To develop a brief ataxia rating scale (BARS) for use by movement disorder specialists and general neurologists. Current ataxia rating scales are cumbersome and not designed for clinical practice. We first modified the International Cooperative Ataxia Rating Scale (ICARS) by adding seven ataxia tests (modified ICARS, or MICARS), and observed only minimally increased scores. We then used the statistics package R to find a five-test subset in MICARS that would correlate best with the total MICARS score. This was accomplished first without constraints and then with the clinical constraint requiring one test each of Gait, Kinetic Function-Arm, Kinetic Function-Leg, Speech, and Eye Movements. We validated these clinical constraints by factor analysis. We then validated the results in a second cohort of patients; evaluated inter-rater reliability in a third cohort; and used the same data set to compare BARS with the Scale for the Assessment and Rating of Ataxia (SARA). Correlation of ICARS with the seven additional tests that when added to ICARS form MICARS was 0.88. There were 31,481 five-test subtests (48% of possible combinations) that had a correlation with total MICARS score of ≥0.90. The strongest correlation of an unconstrained five-test subset was 0.963. The clinically constrained subtest validated by factor analysis, BARS, had a correlation with MICARS-minus-BARS of 0.952. Cronbach alpha for BARS and SARA was 0.90 and 0.92 respectively; and inter-rater reliability (intraclass correlation coefficient) was 0.91 and 0.93 respectively. BARS is valid, reliable, and sufficiently fast and accurate for clinical purposes. © 2009 Movement Disorder Society
ataxia; dysmetria; rating scale; assessment; cerebellum
episodic ataxia type 2; CACNA1A; p.R1346Stop; acetazolamide; cerebellar vermis
Little is known about subjective perceptions of quality of life (QOL) in Huntington’s disease (HD). The current study determined correlates of patient and caregiver QOL and assessed change over time. Participants were 22 patient-caregiver dyads, who rated QOL at baseline and six months later. Overall, patient functional and cognitive impairment were significantly correlated with patient and caregiver QOL. Neuropsychiatric symptoms had differential impact on patient and caregiver QOL. Furthermore, when patients recalled their QOL about a previous time, their recall may have been negatively biased. Treatment implications of results are discussed. Future work is needed because subjective QOL is an important outcome measure in therapeutic trials.
Huntington’s disease; quality of life; caregiver; neuropsychiatric symptoms; self-report
Based on the pre-clinical and the results of a phase 2 futility study, creatine was selected for an efficacy trial in Parkinson’s 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 3 study of creatine (10 gm daily) in participants with early, treated PD, the Long-term Study – 1 (LS-1) is being conducted by the NINDS Exploratory Trials in Parkinson’s Disease (NET-PD) network. The study utilizes a global statistical test (GST) encompassing multiple clinical rating scales to provide a multidimensional assessment of disease progression.
A total of 1,741 PD participants from 45 sites in the U.S. and Canada were randomized 1:1 to either 10-gm 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 (10gm/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.
neuroprotection; Parkinson’s disease; clinical trial; creatine; global statistical test
Huntington disease is characterized clinically by chorea, motor impairment, psychiatric manifestations and dementia. Atrophy of the striatum is the neuropathological hallmark of Huntington disease and previous studies have suggested that striatal atrophy correlates more closely with motor impairment than with chorea. Motor impairment, as measured by motor impairment score, correlates with functional disability in Huntington patients, but chorea does not. In this study, we investigate the relation between neuronal loss and these motor features.
We conducted neuropathological and stereologic assessments of neurons in putamen and subthalamic nuclei in Huntington patients and age-matched controls. In putamen, we estimated the total number and volume of medium spiny neurons labeled with dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP32). In subthalamic nuclei, we estimated the total number of neurons on Hematoxylin/Eosin -Luxol/Fast Blue stains.
In putamen of Huntington disease, immunohistochemistry showed DARPP 32 neuronal atrophy with extensive disruption of neurites and neuropil; stereologic studies found significant decreases in both the number and size of DARPP32 neurons; we also detected a significant reduction of overall putamen volume in Huntington patients compared with controls. In subthalamic nuclei, there was a mild but significant neuronal loss in Huntington group. The loss of neurons in putamen and subthalamic nuclei and the putaminal atrophy were significantly correlated with the severity of motor impairment, but not with chorea.
