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ABSTRACT: 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. © 2012 Movement Disorder Society.
Movement Disorders 10/2012; 27(12):1556-9. · 4.51 Impact Factor
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ABSTRACT: The objective of this paper was to assess the phenotypic variance in patients with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and to further elucidate genotype-phenotype correlations in the illness. A second goal was to generate hypotheses regarding symptom progression based on careful histories in our sample that can now be tested in ongoing longitudinal studies. The variability of clinical signs and symptom progression in FXTAS complicates our understanding of its phenotype and presents a series of problems in clinical trial design. Similarly, pre-motor and non-motor symptoms have not been adequately explored to answer outstanding questions regarding genotype-phenotype associations in FXTAS. This was a cross-sectional study of FMR1 premutation carriers from known fragile X syndrome pedigrees. We report on the first 50 subjects who have completed a full neurologic evaluation and a brain MRI. Subjects were selected on the basis of motor symptoms or abnormal results (>1 SD) on a quantitative instrument designed to detect mild tremor and ataxia (CATSYS 1994). A neuropsychological battery included the WAIS-III, COWA, and WCST. Statistical analysis used ANOVA and Fisher's exact test with p < 0.05. All FMR1 premutation carriers were men of mean age 65 ± 7 years. According to the diagnostic criteria of Jacquemont et al. (Am J Hum Genet 72(4):869-878, 2003), 21 subjects met criteria for definite FXTAS, 10 for probable, 9 for possible, and 10 were indeterminate. Duration of motor symptoms was significantly longer in the definitive group (8.6 ± 6) compared to the other groups (p < 0.01). The presentations in 40 subjects, excluding the indeterminate group, included: tremor 24, ataxia 5, memory symptoms 3, parkinsonism 2, and torticollis 1. The data suggest at least two dominant phenotypic presentations: (a) a tremor-dominant subtype in which the onset of ataxia is delayed; (b) a second in which ataxia is the dominant presentation from the outset. In both subtypes, once ataxia emerges it tends to track frontal cognitive changes (p < 0.01). The data support the view that FXTAS is a late-life neurodegenerative disorder with involvement of motor, non-motor, and cognitive systems. The results suggest at least two presentations with tremor- and ataxia-predominant phenotypes. In both, global cognitive decline appears to track ataxia. Prospective longitudinal studies are needed to validate this proposed evolution of FXTAS and its relevance to future clinical trials design.
Neurogenetics 01/2011; 12(2):123-35. · 3.35 Impact Factor
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ABSTRACT: This study examined changes in the translation of the center of pressure during forward and lateral (90 degrees to the side) gait initiation in two populations of older adults with postural instability.
Twenty-eight older adults transitioning to frailty and 16 persons with Parkinson's disease in the "on medication state" were evaluated during initiation trials. Displacements, velocities, and smoothness of the center of pressure trace were calculated and compared.
Both groups produced movements of the center of pressure that on average were reduced compared to healthy populations. Adults transitioning to frailty were able to scale the output of the motor program so forces that propel the body in the intended direction of movement were maximized as evidenced by movements of the center of pressure. The adults transitioning to frailty produced patterns of center of pressure trajectories that were more similar to healthy adults where as individuals with Parkinson's disease produced trajectories that were counterproductive to producing efficient gait initiation in both the forward and lateral direction.
These findings suggest that persons with Parkinson's disease even when in the medicated state exhibit inefficient postural adjustments during both forward and lateral gait initiation and that these postural adjustments are more susceptible to deterioration from the complex interaction of central and peripheral changes associated with Parkinson's disease than to aging alone.
Clinical Biomechanics 08/2008; 23(6):743-53. · 2.07 Impact Factor
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ABSTRACT: Progressive supranuclear palsy (PSP) is the second most common cause of parkinsonism after Parkinson's disease (PD). The classic syndrome of PSP is widely recognized by neurologists as a combination of down gaze palsy with progressive rigidity and imbalance leading to falls. At the same time, few clinicians are proficient at treating PSP and recognizing the nonclassic presentations of this debilitating disorder often resulting in delays in diagnosis and misguided treatment.
Over the last decade many lines of investigation have helped refine PSP at the clinical, neuroimaging, pharmacologic and molecular levels. It is the purpose of this literature review to help clinicians identify PSP earlier in its course, to better understand its pathophysiology, and to provide a more focused, symptom-based treatment approach. Eighty-two peer-reviewed articles on the topic of PSP and other neurodegenerative disorders have been reviewed.
