Deborah A. Hall

Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results

We present a clinimetric assessment of the Movement Disorder Society (MDS)‐sponsored revision of the Unified Parkinsons Disease Rating Scale (MDS‐UPDRS). The MDS‐UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS‐UPDRS has four parts, namely, I: Non‐motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item‐specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS‐UPDRS (65 items) to 877 English speaking (78% non‐Latino Caucasian) patients with Parkinsons disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS‐UPDRS showed high internal consistency (Cronbachs alpha = 0.79–0.93 across parts) and correlated with the original UPDRS (ρ = 0.96). MDS‐UPDRS across‐part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS‐UPDRS for rating PD.

''Sparse'' Temporal Sampling in Auditory fMRI

The use of functional magnetic resonance imaging (fMRI) to explore central auditory function may be compromised by the intense bursts of stray acoustic noise produced by the scanner whenever the magnetic resonance signal is read out. We present results evaluating the use of one method to reduce the effect of the scanner noise: “sparse” temporal sampling. Using this technique, single volumes of brain images are acquired at the end of stimulus and baseline conditions. To optimize detection of the activation, images are taken near to the maxima and minima of the hemodynamic response during the experimental cycle. Thus, the effective auditory stimulus for the activation is not masked by the scanner noise.

Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines.

Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with core features of action tremor and cerebellar gait ataxia. Frequent associated findings include parkinsonism, executive function deficits and dementia, neuropathy, and dysautonomia. Magnetic Resonance Imaging studies in FXTAS demonstrate increased T2 signal intensity in the middle cerebellar peduncles (MCP sign) in the majority of patients. Similar signal alterations are seen in deep and subependymal cerebral white matter, as is general cortical and subcortical atrophy. The major neuropathological feature of FXTAS is the presence of intranuclear, neuronal, and astrocytic, inclusions in broad distribution throughout the brain and brainstem. FXTAS is caused by moderate expansions (55–200 repeats; premutation range) of a CGG trinucleotide in the fragile X mental retardation 1 (FMR1) gene, the same gene which causes fragile X syndrome when in the full mutation range (200 or greater CGG repeats). The pathogenic mechanism is related to overexpression and toxicity of the FMR1 mRNA per se. Although only recently discovered, and hence currently under‐diagnosed, FXTAS is likely to be one of the most common single‐gene disorders leading to neurodegeneration in males. In this report, we review information available on the clinical, radiological, and pathological features, and prevalence and management of FXTAS. We also provide guidelines for the practitioner to assist with identifying appropriate patients for DNA testing for FXTAS, as well as recommendations for genetic counseling once a diagnosis of FXTAS is made.

Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation

Until recently, individuals with premutation alleles (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X‐associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene–brain–behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)‐positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive‐compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive‐compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X‐activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain‐of‐function model in a neuropsychiatric phenotype.

A conservative approach to the management of uterine leiomyoma: Pituitary desensitization by a luteinizing hormone- releasing hormone analogue

Uterine leiomyoma is the most common solid tumor of the female genital tract and may cause heavy menometrorrhagia and infertility. Uterine myomectomy is not always feasible and total hysterectomy may be necessaryin young women who have not yet completed their families. Herein we report the regression of a presumed uterine leiomyoma induced by long-term treatment with a long-acting luteinizing hormone-releasing hormone (LHRH) agonist, which was administered to suppress ovarian estrogen secretion. sent from the patient. Metrorrhagia subsided within 48 hours from the initiation of treatment, at the time of the rapidly rising estradiol levels that characterize the agonist phase of LHRH, administration (Fig. 2). Another episode of uterine bleeding occurred 13 days after the beginning of therapy, coincident with suppression of serum estradiol to prepubertal levels. During the first 2 months of therapy the patient reported only minor episodes of vagina1 bleeding, usually lasting no longer than 1 day. No further bleeding occurred after the eighth week of therapy, and the hemoglobin level rose steadily from a pretherapy value of 7.4 gm/dl to 12.8 gmldl within 60 days. Plasma estradiol levels became undetectable (~20 pg/mI) during the third week (Fig. 2) and the patient noted the onset of hot flashes shortly thereafter. At 8 weeks of treatment the leiomyoma had decreased to 5 by 5 by 4 cm according to ultrasound examination and a further reduction to 4 by 4 by 4 cm had occurred by the twelfth week (Fig. 1, B). At 15 weeks the size of the mass was noted to be unchanged at 4by4by4cm.

Examining a supramodal network for conflict processing: A systematic review and novel functional magnetic resonance imaging data for related visual and auditory stroop tasks

Cognitive control over conflicting information has been studied extensively using tasks such as the color-word Stroop, flanker, and spatial conflict task. Neuroimaging studies typically identify a fronto-parietal network engaged in conflict processing, but numerous additional regions are also reported. Ascribing putative functional roles to these regions is problematic because some may have less to do with conflict processing per se, but could be engaged in specific processes related to the chosen stimulus modality, stimulus feature, or type of conflict task. In addition, some studies contrast activation on incongruent and congruent trials, even though a neutral baseline is needed to separate the effect of inhibition from that of facilitation. In the first part of this article, we report a systematic review of 34 neuroimaging publications, which reveals that conflict-related activity is reliably reported in the anterior cingulate cortex and bilaterally in the lateral prefrontal cortex, the anterior insula, and the parietal lobe. In the second part, we further explore these candidate conflict regions through a novel functional magnetic resonance imaging experiment, in which the same group of subjects perform related visual and auditory Stroop tasks. By carefully controlling for the same task (Stroop), the same to-be-ignored stimulus dimension (word meaning), and by separating out inhibitory processes from those of facilitation, we attempt to minimize the potential differences between the two tasks. The results provide converging evidence that the regions identified by the systematic review are reliably engaged in conflict processing. Despite carefully matching the Stroop tasks, some regions of differential activity remained, particularly in the parietal cortex. We discuss some of the task-specific processes which might account for this finding.

Aging in Individuals With the FMR1 Mutation

Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.

Cognitive Profile of Fragile X Premutation Carriers With and Without Fragile X-Associated Tremor/Ataxia Syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder.

The mechanisms of tinnitus: perspectives from human functional neuroimaging

In this review, we highlight the contribution of advances in human neuroimaging to the current understanding of central mechanisms underpinning tinnitus and explain how interpretations of neuroimaging data have been guided by animal models. The primary motivation for studying the neural substrates of tinnitus in humans has been to demonstrate objectively its representation in the central auditory system and to develop a better understanding of its diverse pathophysiology and of the functional interplay between sensory, cognitive and affective systems. The ultimate goal of neuroimaging is to identify subtypes of tinnitus in order to better inform treatment strategies. The three neural mechanisms considered in this review may provide a basis for TI classification. While human neuroimaging evidence strongly implicates the central auditory system and emotional centres in TI, evidence for the precise contribution from the three mechanisms is unclear because the data are somewhat inconsistent. We consider a number of methodological issues limiting the field of human neuroimaging and recommend approaches to overcome potential inconsistency in results arising from poorly matched participants, lack of appropriate controls and low statistical power.

FMR1 CGG repeat length predicts motor dysfunction in premutation carriers

Background: Fragile X–associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. Methods: Persons aged ≥50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. Results: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. Conclusions: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment—tremor, ataxia, and parkinsonism—the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X–associated tremor/ataxia syndrome in women. GLOSSARY: AR = activation ratio; FXTAS = fragile X-associated tremor/ataxia syndrome; MCP = middle cerebellar peduncle; mRNA = messenger RNA.