Our findings suggest that neuronal loss and atrophy in striatum and neuronal loss in subthalamic nuclei contribute specifically to the motor impairment of Huntington, but not to chorea.
Putamen; subthalamic nucleus; medium spiny neurons; DARPP32; stereology
Although organochlorines have been reported more frequently in Parkinson’s disease (PD) brains than controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during mid-life, represent a population well suited to determine the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS.
Study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites.
With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found to be present in at least one brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. Prevalence of Lewy pathology was 75% (6/8) among brains with any 2 of the 3 compounds, 48.8% (79/162) among those with 1, and 32.7% (18/55) for those with neither (P=0.007 test for trend). While findings persisted after removing cases with PD and dementia with Lewy bodies, and when adjustments were made for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (p=0.013), results were insignificant when correcting for multiple testing.
While consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study.
Parkinson’s disease; epidemiology; Lewy body; organochlorines; pesticides
Deep brain stimulation relieves disabling symptoms of neurologic and psychiatric diseases when medical treatments fail, yet its therapeutic mechanism is unknown. We hypothesized that ventral intermediate nucleus stimulation for essential tremor activates cortex at short latencies and that this potential is related to suppression of tremor in the contralateral arm. We measured cortical activity with electroencephalography in 5 subjects (7 brain hemispheres) across a range of stimulator settings, and reversal of the anode and cathode electrode contacts minimized the stimulus artifact, allowing visualization of brain activity. Regression quantified the relationship between stimulation parameters and both the peak of the short latency potential and tremor suppression. Stimulation generated a polyphasic event related potential in ipsilateral sensorimotor cortex with peaks at discrete latencies beginning less than one millisecond after stimulus onset (mean latencies 0.9±0.2, 5.6±0.7, and 13.9±1.4 milliseconds, denoted R1, R2, and R3, respectively). R1 showed more fixed timing than the subsequent peaks in the response (p<0.0001, Levene’s test), and R1 amplitude and frequency were both closely associated with tremor suppression (p<0.0001, respectively). These findings demonstrate that effective ventral intermediate nucleus thalamic stimulation for essential tremor activates cerebral cortex at approximately one millisecond after the stimulus pulse. The association between this short latency potential and tremor suppression suggests that deep brain stimulation may improve tremor by synchronizing the precise timing of discharges in nearby axons, and by extension the distributed motor network, to the stimulation frequency or one of its subharmonics.
ventral intermediate nucleus; deep brain stimulation; essential tremor; thalamus; cerebral cortex; event related potential
Caffeine consumption has been associated with a reduced risk of Parkinson disease. The association is strong and consistent in men, but uncertain in women, possibly because of an interaction with hormone replacement therapy. We sought to confirm these findings using data on Parkinson disease incidence in the CPS II Nutrition Cohort, a large prospective study of men and women.
We conducted a prospective study of caffeine intake and risk of PD within the Cancer Prevention Study II Nutrition Cohort. Intakes of coffee and other sources of caffeine were assessed at baseline. Incident cases of PD (n = 317; 197 men and 120 women) were confirmed by treating physicians and medical record review. Relative risks (RR) were estimated using proportional hazards models, adjusting for age, smoking and alcohol consumption.
After adjustment for age, smoking and alcohol intake, high caffeine consumption was associated with a reduced risk of PD. The relative risk comparing the 5th to the 1st quintile of caffeine intake was 0.43 (CI: 0.26, 0.71, p-trend = <0.002) in men, and 0.61 (95% CI: 0.34, 1.09; p for trend =0.05) in women. Among women, this association was stronger among never users of hormone replacement therapy (RR=0.32) than among ever users (RR=0.81, p-interaction = 0.15). Consumption of decaffeinated coffee was not associated with PD risk.
Findings from this large prospective study of men and women are consistent with a protective effect of caffeine intake on PD incidence, with an attenuating influence of hormone replacement therapy in women.
Parkinson; epidemiology; coffee; caffeine; tea
Links between impulsive compulsive behaviors in treated Parkinson’s disease, behavioral addictions and substance abuse have been postulated, but no direct comparisons have been carried out so far.
We directly compared patients with Parkinson’s disease with and without impulsive compulsive behaviors with illicit drug abusers, pathological gamblers and age-matched healthy controls using the beads task, a test of reflection impulsivity and a working memory task.