It is clear that PSP continues to be an under-recognized disorder with multilevel involvement of the neuraxis that helps differentiate it from other akinetic rigid syndromes such as PD. A greater appreciation of its atypical presentations, more attention to its neurobehavioral signs and better imaging techniques are some of the advances that will help facilitate earlier detection, which may reduce morbidity by helping anticipate early falls and minimizing unnecessary diagnostic procedures. Surgical approaches to PSP have been ineffective so far. Carefully targeted symptomatic treatment with drugs and other therapies is available and effective at reducing morbidity and improving quality of life.
The Neurologist 04/2008; 14(2):79-88. · 1.26 Impact Factor
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ABSTRACT: The objectives of this study is to examine the effects of neuromuscular therapy (NMT) on motor and nonmotor symptoms in Parkinson's disease (PD). Thirty-six subjects with PD were randomly assigned to NMT or music relaxation (MR, or active control). Subjects received treatment twice a week for 4 weeks. Testing was conducted at baseline, after final treatment, and 8 days after final treatment. Primary outcome measures were the Motor subscale of the United Parkinson Disease Rating Scale (UPDRS) and the Clinical Global Impression scale (CGI-Change). Secondary outcome measures included a PD-specific quality of life scale (PDQ-39), quantitative measures of motor function, and severity scales for anxiety and depression symptoms. NMT resulted in a significant and sustained improvement in the Motor subscale of the UPDRS (P < or = 0.0001), most notable in the tremor scores. Also improved 1 week after the last treatment were the CGI scores (P = 0.007) and the finger-tapping speed (P = 0.001). The MR active control group had a slight improvement in tremor but evidenced no other change in motor function. Both groups exhibited a modest improvement in quality of life immediately after the last treatment. This effect was sustained for 8 days only in the MR group. In the nonmotor domains, the MR group evidenced improvements in mood (P = 0.001) and anxiety (P = 0.002), whereas NMT had no effect on mood (P = 0.09), and its initial effect on anxiety (P = 0.0009) dissipated after 8 days (P = 0.40). Group differences for UPDRS motor score and patient CGI-Change were superior in the NMT compared to the MR group. There was no group difference in PDQ-39 scores or in nonmotor measures. The findings suggest that NMT can improve motor and selected nonmotor symptoms in PD and that this effect is more durable for the motor symptoms. The results of this pilot study warrant larger controlled studies to examine dose range, durability, and mechanisms of NMT in PD function.
Movement Disorders 01/2007; 21(12):2127-33. · 4.51 Impact Factor
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ABSTRACT: To determine whether the magnitude of the separation between the center of pressure (COP) and the whole-body center of mass (COM) during gait initiation can differentiate patients with varying severity of Parkinson's disease (PD) disability.
Cross-sectional, intact groups research design.
Biomechanics research laboratory.
Forty-three patients were stratified into 2 groups based on the Hoehn and Yahr (H&Y) disability score, which heavily favors balance in determining disability. The 2 groups were: H&Y score of 2.0 or less (n=23; age, 61+/-10y) or H&Y score of 2.5 or higher (n=20; age, 70+/-9y).
Not applicable.
The peak COP-COM distance represents the maximum separation between the location of the whole-body COM and the ground reaction force's COP, and thus is an indicator of dynamic balance control. The peak COP-COM was evaluated during 3 phases of the COP trajectory during a gait initiation task.
The peak magnitude of the COP-COM distance was significantly greater during the end of the single-support phase in the less disabled patients (H&Y score <or=2.0) than in more balance disabled patients (H&Y score >or=2.5) (P=.004).
The differences in COP-COM distances between these H&Y groups suggest that patients with PD who have impaired postural control produce shorter COM-COP distances than do persons without clinically detectable balance impairment. This method of evaluation could prove a useful quantitative index to examine the impact of interventions designed to improve ambulation and balance in PD.
Archives of Physical Medicine and Rehabilitation 11/2005; 86(11):2172-6. · 2.28 Impact Factor
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ABSTRACT: Twenty-nine elderly patients who failed treatment with clozapine, risperidone, or olanzapine entered this 24-week, single-center, open-label trial to assess the efficacy of quetiapine (12.5-400 mg/day) for psychosis in patients with Parkinson's disease (PD). Psychiatric, motor, and cognitive assessments were administered at baseline and at periodic intervals for 24 weeks. These included the Brief Psychiatric Rating Scale (BPRS), Neuropsychiatric Inventory (NPI), Unified Parkinson's Disease Rating Scale (UPDRS) and tests of intellectual functioning, attention, and memory. Repeated measures statistical analysis was used to assess change from baseline. The results revealed significant improvements in the 24-week BPRS total score and NPI psychosis subscale scores, with no decline in UPDRS total or motor subscale scores. There was also significant improvement in recall scores on cognitive measures. These results indicate that quetiapine may treat psychotic symptoms and improve cognition without worsening motor function in patients with PD, suggesting that quetiapine is an effective and well-tolerated antipsychotic in this population.
