Stephen G. Reich

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Pallidal activity during dystonia: somatosensory reorganisation and changes with severity.

A woman with progressive, medically intractable right upper limb dystonia underwent a pallidotomy with only transient improvement. During the procedure her dystonia became more severe as she repeatedly made a fist to command in order to provoke dystonia transiently (movement provoked dystonia). Comparisons within cells in the internal segment of the globus pallidus (Gpi) disclosed that the firing rate was the same at rest, with making a fist, and during movement provoked dystonia. However, the firing rate compared between cells decreased significantly throughout the procedure as the patient made a fist repeatedly. During the second half of the procedure the firing rate of cells in the Gpi was similar to that in hemiballismus. The proportion of cells in the GPi which responded to sensory stimulation was significantly higher in dystonia (53%) than in hemiballismus (13%). These results suggest that pallidal activity can correlate inversely with the severity of dystonia, perhaps due to activity dependent changes in neuronal function resulting from repeated voluntary movement.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

The use of alternative therapies by patients with Parkinson’s disease

Objective: To determine the prevalence and spectrum of use of alternative therapy (AT) by patients with PD and to determine whether use of AT correlates with demographic, social, or disease-specific characteristics. Methods: The authors administered a structured questionnaire, by interview, regarding the use of AT to 201 patients with PD. Demographic, social, and disease-specific characteristics were recorded for all patients. Results: Eighty-one patients (40%) used at least one AT. Vitamins and herbs, massage, and acupuncture were most common. Users of AT were younger (p = 0.0021) and had a younger age at onset of PD (p = 0.0011) than nonusers of AT. There was no correlation with sex or race. Patients who used AT had a higher income (p = 0.038) and education level (p = 0.006) than did nonusers of AT. There was no association between the use of AT and the Hoehn and Yahr score, duration of PD, duration of treatment with levodopa, surgery for PD, and presence of fluctuations. Conclusions: The use of AT is common in patients with PD. The age at onset of PD is the most potent predictor of AT use. There is no association between the use of AT and the severity of PD. The widespread and largely unexamined use of AT for PD requires more attention. This should be directed at testing their safety and efficacy and improving physician and patient knowledge about the potential benefits, costs, limitations, and risks of AT.

Overexpression of four-repeat Tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease

Perturbations in the microtubule‐associated protein tau occur in several human neurodegenerative diseases. In Alzheimers disease and progressive supranuclear palsy (PSP), tau proteins assemble into straight and paired helical filaments that form intraneuronal deposits of neurofibrillary tangles (NFTs). The mechanisms underlying the aberrant assembly of tau into NFTs is unknown. To determine whether alterations in the expression of the carboxyl‐terminal variants of tau contribute to NFT formation, we analyzed tau mRNA isoform expression in select regions of control, Alzheimers disease, and PSP brains. In Alzheimers disease, there were no alterations in tau mRNA isoform expression. However, in PSP, the levels of tau mRNA isoforms containing four microtubule binding domains were increased in the brainstem but not the frontal cortex or cerebellum. The brainstem in PSP has extensive NFT pathology, whereas the frontal cortex and cerebellum are relatively spared, suggesting that alterations in tau mRNA isoform expression occur in NFT‐vulnerable regions in this disease. An increase in the four‐repeat tau mRNA may lead to an increase in four‐repeat tau protein isoforms and may contribute to the formation of NFTs in PSP. A similar increase in four‐repeat tau mRNA has been reported for mutations associated with frontotemporal dementia and parkinsonism linked to chromosome 17.

Patterns of bursting occurring in thalamic cells during parkinsonian tremor

It has been proposed that parkinsonian tremor is produced either by the activity of an intrinsic thalamic pacemaker or by the oscillation of an unstable long loop reflex arc. The former (central) hypothesis proposes that overactivity of neurons in the internal segment of the globus pallidus inhibits or hyperpolarizes thalamic neurons. When hyperpolarized, thalamic cells oscillate with bursting of the type associated with low threshold calcium spikes (low threshold spike-bursts). Low threshold spike-bursts can be identified by particular patterns of interspike intervals within the burst. The alternative (peripheral) hypothesis proposes that tremor results from oscillation of a reflex arc transmitting activity from muscle stretch receptors to thalamus, motor cortex, and back to the stretched muscle. When the gain of this reflex is increased, the arc may become unstable and oscillate. Oscillations produced by peripheral inputs may produce an acceleration-deceleration pattern within the burst which results in sinusoidal modulation of a spike train if bursting is periodic. We have assessed these two hypotheses by studying the pattern of interspike intervals occurring within bursts recorded in patients with parkinsonian tremor. The spike trains were analysed for 118 cells located in the ventral nuclear group including ventralis intermedius (thalamic cerebellar relay nucleus, n=48) and ventralis oralis posterior (thalamic pallidal relay nucleus, n=39) of patients with parkinsonian tremor. Two cells recorded in ventralis intermedius of a sleeping patient with chronic pain showed bursting activity similar to the low threshold spike-bursts recorded in sleeping animals, suggesting a common mechanism for low threshold spike-bursts across species. Forty-two cells recorded in patients with parkinsonian tremor (ventralis intermedius, n=19; ventralis oralis posterior, n=12) were classified as tremor-related cells because their activity was characterized by both a concentration of power at tremor frequency and significant correlation with tremor. Eleven tremor-related cells, 10 located in ventralis intermedius or ventralis oralis posterior and most responding to sensory inputs, had an acceleration-deceleration pattern of intraburst firing. Only one cell, a tremor-related cell in ventralis intermedius, showed the pattern expected of presumed low threshold spike-bursts. Therefore, intraburst interspike interval patterns consistent with either the central or the peripheral hypothesis were recorded in the thalamus of patients with parkinsonian tremor. Twenty-one tremor-related cells (15 cells in ventralis intermedius or ventralis oralis posterior) had bursts with intraburst interspike intervals which were independent of position of the interspike interval within the burst. Therefore, the activity of the majority of cells was not consistent with either hypothesis, suggesting that another oscillatory process may contribute to parkinsonian tremor.