We found that all patients with Parkinson’s disease made more impulsive and irrational choices than the control group. Parkinson’s disease patients who had an impulsive compulsive behavior showed similar behavior to illicit substance abusers whereas patients without impulsive compulsive behaviors more closely resembled pathological gamblers. In contrast we found no difference in working memory performance within the Parkinson’s disease groups. However Parkinson’s disease patients without impulsive compulsive behaviors remembered distractors significantly less than all other patients during working memory tests.
We were able to correctly classify 96% of the Parkinson’s disease patients with respect to whether or not they had an impulsive compulsive behavior by analyzing 3 trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3% and we propose that this task may prove to be a powerful screening tool to detect an impulsive compulsive behavior in Parkinson’s disease. Our results also suggest that intact cortical processing and less distractibility in Parkinson’s disease patients without impulsive compulsive behaviors may protect them from developing behavioral addictions.
Impulsive compulsive behavior; Parkinson’s disease; reflection impulsivity; pathological gambling; substance abuse; beads task
Huntington’s disease is an inherited neurodegenerative disorder caused by a triplet repeat, CAG expansion mutation. Although CAG repeat length is thought to correlate with pathologic burden and disease severity, considerable variability in clinical phenotype remains. This study examined whether neuropathologic burden at autopsy corresponded with severity of clinical phenotype in Huntington’s disease.
The brains of 24 patients with a clinical and genetic diagnosis of Huntington’s disease were analyzed at autopsy. Subjects were stratified on the basis of Vonsattel staging as mild/moderate (Stage 1–2, n=7) or severe (Stage 3–4, n=17). Clinical severity was assessed on the basis of the Mini Mental State Exam (0–30) and two Unified Huntington's Disease Rating Scale functional components, the Independence Scale (10–100) and the Total Functional Capacity (0–13).
The mild/moderate subjects were significantly older, had lower CAG repeat lengths, and greater fixed brain weights than those classified as severe. Patients who were pathologically classified as severe at autopsy were, on average, younger at age of onset and death, and less well educated. Despite obvious clinical and pathological differences between mild-moderate and severe Huntington’s disease subjects at autopsy, mean Mini Mental State Exam scores of the two groups prior to death were surprisingly similar. Correlations between Vonsattel stage and functional assessment scores prior to death were low and not statistically significant.
Our results suggest that the extent of striatal changes in Huntington’s disease may not always correlate with clinical disease severity measured by Unified Huntington's Disease Rating Scale functional scales.
Autopsy study; Huntington’s disease; Independence scale; Total Functional Capacity; Unified Huntington's Disease Rating Scale; Vonsattel staging
Mild cognitive impairment is increasingly recognized as a construct in Parkinson’s disease (PD) and occurs in about 25% of non-demented PD patients. Although executive dysfunction is the most frequent type of cognitive deficit in PD, the cognitive phenotype of PD mild cognitive impairment (PD-MCI) is broad. PD-MCI subtypes are represented by amnestic and nonamnestic domain impairment as well as single- and multiple-domain impairment. However, it is unclear whether patients with different PD-MCI subtypes also differ in other clinical characteristics besides cognitive profile.
We studied 128 PD-MCI subjects at our Movement Disorders center, comparing clinical, motor, and behavioral characteristics across the PD-MCI subtypes.
We found varying proportions of impairment subtypes: nonamnestic single-domain (47.7%), amnestic multiple-domain (24.2%), amnestic single-domain (18.8%), and nonamnestic multiple-domain (9.5%). Attentional/executive functioning and visuospatial abilities were the most frequently impaired domains. PD-MCI subtypes differed in their motor features with nonamnestic multiple-domain PD-MCI subjects showing particularly pronounced problems with postural instability and gait. Differences among PD-MCI subtypes in age, PD duration, medication use, mood or behavioral disturbances, or vascular disease were not significant.
