Oscillating central motor networks in pathological tremors and voluntary movements. What makes the difference?

Parkinsonian tremor (PD), essential tremor (ET) and voluntarily mimicked tremor represent fundamentally different motor phenomena, yet, magnetoencephalographic and imaging data suggest their origin in the same motor centers of the brain. Using EEG-EMG coherence and coherent source analysis we found a different pattern of corticomuscular delays, time courses and central representations for the basic and double tremor frequencies typical for PD suggesting a wider range defective oscillatory activity. For the basic tremor frequency similar central representations in primary sensorimotor, prefrontal/premotor and diencephalic (e.g. thalamic) areas were reproduced for all three tremors. But renormalized partial directed coherence of the spatially filtered (source) signals revealed a mainly unidirectional flow of information from the diencephalon to cortex in voluntary tremor, e.g. a thalamocortical relay, as opposed to a bidirectional subcortico-cortical flow in PD and ET promoting uncontrollable, e.g. thalamocortical, loop oscillations. Our results help to understand why pathological tremors although originating from the physiological motor network are not under voluntary control and they may contribute to the solution of the puzzle why high frequency thalamic stimulation has a selective effect on pathological tremor leaving voluntary movement performance almost unaltered.

Chromosome loss, hyperrecombination, and cell cycle arrest in a yeast mcm1 mutant.

The original mcm1-1 mutant was identified by its inability to propagate minichromosomes in an ARS-specific manner, suggesting that it is defective in the initiation of DNA synthesis at ARSs. This mutant is also defective in expression of alpha-mating-type-specific genes. Further genetic and biochemical studies confirmed that Mcm1 is a transcription factor that mediates the transcriptional regulation of a number of genes, including genes outside of the mating type complement, by interacting with different cofactors. Although MCM1 is an essential gene, none of the previously characterized mcm1 mutants exhibits significant growth defects. To assess which of the many roles of Mcm1 is essential for growth, we constructed and characterized a temperature-sensitive conditional mutant of mcm1, mcm1-110L. This mutant exhibits a temperature-dependent cell-cycle arrest, with a large, elongated bud and a single, undivided nucleus that has a DNA content of close to 2n. In addition, it shows elevated levels of chromosome loss and recombination. In spite of the severity of the mcm1-110L mutation, this mutant still retains an ARS-specific pattern of minichromosome instability. All of these phenotypes are precisely those exhibited by mutants in three MCM genes, MCM2, MCM3, and MCM5/CDC46, that have been shown to play interacting roles in the early steps of DNA replication.

Saccharomyces cerevisiae protein involved in plasmid maintenance is necessary for mating of MAT alpha cells.

We previously reported the isolation of yeast mutants that seem to affect the function of certain autonomously replicating sequences (ARSs). These mutants are known as mcm for their defect in the maintenance of minichromosomes. We have now characterized in more detail one ARS-specific mutation, mcm1-1. This Mcm1 mutant has a second phenotype; MAT alpha mcm1-1 strains are sterile. MCM1 is non-allelic to other known alpha-specific sterile mutations and, unlike most genes required for mating, it is essential for growth. The alpha-specific sterile phenotype of the mcm1-1 mutant is manifested by its failure to produce a normal amount of the mating pheromone, alpha-factor. In addition, transcripts of the MF alpha 1 and STE3 genes, which encode the alpha-factor precursor and the alpha-factor receptor, respectively, are greatly reduced in this mutant. These and other properties of the mcm1-1 mutant suggest that the MCM1 protein may act as a transcriptional activator of alpha-specific genes. We have cloned, mapped and sequenced the wild-type and mutant alleles of MCM1, which is located on the right arm of chromosome XIII near LYS7. The MCM1 gene product is a protein of 286 amino acid residues and contains an unusual region in which 19 out of 20 residues are either aspartic or glutamic acid, followed by a series of glutamine tracts. MCM1 has striking homology to ARG80, a regulatory gene of the arginine metabolic pathway located about 700 base-pairs upstream from MCM1. A substitution of leucine for proline at amino acid position 97, immediately preceding the polyanionic region, was shown to be responsible for both the alpha-specific sterile and minichromosome-maintenance defective phenotypes of the mcm1-1 mutant.

Potential pharmacotherapy of Alzheimer disease. A comparison of various forms of physostigmine administration.

