Jacob I. Sage

A clinical genetic study of Parkinson's disease: Evidence for dominant transmission

We used a family history questionnaire, semi-structured interview, and personal examination of secondary cases to collect data on the prevalence of Parkinsons disease (PD) in relatives of patients seen consecutively for 1 year and assessed the proportion of secondary cases of PD as a function of pedigree completeness. Survival analysis methods were applied to estimate the lifetime risk and age-at-onset distribution of PD among first-degree relatives of probands. When we considered siblings of probands with affected parents, the cumulative risk increased significantly over siblings of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. We further analyzed 80 multicase families with two or more affected individuals. Age-adjusted segregation ratios approaching 0.5 and similar proportions of affected parents and siblings, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD

Association of a serotonin transporter gene promoter polymorphism with harm avoidance behaviour in an elderly population

A polymorphic 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to affect the level of expression of the serotonin transporter protein. An association between anxiety-related behavioural traits and the short form of the 5-HTTLPR has been reported. We determined the 5-HTTLPR genotype in genomic DNA samples from 84 subjects (47 Parkinsons disease patients and 37 controls) with a mean age of 67.4 years. The TPQ of Cloninger was used to obtain values for harm avoidance (HA), reward dependence and novelty seeking for all subjects. Analysis of variance showed a significant influence of the s-allele of the 5-HTTLPR on HA in both subject groups, with no significant interaction between diagnosis and genotype. Subjects with the l/l-genotype had significantly lower mean HA scores than the l/s subjects (P < 0.04) and s/s subjects (P < 0.003). A linear change in HA with genotype was observed, indicating a gene dose effect of the 5-HTTLPR s-allele on this personality dimension. Based on these findings it is suggested that there may be increased influence of the 5-HTTLPR short allele on anxiety-related traits during aging. Psychiatr Genet 8:41–44 c 1998 Lippincott-Raven Publishers.

Hand preshaping in Parkinson’s disease: effects of visual feedback and medication state

Previous studies in our laboratory examining pointing and reach-to-grasp movements of Parkinson’s disease patients (PDPs) have found that PDPs exhibit specific deficits in movement coordination and in the sensorimotor transformations required to accurately guide movements. We have identified a particular difficulty in matching unseen limb position, sensed by proprioception, with a visible target. In the present work, we further explored aspects of complex sensorimotor transformation and motor coordination using a reach-to-grasp task in which object shape, visual feedback, and dopaminergic medication were varied. Normal performance in this task requires coordinated generation of appropriate reach, to bring the hand to the target, and differentiated grasp, to preshape the hand congruent with object form. In Experiment 1, we tested PDPs in the off-medication state. To examine the dependence of subjects on visual feedback and their ability to implement intermodal sensory integration, we required them to reach and grasp the target objects in three conditions: (1) Full Vision, (2) Object Vision with only the target object visible and, (3) No Vision with neither the moving arm nor the target object visible. PDPs exhibited two types of deficits. First, in all conditions, they demonstrated a generalized slowing of movement or bradykinesia. We consider this an intensive deficit, since it involves largely a modulation of the gain of specific task parameters: in this case, velocity of movement. Second, they were less able than controls to extract critical proprioceptive information and integrate it with vision in order to coordinate the reach and grasp components of movement. These deficits which involve the coordination of different inputs and motor components, we classify as coordinative deficits. As in our previous work, the PDPs’ deficits were most marked when they were required to use proprioception to guide their hand to a visible target (Object Vision condition). But even in the full-vision condition, their performance only became fully accurate when both the target and effector (hand) were simultaneously visible. In Experiment 2, PDPs were tested on their dopaminergic replacement therapy. Dopaminergic treatment significantly ameliorated the bradykinesia of the PDPs, but produced no changes in the hand preshaping deficiencies of PDPs. These results suggest that adequate treatment of the PDPs may more readily compensate for intensive, than coordinative deficits, since the latter are likely to depend on specific and time-dependent neural interdependencies that are unlikely to be remediated simply by increasing the gain of a pathway.