In addition to differing cognitive profiles, PD-MCI subtypes differ in motor phenotype and severity but not in mood, behavioral, or vascular co-morbidities. Greater postural instability and gait disturbances in the nonamnestic multiple-domain subtype emphasize shared non-dopaminergic neural substrates of gait and cognition in PD. Furthermore, increased burden of cognitive dysfunction, rather than type of cognitive deficit, may be associated with greater motor impairment in PD-MCI.
amnestic; dementia; gait; mild cognitive impairment; nonamnestic
Many patients with idiopathic Parkinson’s disease experience difficulties maintaining daytime alertness. Controversy exists regarding whether this reflects effects of anti-Parkinsonian medications, the disease itself or other factors such as nocturnal sleep disturbances. In this study we examined the phenomenon by evaluating medicated and unmedicated Parkinson’s patients with objective polysomnographic measurements of nocturnal sleep and daytime alertness.
Patients (n = 63) underwent a 48-hour laboratory-based study incorporating 2 consecutive nights of overnight polysomnography and 2 days of Maintenance of Wakefulness Testing. We examined correlates of individual differences in alertness, including demographics, clinical features, nocturnal sleep variables and class and dosage of anti-Parkinson’s medications.
Results indicated that: 1) relative to unmediated patients, all classes of dopaminergic medications were associated with reduced daytime alertness and this effect was not mediated by disease duration or disease severity; 2) increasing dosages of dopamine agonists were associated with less daytime alertness, whereas higher levels of levodopa were associated with higher levels of alertness. Variables unrelated to Maintenance of Wakefulness Test defined daytime alertness included age, sex, years with diagnosis, motor impairment score and most nocturnal sleep variables.
Deficits in objectively assessed daytime alertness in Parkinson’s disease appear to be a function of both the disease and the medications and their doses utilized. The apparent divergent dose-dependent effects of drug class in Parkinson’s disease are anticipated by basic science studies of the sleep/wake cycle under different pharmacological agents.
Parkinson’s Disease; Daytime Alertness; Sleep; Maintenance of Wakefulness Test; Dopaminergic Treatment
Pulmonary function abnormalities in Parkinson’s disease (PD) might predispose patients to obstructive sleep apnea (OSA) and daytime sleepiness. Fifty-five idiopathic PD patients (mean age = 63.9) underwent three consecutive nights of in-laboratory polysomnography on their usual dopaminergic medications. Sleep apnea severity was compared to published, normative, population-based data from the Sleep Heart Health Study. Demographic and clinical data were compared in patients with and without OSA. The apnea-hyponea index (AHI) was stable across nights in PD patients, and was not different between PD patients and normative controls. Epworth Sleepiness Scale scores, Body Mass Index, and snoring did not correlate with AHI. Severity of OSA is stable across multiple nights in PD patients. Rates of OSA in PD are similar to those seen in the general population. Daytime sleepiness, snoring, and obesity may not be helpful in identifying OSA in PD.
Parkinson’s Disease; Obstructive Sleep Apnea; Excessive Daytime Sleepiness
Many patients with Parkinson disease (PD) develop dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account in part for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases.
29 cognitively normal PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and PiB imaging with PET. Apolipoprotein (APOE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference.
PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the APOEε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition.
DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.
dementia; Lewy; Parkinson; amyloid; PiB
Recommended doses of carbidopa are 75–200 mg/day. Higher doses could inhibit brain aromatic amino acid decarboxylase and reduce clinical effects.
We compared 4-week outpatient treatments with carbidopa 75 mg and 450 mg/day administered with levodopa on the subjects’ normal schedule. After each treatment phase subjects had two 2-hour levodopa infusions. The first infusion examined the effects of carbidopa doses administered the preceding four weeks and the second infusion determined the acute effects of the two dosages of carbidopa. The antiparkinsonian effects and levodopa and carbidopa plasma concentrations were monitored during the infusions.
Twelve subjects completed the study. Carbidopa concentrations were eight times higher after the high carbidopa phase. Area under the curve (AUC) for clinical ratings did not differ for the four levodopa infusions although AUC for plasma levodopa was modestly increased with 450 mg of carbidopa. Nine subjects reported the high carbidopa outpatient phase was associated with greater response to levodopa.
Doses of 450 mg/day of carbidopa did not reduce the responses to levodopa infusion, extending the safe range of carbidopa to 450 mg/day.
Carbidopa; levodopa; Parkinson’s disease
Sham surgery controls are increasingly used in neurosurgical clinical trials in Parkinson disease (PD), but remain controversial. We interviewed participants of such trials, specifically examining their understanding and attitudes regarding sham surgery.