This paper reviews clinical trials with physostigmine administered to Alzheimer patients using three different routes of administration: oral, i.v. and intracerebroventricular (i.c.v.). It compares results obtained with three different routes by the authors as well as by other authors. Particular emphasis is given to a novel type of physostigmine administration, the i.c.v. route. Advantages and disadvantages, as well as side effects of each route are presented and discussed.

Choline levels are increased in cerebrospinal fluid of Alzheimer patients.

We measured choline (Ch), acetylcholinesterase activity (AChE) and total protein in the cerebrospinal fluid (CSF) of 66 Alzheimer patients (ages 54-89 years) and 22 age-matched controls (ages 52-80 years), looking for markers of the well-established cholinergic deficit and neuronal degeneration in Alzheimer disease (AD). Three or more lumbar punctures were performed in 21 patients over a span of 24 months in order to study the changes in these CSF components with disease progression. We found a statistically significant reduction in AChE and an increase in Ch with advancing dementia. These changes were not related to patient age. We suggest that the rise in CSF choline is related to neuronal membrane breakdown and reduced Ch uptake by cholinergic neurons. The reduction in CSF AChE is consistent with the depletion of cholinergic neurons in AD.

Cholinesterases in cerebrospinal fluid. A longitudinal study in Alzheimer disease.

We measured acetylcholinesterase (AChE) and butyrylcholinesterase activities in the lumbar cerebrospinal fluid (CSF) of 39 patients with dementia of Alzheimer type and 21 age-matched controls. The mean lumbar CSF AChE activity in our patients did not differ significantly from that of controls. The 7S and 11S molecular forms were also unchanged. When CSF was analyzed at six-month intervals, there was no significant decline in AChE activity over a span of 12 months. Our results and those of previous studies demonstrate that CSF AChE is not a useful diagnostic marker of Alzheimer disease.

Hemianopsia in dementia with Lewy bodies.

OBJECTIVE: To describe the pathologic changes that caused a left homonymous hemianopsia in a patient with dementia with Lewy bodies. DESIGN: Report of a case and postmortem studies. MAIN OUTCOME AND RESULTS: A 66-year-old woman experienced parkinsonism and left homonymous hemianopsia early in the course of a rapidly progressive dementia that culminated in death only 21 months after the onset of her symptoms. Postmortem examination revealed pathologic features consistent with the diagnosis of dementia with Lewy bodies. The only apparent explanation for her visual field deficit was a disproportionately large number of neurofibrillary tangles in the right striate, peristriate, and inferotemporal cortices. CONCLUSION: A clinically obvious homonymous hemianopsia can result from the occipital and inferotemporal cortical degeneration in dementia with Lewy bodies.

Physiologic and essential tremor.

We studied physiologic and essential hand tremor using inertial loading; hand acceleration and forearm EMG data were analyzed by auto- and cross-spectral analysis. Early essential tremor was qualitatively similar to the 8- to 12-Hz component of physiologic tremor, suggesting that this tremor component is a forme fruste of essential tremor. Advanced essential tremor had a frequency of 4 to 8 Hz. Patients with tremor frequencies in both ranges were observed in each of 10 families. In antagonistic forearm muscles, both synchronous and alternating tremor bursts were observed in 11 of 44 patients. Essential tremor should not be classified solely on the basis of frequency or EMG pattern.

Diagnostic criteria for essential tremor and differential diagnosis.

Classic essential tremor (ET) is a condition in which the upper limbs (approximately 95% of patients) and, less commonly, the head (approximately 34%), face (approximately 5%), voice (approximately 12%), trunk (approximately 5%), and lower limbs (approximately 20%) exhibit a mixed postural and kinetic tremor without other neurologic abnormalities. Most patients with ET probably inherit the disease through an autosomal dominant gene, but the true ratio of hereditary versus sporadic ET is unknown. Isolated focal, position-specific, and task-specific tremors are probably not ET in most patients and are often due to subtle dystonia. Unilateral tremor, gait disturbance, rigidity, bradykinesia, rest tremor, and rapid onset of symptoms are indications of other tremorogenic disorders.

Essential tremor frequency decreases with time.

