinson's disease. The MPTP model has provided the best available tool to date for the assessment of efficacy and side-effects of symptomatic treatments of Parkinson's disease. In addition, the mechanism of action of MPTP has offered a basis for the development of novel therapeutic strategies aimed at the prevention of Parkinson's disease.

Cognitive change following MPTP exposure.

In a previous study, we demonstrated that patients with MPTP-induced parkinsonism (MPTP-IP) had a pattern of cognitive change similar to that in nondemented patients with idiopathic Parkinson's disease (PD). The present study addressed cognitive change in MPTP-exposed but relatively asymptomatic (MPTP-AS) individuals. We examined them for general intellectual function, construction, language, memory, executive function, attention, and reaction time, and compared their performance with data obtained in the previous study from patients with MPTP-IP and drug addict controls. Each MPTP-AS individual had some subtle parkinsonian signs, but in no case would these be sufficient for a diagnosis of PD. PET studies showed that these individuals had significantly reduced uptake of labeled 6-fluorodopa into the striatum. MPTP-AS and MPTP-IP groups performed comparably and were significantly worse than controls on tests of construction and category naming. The MPTP-AS group performed at a level between the other 2 groups on a test of executive function. The 3 groups performed comparably on all other measures. The similarity of the pattern of intellectual change in MPTP-AS to that seen in MPTP-IP and idiopathic PD supports the idea that the dopamine system mediates a specific set of cognitive functions and suggests that cognitive change can occur in the presence of few or no motor signs of parkinsonism.

Mild parkinsonism in persons exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) produces moderate to severe parkinsonism in humans, but has not been reported to cause a syndrome similar to early Parkinson's disease. We now report 22 cases of mild parkinsonism resulting from exposure to MPTP.