Movement Disorders 02/2004; 19(1):29-35. · 4.51 Impact Factor
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Kelly E Lyons,
Rajesh Pahwa,
Cynthia L Comella,
Mahmood S Eisa,
Rodger J Elble,
Stanley Fahn,
Joseph Jankovic, Jorge L Juncos,
William C Koller,
William G Ondo,
Kapil D Sethi,
Matthew B Stern,
Caroline M Tanner,
Ron Tintner,
Ray L Watts
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ABSTRACT: Essential tremor can cause significant functional disability in some patients. The arms are the most common body part affected and cause the most functional disability. The treatment of essential tremor includes medications, surgical options and other forms of therapy. Presently there is no cure for essential tremor nor are there any medications that can slow the progression of tremor. Treatment for essential tremor is recommended if the tremor causes functional disability. If the tremor is disabling only during periods of stress and anxiety, propranolol and benzodiazepines can be used during those periods when the tremor causes functional disability. The currently available medications can improve tremor in approximately 50% of the patients. If the tremor is disabling, treatment should be initiated with either primidone or propranolol. If either primidone or propranolol do not provide adequate control of the tremor, then the medications can be used in combination. If patients experience adverse effects with propranolol, occasionally other beta-adrenoceptor antagonists (such as atenolol or metoprolol) can be used. If primidone and propranolol do not provide adequate control of tremor, occasionally the use of benzodiazepines (such as clonazepam) can provide benefit. Other medications that may be helpful include gabapentin or topiramate. If a patient has disabling head or voice tremor, botulinum toxin injections into the muscles may provide relief from the tremor. Botulinum toxin in the hand muscles for hand tremor can result in bothersome hand weakness and is not widely used. There are other medications that have been tried in essential tremor and have questionable efficacy. These drugs include carbonic anhydrase inhibitors (e.g. methazolamide), phenobarbital, calcium channel antagonists (e.g. nimodipine), isoniazid, clonidine, clozapine and mirtazapine. If the patient still has disabling tremor after medication trials, surgical options are usually considered. Surgical options include thalamotomy and deep brain stimulation of the thalamus. These surgical options provide adequate tremor control in approximately 90% of the patients. Surgical morbidity and mortality for these procedures is low. Deep brain stimulation and thalamotomy have been shown to have comparable efficacy but fewer complications have been reported with deep brain stimulation. In patients undergoing bilateral procedures deep brain stimulation of the thalamus is the procedure of choice to avoid adverse effects seen with bilateral ablative procedures. The use of medication and/or surgery can provide adequate tremor control in the majority of the patients.
Drug Safety 02/2003; 26(7):461-81. · 3.63 Impact Factor
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ABSTRACT: To investigate whether a single daily dose of testosterone replacement gel has beneficial effects on testosterone deficiency symptoms, cognitive function, nonmotor symptoms of Parkinson disease (PD), and motor symptoms of PD.
Recently it has been observed that testosterone replacement therapy improves refractory nonmotor symptoms in testosterone-deficient men with PD. Many of the symptoms of testosterone deficiency are nonspecific and overlap with the nonmotor symptoms of PD, such as decreased enjoyment of life, lack of energy, sexual dysfunction, and depression. Replacement therapy for men with PD and comorbid testosterone deficiency may be an important addition to antiparkinsonian management strategies.
A prospective open-labeled pilot study of testosterone topical gel (5 g of AndroGel; Unimed Pharmaceutical Inc, Deerfield, Ill) administered daily to testosterone-deficient (free testosterone <80 pg/mL) men with PD. All 10 patients were followed up for 1 month and 6 patients were followed up for a total of 3 months. Patients were administered a battery of testosterone deficiency questionnaires, cognitive studies, and scales of PD nonmotor and motor function at baseline, 1, and 3 months.
With the daily transdermal testosterone gel, patients had an average increase in levels of free testosterone from baseline (53 pg/mL) to a 1-month follow-up visit (131 pg/mL; P =.06) and to a 3-month follow-up visit (98 pg/mL; P =.04). Testosterone deficiency symptoms improved in these patients (St Louis Testosterone Deficiency Questionnaire) from baseline (7.9 deficiency symptoms) to 1 month (5.6 deficiency symptoms, P =.04) and 3 months (5.8 deficiency symptoms, P =.08). The Unified Parkinson's Disease Rating Scale IV showed improvement at 1 month (P =.008). Additionally, there were trends toward improvement in the following scales: Unified Parkinson's Disease Rating Scale I at the 3-month follow-up (P =.09), Letter Fluency at the 3-month follow-up (P =.08), and the Hamilton Anxiety Scale at the 1-month follow-up (P =.09).