The tau A0 allele in Parkinson's disease.

Parkinsons disease (PD) is primarily an α‐synucle‐ inopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta‐analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta‐analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy‐Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis.

Visuomotor learning in immersive 3D virtual reality in Parkinson’s disease and in aging

Successful adaptation to novel sensorimotor contexts critically depends on efficient sensory processing and integration mechanisms, particularly those required to combine visual and proprioceptive inputs. If the basal ganglia are a critical part of specialized circuits that adapt motor behavior to new sensorimotor contexts, then patients who are suffering from basal ganglia dysfunction, as in Parkinson’s disease should show sensorimotor learning impairments. However, this issue has been under-explored. We tested the ability of 8 patients with Parkinson’s disease (PD), off medication, ten healthy elderly subjects and ten healthy young adults to reach to a remembered 3D location presented in an immersive virtual environment. A multi-phase learning paradigm was used having four conditions: baseline, initial learning, reversal learning and aftereffect. In initial learning, the computer altered the position of a simulated arm endpoint used for movement feedback by shifting its apparent location diagonally, requiring thereby both horizontal and vertical compensations. This visual distortion forced subjects to learn new coordinations between what they saw in the virtual environment and the actual position of their limbs, which they had to derive from proprioceptive information (or efference copy). In reversal learning, the sign of the distortion was reversed. Both elderly subjects and PD patients showed learning phase-dependent difficulties. First, elderly controls were slower than young subjects when learning both dimensions of the initial biaxial discordance. However, their performance improved during reversal learning and as a result elderly and young controls showed similar adaptation rates during reversal learning. Second, in striking contrast to healthy elderly subjects, PD patients were more profoundly impaired during the reversal phase of learning. PD patients were able to learn the initial biaxial discordance but were on average slower than age-matched controls in adapting to the horizontal component of the biaxial discordance. More importantly, when the biaxial discordance was reversed, PD patients were unable to make appropriate movement corrections. Therefore, they showed significantly degraded learning indices relative to age-matched controls for both dimensions of the biaxial discordance. Together, these results suggest that the ability to adapt to a sudden biaxial visuomotor discordance applied in three-dimensional space declines in normal aging and Parkinson disease. Furthermore, the presence of learning rate differences in the PD patients relative to age-matched controls supports an important contribution of basal ganglia-related circuits in learning novel visuomotor coordinations, particularly those in which subjects must learn to adapt to sensorimotor contingencies that were reversed from those just learned.

Design innovations and baseline findings in a long-term parkinson’s trial: The national institute of neurological disorders and stroke exploratory trials in parkinson’s disease long-term study-1

Based on the preclinical data and the results of a phase II futility study, creatine was selected for an efficacy trial in Parkinsons disease (PD). We present the design rationale and a description of the study cohort at baseline. A randomized, multicenter, double‐blind, parallel‐group, placebo‐controlled phase III study of creatine (10 g daily) in participants with early, treated PD, the Long‐term Study–1 (LS‐1), is being conducted by the National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinsons Disease network. The study utilizes a global statistical test (GST) encompassing five clinical rating scales to provide a multidimensional assessment of disease progression. A total of 1,741 PD participants from 45 sites in the United States and Canada were randomized 1:1 to either 10 g of creatine/day or matching placebo. Participants are being evaluated for a minimum of 5 years. The LS‐1 baseline cohort includes participants treated with dopaminergic therapy and generally mild PD. LS‐1 represents the largest cohort of patients with early treated PD ever enrolled in a clinical trial. The GST approach should provide high power to test the hypothesis that daily administration of creatine (10 g/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5‐year follow‐up visit against the background of dopaminergic therapy and best PD care.