OBJECTIVE: To quantify the extent to which tremor frequency changes with time in patients with essential tremor. BACKGROUND: Tremor frequency tends to be lower in older patients. The author's previous study of 18 patients with essential tremor produced evidence that tremor frequency decreases slowly over a period of 4 to 8 years. A decrement in frequency will increase tremor amplitude because there is less attenuation of lower-frequency tremor by the low-pass filtering properties of muscle and limb mechanics. METHODS: Nineteen women and 25 men with essential tremor and no other neurologic conditions were followed for 4 years. Accelerometry and surface electromyography (EMG) were used to measure hand tremor and motor unit entrainment in the extensor carpi radialis brevis every 2 years. Tremor frequency was computed from the spectral peak in the rectified filtered EMG spectrum under the condition of 300-gram loading. RESULTS: The patients' mean +/- SD age was 68.0+/-9.95 years. The mean tremor frequency at baseline was 5.79+/-1.32 Hz. The mean decrement in tremor frequency over 4 years was 0.332 Hz (95% CI = 0.141 to 0.523) and was 0.270 Hz (95% CI = 0.122 to 0.418) when a 61-year-old outlier patient was excluded. Tremor frequency and patient age were linearly related: frequency = -0.061(age) + 9. 94 (r = 0.459; p<0.002). CONCLUSIONS: The frequency of essential tremor decreases by approximately 0.06 to 0.08 Hz/year. This decrement in frequency is consistent with the linear relationship between age and tremor frequency.

The pathophysiology of essential tremor.

The pathophysiologic abnormalities that underlie essential tremor (ET) are difficult to decipher because autopsy studies reveal no gross or microscopic abnormalities. Electrophysiologic studies are consistent with a central source of tremorogenic oscillation. The inferior olive and cerebellum are implicated by PET studies. Harmaline tremor in animals shares many features with ET, and the inferior olive has been identified as the source of oscillation in this animal model. Therefore, a disturbance of olivocerebellar rhythmicity is at present the most popular hypothesis for the etiology of ET. Although electrophysiologic tests are available that are helpful in the diagnosis of ET, a gold-standard test or biologic marker for ET is still lacking.

Longitudinal study of essential tremor.

We measured wrist tremor and forearm EMG in 18 patients with essential tremor on two occasions separated by periods of 4 to 8 years. The frequency of tremor decreased 0.28 Hz to 3.21 Hz in 10 patients and changed less than 0.25 Hz in the remaining eight patients. Thus, the frequency of essential tremor may decrease over time.

Estrogen for Alzheimer's disease in women: randomized, double-blind, placebo-controlled trial.

BACKGROUND: AD, the most prevalent cause of dementia, affects twice as many women as men. Therapeutic options are limited, but results of prior studies support the hypothesis that estrogen treatment may improve symptoms of women with this disorder. METHODS: Forty-two women with mild-to-moderate dementia due to AD were enrolled into a randomized, double-blind, placebo-controlled, parallel-group trial of unopposed conjugated equine estrogens (1.25 mg/day) for 16 weeks. RESULTS: Outcome data were available for 40 women at 4 weeks and 36 women at 16 weeks. At both 4 and 16 weeks, there were no significant differences or statistical trends between treatment groups on the primary outcome measure (the cognitive subscale of the Alzheimer's Disease Assessment Scale), clinician-rated global impression of change, or caregiver-rated functional status. Exploratory analyses of mood and specific aspects of cognitive performance also failed to demonstrate substantial group differences. CONCLUSION: Although conclusions are limited by small sample size and the possibility of a type II error, results suggest that short-term estrogen therapy does not improve symptoms of most women with AD. These findings do not address possible long-term effects of estrogen in AD, possible interactions between estrogen and other treatment modalities, or putative effects of estrogen in preventing or delaying onset of this disorder.

The role of aging in the clinical expression of essential tremor.

Essential tremor is the most common form of abnormal tremor. It is a monosymptomatic disorder characterized by action tremor but no other sign of motor dysfunction. More than half of all cases are inherited through a Mendelian dominant gene. Mild essential tremor is probably the cause of tremulousness that is frequently attributed to aging. The prevalence of essential tremor increases with age, and aging appears to have an independent effect on the clinical characteristics of essential tremor. Autopsies have revealed no discernible pathology. Essential tremor probably emerges from subtle pathologic transformation of a physiologic neuronal oscillator, possibly the inferior olive. A more complete characterization of the effects of aging on motor pathways may be necessary to fully understand the natural history and pathogenesis of this disorder.

Quantification of tremor with a digitizing tablet.