A daily dose of transdermal testosterone gel improved testosterone deficiency symptoms in men with PD. Although there were trends in improvement in other nonmotor and motor symptoms of PD, future placebo control studies will need to be powered to answer these important questions. Whether testosterone deficiency is simply a comorbidity in PD or whether it plays a role in the pathogenesis of disease also remains for future study.
Archives of Neurology 12/2002; 59(11):1750-3. · 7.58 Impact Factor
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Marla Gearing, Jorge L Juncos,
Vincent Procaccio,
Claire-Anne Gutekunst,
Elaine M Marino-Rodriguez,
Kymberly A Gyure,
Shoichiro Ono,
Robert Santoianni,
Nicolas S Krawiecki,
Douglas C Wallace,
Bruce H Wainer
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ABSTRACT: The neuropathology of the primary dystonias is not well understood. We examined brains from identical twins with DYT1-negative, dopa-unresponsive dystonia. The twins exhibited mild developmental delays until age 12 years when they began developing rapidly progressive generalized dystonia. Genetic, metabolic, and imaging studies ruled out known causes of dystonia. Cognition was subnormal but stable until the last few years. Death occurred at ages 21 and 22 years. The brains were macroscopically unremarkable. Microscopic examination showed unusual glial fibrillary acidic protein-immunoreactive astrocytes in multiple regions and iron accumulation in pallidal and nigral neurons. However, the most striking findings were 1) eosinophilic, rod-like cytoplasmic inclusions in neocortical and thalamic neurons that were actin depolymerizing factor/cofilin-immunoreactive but only rarely actin-positive; and 2) abundant eosinophilic spherical structures in the striatum that were strongly actin- and actin depolymerizing factor/cofilin-positive. Electron microscopy suggested that these structures represent degenerating neurons and processes; the accumulating filaments had the same dimensions as actin microfilaments. To our knowledge, aggregation of actin has not been reported previously as the predominant feature in any neurodegenerative disease. Thus, our findings may shed light on a novel neuropathological change associated with dystonia that may represent a new degenerative mechanism involving actin, a ubiquitous constituent of the cytoskeletal system.
Annals of Neurology 11/2002; 52(4):465-76. · 11.09 Impact Factor
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Clifford W Shults,
David Oakes,
Karl Kieburtz,
M Flint Beal,
Richard Haas,
Sandy Plumb, Jorge L Juncos,
John Nutt,
Ira Shoulson,
Julie Carter,
Katie Kompoliti,
Joel S Perlmutter,
Stephen Reich,
Matthew Stern,
Ray L Watts,
Roger Kurlan,
Eric Molho,
Madaline Harrison,
Mark Lew
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ABSTRACT: Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression.
To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD.
Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial.
Academic movement disorders clinics.
Eighty subjects with early PD who did not require treatment for their disability.
Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d.
The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit.
The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was.09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P =.04).
Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.
Archives of Neurology 11/2002; 59(10):1541-50. · 7.58 Impact Factor
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ABSTRACT: Persons with Parkinson disease (PD) exhibit decreased muscular fitness including decreased muscle mass, muscle strength, bioenergetic capabilities and increased fatigability.
This purpose of this investigation was to evaluate the therapeutic effects of resistance training with and without creatine supplementation in patients with mild to moderate PD.
Twenty patients with idiopathic PD were randomized to receive creatine monohydrate supplementation plus resistance training (CRE) or placebo (lactose monohydrate) plus resistance training (PLA), using a double-blind procedure. Creatine and placebo supplementation consisted of 20 g/d for the first 5 days and 5 g/d thereafter. Both groups participated in progressive resistance training (24 sessions, 2 times per week, 1 set of 8-12 repetitions, 9 exercises). Participants performed 1-repetition maximum (1-RM) for chest press, leg extension, and biceps curl. Muscular endurance was evaluated for chest press and leg extension as the number of repetitions to failure using 60% of baseline 1-RM. Functional performance was evaluated as the time to perform 3 consecutive chair rises.
Statistical analyses (ANOVA) revealed significant Group x Time interactions for chest press strength and biceps curl strength, and post hoc testing revealed that the improvement was significantly greater for CRE. Chair rise performance significantly improved only for CRE (12%, P=.03). Both PLA and CRE significantly improved 1-RM for leg extension (PLA: 16%; CRE: 18%). Muscular endurance improved significantly for both groups.
These findings demonstrate that creatine supplementation can enhance the benefits of resistance training in patients with PD.
Neurorehabilitation and neural repair 21(2):107-15. · 4.49 Impact Factor