Follow-up study of risk factors in progressive supranuclear palsy

The cause of progressive supranuclear palsy (PSP) is not known and has been little studied.The one previous controlled epidemiologic survey, performed at our center in 1986, found small-town experience and greater educational attainment as PSP risks, but, in retrospect, these results may have been produced by ascertainment bias. Since that time, several anecdotal reports have implicated heredity and various environmental exposures in the cause of some cases of PSP. To clarify the results of the previous study and to evaluate the more recently implicated candidate factors in a controlled fashion, we mailed a validated 69-item questionnaire to 91 personally examined patients with PSP and 104 unmatched controls with other neurologic conditions for which they had been referred to our tertiary neurologic center. We were able to match 75 subjects from each group by year of birth, sex, and race and subjected them to a separate matched-pair analysis. We allowed surrogates to supply any or all of the responses. Questions concerned hydrocarbon, pesticide, and herbicide exposure; urban/rural living; auto repair and other occupations; head trauma; educational attainment; maternal age; and family history of PSP, parkinsonism, dementia, and other neurologic conditions. A statistically significant finding was that patients with PSP were less likely to have completed at least 12 years of school (matched odds ratio = 0.35, 95% CI = 0.12-0.95, p = 0.022; unmatched odds ratio = 0.44, 95% CI = 0.21-0.89, p = 0.020). We hypothesize that this result may be a proxy for poor early-life nutrition or for occupational or residential exposure to an as-yet unsuspected toxin. Future studies should examine these potential risk factors in PSP. NEUROLOGY 1996;47: 148-154

A novel quantitative method for 3D measurement of Parkinsonian tremor.

OBJECTIVE To demonstrate the usefulness of a three dimensional (3D) motion analysis system for the quantitative measurement of tremor in patients with Parkinsons disease (PD). METHODS Six PD patients with hand tremors were studied using a system that employed 3D electromagnetic position sensors to measure the actual, cumulative displacement of the tremoring finger. Patients were studied in different hand positions and activating conditions before and 30, 60, 90 and 120 min after intake of Pramipexole, a dopamine agonist known to reduce tremor. Tremor amplitude and frequency, before and after drug intake, were compared using Mann-Whitney U test and Wilcoxon rank test, respectively. RESULTS The motion analysis system allowed discrimination of tremor related events from movement artifact and allowed the calculation of real world movement of the finger tremor despite altered hand positions and orientation. Average 3D tremor frequency ranged from 3.71 to 4.34 Hz. Median tremor amplitude (total distance traveled per 5 s interval) decreased with drug from 4.9 to 1.6 cm for resting tremor, 4.5 to 3.7 cm for postural tremor, 3.4 to 3.3 cm for precision tremor, 10.2 to 3.3 cm for tapping activation and 108.6 to 5.7 cm for counting activation. CONCLUSIONS Our method of 3D analysis provides a robust, single quantitative measure of tremor amplitude that is intuitive and likely to reflect the functional impact of tremor. This methodology should be useful in comparing tremor across patients and in measuring the efficacy of therapeutic interventions.

Continuous levodopa infusions to treat complex dystonia in Parkinson's disease

We report the clinical spectrum of 3 patients with Parkinsons disease who experienced complex patterns of levodopa-related dystonia. Dystonia was unrelieved by multiple medication regimens but responded well to continuous, duodenal levodopa infusions. Patients were able to remain mobile without severe dystonia despite a very narrow window of benefit between the levodopa concentration necessary to achieve the “on” state and that which caused the onset of dystonic spasms.

Meige syndrome in the spectrum of Lewy body disease

We report a patient with Meige syndrome (segmental cranial dystonia) who had neuropathology changes of Parkinsons disease on postmortem examination. Neuropathologic examination showed typical and atypical Lewy bodies in the pigmented nuclei of the brainstem (substantia nigra, locus ceruleus), the nucleus basalis of Meynert, and the nucleus ambiguus. Neurochemical analysis of postmortem brain tissue showed evidence for decreased dopamine turnover in the substantia nigra, striatum, and nucleus accumbens. We propose that some cases of Meige syndrome may be included in the spectrum of Lewy body disease.