Handwriting and drawing are commonly employed in the clinical assessment of tremor. These tasks have been quantified heretofore by subjective rating schemes, which are incapable of providing precise measures of the amplitude and frequency of tremor. A commercially-available digitizing tablet and personal computer can be interfaced so as to reliably record any pathologic tremor that is induced by writing or drawing. Numerical differentiation and spectral analysis can be used to conveniently quantify the amplitude and frequency of tremor. However, digitizing tablets lack sufficient sensitivity to measure physiologic tremor.

Activity of muscle spindles, motor cortex and cerebellar nuclei during action tremor.

Repeated electrode penetration of the dentate and interpositus nuclei in a rhesus monkey transformed an 11-13 Hz physiologic tremor into a much larger action tremor at 5-7 Hz. This tremor was associated with muscle spindle spike train modulation and reflexly evoked tremor modulation of interpositus and motor cortex neurons as well as electromyogram (EMG). No tremor modulation was observed in spike trains recorded from dentate. The timing relationships of the spindle, EMG, and interpositus tremor discharges suggest that the interpositus plays a direct role in tremor suppression. Dentate, by contrast, may function indirectly by setting optimal transcortical long loop reflex dynamics concerned with intended voluntary movement.

The syndrome of senile gait.

Infrared computed stroboscopic photometry was used to quantify the kinematic profiles of walking in 10 elderly patients with symmetrical neurological disturbances of gait and in 19 age-matched neurologically healthy people. Clinical examination of the patients revealed similar profiles of walking even though their diagnoses were vascular dementia (2), normal pressure hydrocephalus (2), Alzheimer dementia with possible normal pressure hydrocephalus (2), mixed Alzheimer and vascular dementia (1), peripheral neuropathy (1), Alzheimer dementia with parkinsonian features (1), and undetermined (1). Quantitatively, the patients' gait kinematics deviated greatly from control values, but these deviations were statistically attributable to reductions in stride. We suggest that many gait disturbances in elderly people are similar, regardless of etiology, because the characteristics of these gait disturbances are heavily veiled by nonspecific stride-dependent changes that comprise the syndrome of senile gait.

Stride-dependent changes in gait of older people.

Infrared computerized stroboscopic photometry was used to measure the kinematic profile of walking of 20 young adults and 20 neurologically healthy elderly people. Compared with the young adults, the elderly exhibited 17-20% reductions in the velocity of gait and length of stride. The elderly also exhibited comparable reductions in the maximum toe-floor clearance, arm swing, and rotations of the hips and knees, but these alterations in gait were attributable to the reduction in stride length, which may have non-neurological causes. The influence of reduced gait velocity and stride length on the other characteristics of walking must be considered when evaluating the pattern of walking in elderly people.

Distribution of amyloid in the brainstem of patients with Alzheimer disease.

A4 protein (beta-protein, beta-amyloid) deposits were identified with silver stains in postmortem brainstem sections from 13 patients with Alzheimer disease (AD), 6 patients with mixed Alzheimer disease and Parkinson disease (AD-PD), 5 disease controls, and 2 elderly controls. A rostro-caudal gradient of A4 was found in patients with AD and AD-PD, such that A4 was most prevalent in the midbrain and least prevalent in the medulla. The brainstem of the controls contained little or no A4. The midbrain tectum and tegmentum contained the greatest densities of A4, but the red nucleus and substantia nigra pars reticulata were largely spared. This distribution of A4 suggests that A4 deposition is a function of synaptic connectivity rather than passive diffusion from vascular sources.

Visualization of brain iron by mid-field MR.

Brain iron was visualized on a mid-field (0.5 T) scanner using a spin-echo pulse sequence. Methemoglobin was hyperintense on T1- and T2-weighted images. Deoxyhemoglobin, hemosiderin, and ferritin were seen as decreased intensity on T2-weighted images. The spin-echo pulse sequences were improved for identification of deoxyhemoglobin, hemosiderin, and ferritin by prolonging the TR to 3000 msec and the TE to 80-120 msec. Phase-encoding artifacts at the level of the sylvian fissures caused increased noise, obscuring the brain iron in the lentiform nuclei with the TE of 120 msec. This artifact was substantially reduced or eliminated by lowering the TE to 80 msec, changing the phase-encoding gradient to the Y axis, or using additional pulsing in the slice and read gradients. Use of either the improved spin-echo or gradient-echo pulse sequences on a mid-field MR scanner provides improved evaluation of brain iron.