We conducted semi-structured qualitative interviews with participants of three sham surgery controlled trials for PD, focusing on their understanding of sham design, their reactions to it, its impact on decision-making, and their understanding of post-trial availability of the experimental intervention and its impact on decisions to participate.
All subjects (N=90) understood the two-arm design; most (86%) described the procedural differences between the arms accurately. 92% referred to scientific or regulatory reasons as rationales for the sham control, with 62% specifically referring to the placebo effect. 91% said post-trial availability of the experimental intervention had a strong (48%) or some (43%) influence on their decision to participate but only 68% understood the conditions for post-trial availability.
Most subjects in sham surgery controlled PD trials comprehend the sham surgery design and its rationale. Although there is room for improvement, most subjects of sham surgery trials appear to be adequately informed.
sham surgery; gene therapy; Parkinson disease; bioethics
Several metabolic markers or conditions have been explored as possible risk or protective factors for Parkinson’s disease (PD); however, results remain conflicting. We further investigated these associations using a case-control study design.
We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (± 1 year) and sex to a general population control. We reviewed the complete medical records of cases and controls in the medical records-linkage system to abstract information about body mass index (BMI), cholesterol levels, hypertension, and diabetes mellitus preceding the onset of PD (or the index year).
There were no significant differences between cases and controls for the metabolic markers or conditions investigated. No significant associations were found using 2 cut-offs for BMI levels (BMI ≥ 25 or BMI ≥ 30 kg/m2) and 3 cut-offs for cholesterol levels (> 200, > 250, or > 300 mg/dl). A diagnosis of hypertension or the documented use of anti-hypertensive medications were not significantly associated with the subsequent risk of PD (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.65–1.54; P = .99), nor was a diagnosis of diabetes mellitus or the use of glucose-lowering medications (OR, 0.77; 95% CI, 0.37–1.57; P =.47).
Our study, based on historical information from a records-linkage system, does not support an association between BMI, cholesterol levels, hypertension, or diabetes mellitus and later development of PD.
Parkinson’s disease; body mass index; cholesterol level; hypertension; diabetes mellitus
Addictive behaviors such as cigarette smoking and coffee drinking have been associated with a reduced risk of Parkinson disease. Whether alcohol consumption is also associated with risk is less certain.
We prospectively followed 132,403 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2005. Alcohol intake was assessed at baseline. Incident cases of Parkinson Disease (n = 605; 389 male and 216 female) were confirmed by treating physicians and medical record review. Relative risks were estimated using proportional hazards models, adjusting for age, smoking and other risk factors.
Alcohol consumption was not significantly associated with Parkinson Disease risk. After adjustment for age, smoking, and other risk factors, the Relative Risk comparing men consuming 30 or more grams of alcohol (highest category) to non-drinker men was 1.29 (95% CI: 0.90, 1.86, p-trend: 0.40) and the Relative Risk comparing women consuming 15 or more grams of alcohol (highest category) per day to non-drinker women was 0.77 (95% CI: 0.41, 1.45, p-trend: 0.87). Consumption of beer, wine or liquor was also not associated with Parkinson Disease risk.
The results of this large prospective study do not support an association between alcohol intake and risk of Parkinson disease.
Changes in cardiovascular physiology in PD are common and may occur prior to diagnostic Parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability or carotid stenosis with the risk of Parkinson disease (PD) diagnosis in the Cardiovascular Health Study, a community-based cohort of older adults.
ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24-hour Holter monitoring) or any carotid stenosis (≥1%) by ultrasound were modeled as primary predictors for incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least one of the following: self-report, anti-Parkinsonian medication use, or ICD9. If unadjusted models were significant, they were adjusted or stratified for age, sex and smoking status and those in which predictors were still significant (p≤0.05) were additionally adjusted for race, diabetes, total cholesterol, low density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke and C-reactive protein.
Of 5,888 participants, 154 incident PD cases were identified over 14 years of follow-up. After adjusting models with all covariates, those with any ECG abnormality (Odds Ratio: 1.45, 95% CI: 1.02-2.07,p=0.04) or any carotid stenosis (OR: 2.40, 95% CI (1.40-4.09,p=0.001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors.
This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential pre-motor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset.