Thalamic neuronal activity correlated with essential tremor

Animal studies suggest that an olivocerebello-bulbospinal pathway mediates harmaline induced tremor, which resembles essential tremor in humans. However, recent evidence suggests that thalamocortical pathways participate in essential tremor. Thalamic single neuron activity has been analysed during thalamotomy for essential tremor. It has been shown by spectral cross correlation analysis that thalamic activity has a significant, linear relation to forearm EMG activity during tremor. The presence of this tremor related activity at the site where a lesion abolishes essential tremor suggests that the thalamus has an important role in the mechanism of essential tremor.

Adaptive Fourier modeling for quantification of tremor

A new computational method for quantification of tremor, the weighted frequency Fourier linear combiner (WFLC), is presented. This technique rapidly determines the frequency and amplitude of tremor by adjusting its filter weights according to a gradient search method. It provides continual tracking of frequency and amplitude modulations over the course of a test. By quantifying time-varying characteristics, the WFLC assists in correctly interpreting the results of spectral analysis, particularly for recordings exhibiting multiple spectral peaks. It therefore supplements spectral analysis, providing a more accurate picture of tremor than spectral analysis alone. The method has been incorporated into a desktop tremor measurement system to provide clinically useful analysis of tremor recorded during handwriting and drawing using a digitizing tablet. Simulated data clearly demonstrate tracking of variations in frequency and amplitude. Clinical recordings then show specific examples of quantification of time-varying aspects of tremor.

Stereotactic thalamotomy in the treatment of essential tremor of the upper extremity: reassessment including a blinded measure of outcome

The effectiveness of high frequency stimulation of the thalamic nucleus ventralis intermedius (Vim-HFS) for treatment of tremor has been studied by blinded assessment. The effectiveness of thalamotomy for essential tremor of the upper extremity by use of a blinded measure of outcome is now reported. Thalamotomy was performed in 21 patients (three operated on bilaterally) with medically intractable, essential tremor. Assessments of function, handwriting/drawing, and tremor amplitude were done before and at 3 and 12 months after surgery. The handwriting/drawing score was rated by a neurologist blinded to patient identity, laterality, and operative status. By comparison with baseline, both the total functional score and the total score from blinded assessment of handwriting/drawing improved significantly at 3 and 12 months after surgery. The two scores were significantly correlated, suggesting that the blinded assessment is a good predictor of a total disability from tremor. Complications after unilateral thalamotomy included transient dysarthria, permanent perioral numbness, and permanent mild disequilibrium in one patient each. Permanent mild dysarthria occurred in two of three patients operated bilaterally. Thus a blinded assessment of outcome establishes that unilateral thalamotomy is an effective, safe procedure for the treatment of essential tremor.

Ocular Motility in Parkinson's Disease

INTRODUCTION Parkinsons disease is associated with multiple abnormalities of both the afferent and efferent visual systems. Blepharospasm, paucity of blinking, apraxia of lid opening, visual neglect, reduced vergence, reduced upgaze, and blurred vision are reported findings in these patients. The association of these findings with the disease, and their duration, severity, and treatment have not been systematically investigated. PATIENTS AND METHODS Patients with Parkinsons disease were prospectively examined. An age-matched control group was recruited from accompanying family members and volunteers. Data recorded included presence of visual complaint, the severity of the Parkinsons disease by Hoehn and Yahr Stage (scale = 1 to 5), duration of disease, pharmacologic therapy, visual acuity, ocular motility, accommodation, convergence amplitudes, and the near point of convergence. RESULTS Thirty-nine patients were entered into each group, each with 21 men and 18 women. The average patient had had the disease for 8.9 years with a severity index of 2.6. Asthenopia, upgaze deficiency, and convergence insufficiency were significantly more common in the patients with Parkinsons disease than in the controls. Mean geometric visual acuity was poorer in the Parkinsons patients (20/39 compared with 20/28); P < .001). DISCUSSION Visual complaints were significantly more common in the Parkinsons patients than in the age-matched controls. The frequency of ocular abnormalities was not related to the duration of the disease. Increasing severity seemed to be correlated with the presence of convergence insufficiency and a decline in acuity.