Parkinson disease; neuroepidemiology; non-motor features; cardiovascular physiology; neurodegeneration
Converging research efforts suggest that nicotine and other drugs that act at nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinson’s disease. This idea initially stemmed from the results of epidemiological studies which demonstrate that smoking is associated with a decreased incidence of Parkinson’s disease. The subsequent finding that nicotine administration protected against nigrostriatal damage in parkinsonian animal models led to the idea that nicotine in tobacco products may contribute to this apparent protective action. Nicotine most likely exerts its effects by interacting at nAChRs. Accumulating research indicates that multiple subtypes, including α4β2, α6β2 and/or α7 containing nAChRs, may be involved. Stimulation of nAChRs initially activates various intracellular transduction pathways primarily via alterations in calcium signaling. Consequent adaptations in immune responsiveness and trophic factors may ultimately mediate nicotine’s ability to reduce/halt the neuronal damage that arises in Parkinson’s disease. In addition to a potential neuroprotective action, nicotine also has anti-depressant properties and improves attention/cognition. Altogether, these findings suggest that nicotine and nAChR drugs represent promising therapeutic agents for the management of Parkinson’s disease.
Neuroprotection; Nicotine; Nicotinic; Nigrostriatal damage; Parkinson’s disease
We investigated olfactory defects in fragile X-associated tremor/ataxia syndrome (FXTAS), a finding reported on in other neurodegenerative disorders with clinical features that overlap those of FXTAS.
We measured olfactory identification capacity in 41 FMR1 premutation carriers and 42 controls using the University of Pennsylvania Smell Identification Test (UPSIT). Carriers received neurologic evaluations using motor rating scales for tremor, ataxia, and parkinsonism. Cognitive function was measured using the Montreal Cognitive Assessment test.
Frequency of olfactory defects was higher in carriers, compared to controls (61% versus 29%; P = 0.003). There was no statistically significant group difference in severity of olfaction defects, after accounting for differences in age, and in rates of head injury and smoking. However, both the frequency (odds ratio = 3.9; 95% confidence interval: 0.81–19.1) and severity (28.6 versus 33.4; P = 0.01) of these defects were greater in cognitively impaired, compared to cognitively intact, carriers. There was no correlation between UPSIT scores and the above-mentioned motor rating scales.
FMR1 premutation carriers are susceptible to olfactory identification defects. The severity of these defects is comparable to that reported in hereditary ataxias, but less than that in PD and Alzheimer’s disease. This concurrence across neurodegenerative disorders suggests a shared system vulnerability that correlates with, but is not limited to, cognitive impairment, because it is also found in cognitively intact carriers. These results need to be corroborated in a larger prospective study of FMR1 premutation carriers that extends beyond olfactory identification to include measures of smell thresholds.
FXTAS; olfaction; cognition; FMR1; tremor; ataxia
This study is a retrospective analysis of thalamic neuronal and electromyogram activities between subjects with organic dystonia and a subject with psychogenic dystonia, in whom a thalamotomy was carried out before a diagnosis psychogenic dystonia was made.
The electromyogram signal to noise ratio in the lowest frequency band (<0.76Hz, dystonia frequency – DF) in the electromyogram was not significantly different by diagnosis or muscle (Table 1). The coherence at dystonia frequency for wrist flexors X biceps electromyograms was significantly higher in organic dystonia, while the phase was not apparently different from zero for either diagnosis.
In a thalamic pallidal relay nucleus (ventral oral posterior), neuronal firing rates were not apparently different between psychogenic and organic dystonia. The neuronal signal to noise ratio in ventral oral posterior was significantly higher in organic dystonia than in psychogenic dystonia, while both were greater than in controls with chronic pain. Spike X electromyogram coherence was not apparently different between psychogenic and organic dystonia. The proportion of thalamic cells responding to joint movements was higher in the cerebellar relay nucleus (ventral intermediate) of psychogenic dystonia than organic dystonia.
These results suggest that some features, such as firing rates and thalamic reorganization, are similar in psychogenic and organic dystonia. Other features differ, such as the coherence between the electromyograms from different muscles, and the thalamic neuronal signal to noise ratio, which may reflect pathophysiological factors in organic dystonia.
Psychogenic Dystonia; Organic Dystonia; Human thalamus; Neuronal activity; Plasticity; Dystonia related activity