Now showing 1 - 7 of 7
  • Publication
    A Headset Method for Measuring the Visual Temporal Discrimination Threshold in Cervical Dystonia
    (Columbia University Library/Information Service, Center for Digital Research and Scholarship, 2014-07) ; ; ; ; ;
    The visual temporal discrimination threshold (TDT) is the shortest time interval at which one can determine two stimuli to be asynchronous and meets criteria for a valid endophenotype in adult-onset idiopathic focal dystonia, a poorly penetrant disorder. Temporal discrimination is assessed in the hospital laboratory; in unaffected relatives of multiplex adult-onset dystonia patients distance from the hospital is a barrier to data acquisition. We devised a portable headset method for visual temporal discrimination determination and our aim was to validate this portable tool against the traditional laboratory-based method in a group of patients and in a large cohort of healthy controls.
  • Publication
    Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study
    Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit–risk profile for patients with relapsing–remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. Objective: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). Methods: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. Results: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1–5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. Conclusion: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.
      260Scopus© Citations 105
  • Publication
    Young Women do it Better: Sexual Dimorphism in Temporal Discrimination
    The temporal discrimination threshold (TDT) is the shortest time interval at which two sensory stimuli presented sequentially are detected as asynchronous by the observer. TDTs are known to increase with age. Having previously observed shorter thresholds in young women than in men, in this work we sought to systematically examine the effect of sex and age on temporal discrimination. The aims of this study were to examine, in a large group of men and women aged 20–65 years, the distribution of TDTs with an analysis of the individual participant’s responses, assessing the 'point of subjective equality' and the 'just noticeable difference' (JND). These respectively assess sensitivity and accuracy of an individual’s response. In 175 participants (88 women) aged 20–65 years, temporal discrimination was faster in women than in men under the age of 40 years by a mean of approximately 13 ms. However, age-related decline in temporal discrimination was three times faster in women so that, in the age group of 40–65 years, the female superiority was reversed. The point of subjective equality showed a similar advantage in younger women and more marked age-related decline in women than men, as the TDT. JND values declined equally in both sexes, showing no sexual dimorphism. This observed sexual dimorphism in temporal discrimination is important for both (a) future clinical research assessing disordered mid-brain covert attention in basal-ganglia disorders, and (b) understanding the biology of this sexual dimorphism which may be genetic or hormonal.
      304Scopus© Citations 10
  • Publication
    Correlates of abnormal sensory discrimination in laryngeal dystonia
    Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder.
      95Scopus© Citations 38
  • Publication
    Age-related Sexual Dimorphism in Temporal Discrimination and in Adult-onset Dystonia Suggests GABAergic Mechanisms
    Background: Adult-onset isolated focal dystonia (AOIFD) presenting in early adult life is more frequent in men, whereas in middle age it is female predominant. Temporal discrimination, an endophenotype of adult-onset idiopathic isolated focal dystonia, shows evidence of sexual dimorphism in healthy participants. Objectives: We assessed the distinctive features of age-related sexual dimorphism of (i) sex ratios in dystonia phenotypes and (ii) sexual dimorphism in temporal discrimination in unaffected relatives of cervical dystonia patients. Methods: We performed (i) a meta-regression analysis of the proportion of men in published cohorts of phenotypes of adult-onset dystonia in relation to their mean age of onset and (ii) an analysis of temporal discrimination thresholds in 220 unaffected first-degree relatives (125 women) of cervical dystonia patients. Results: In 53 studies of dystonia phenotypes, the proportion of men showed a highly significant negative association with mean age of onset (p < 0.0001, pseudo-R2 = 59.6%), with increasing female predominance from 40 years of age. Age of onset and phenotype together explained 92.8% of the variance in proportion of men. Temporal discrimination in relatives under the age of 35 years is faster in women than men but the age-related rate of deterioration in women is twice that of men; after 45 years of age, men have faster temporal discrimination than women. Conclusion: Temporal discrimination in unaffected relatives of cervical dystonia patients and sex ratios in adult-onset dystonia phenotypes show similar patterns of age-related sexual dimorphism. Such age-related sexual dimorphism in temporal discrimination and adult-onset focal dystonia may reflect common underlying mechanisms. Cerebral GABA levels have been reported to show similar age-related sexual dimorphism in healthy participants and may be the mechanism underlying the observed age-related sexual dimorphism in temporal discrimination and the sex ratios in AOIFD.
      216Scopus© Citations 14
  • Publication
    Dementia in SPG4 hereditary spastic paraplegia : Clinical, genetic, and neuropathologic evidence
    Background: Cognitive impairment and dementia has been reported in autosomal dominant hereditary spastic paraparesis (HSP) linked to the SPG4 locus. There has only been one postmortem examination described; not all accept that progressive cognitive decline is a feature of this disorder.Objective: A family with SPG4-HSP known to have a deletion of exon 17 in the spastin gene (SPG4delEx17) was cognitively assessed over a 7-year period. The index family member died and a postmortem examination was performed.Methods: Thirteen family members older than 40 years were clinically and cognitively assessed using the Cambridge Cognitive Assessment over a 7-year period. The presence of SPG4delEx17 was assessed; a neuropathologic examination of the brain of the index family member was performed.Results: Cognitive decline occurred in 6 of the 13 family members and in all 4 older than 60 years. Two genetic deletions were identified: SPG4delEx17 in 12 of the 13 family members and a deletion of SPG6 (SPG6del) in 5. Eight individuals had the SPG4delEx17 deletion only; 4 had evidence of progressive cognitive impairment. Four family members had both SPG4delEx17 and SPG6del; 2 of these had cognitive impairment. One family member with the SPG6del alone had neither HSP nor cognitive impairment. The index case with both deletions died with dementia; the brain showed widespread ubiquitin positivity within the neocortex and white matter.Conclusion: Cognitive decline and dementia is a feature of SPG4-HSP due to a deletion of exon 17 of the spastin gene. Neurology (R) 2009; 73: 378-384
      638Scopus© Citations 43
  • Publication
    Cervical dystonia: A disorder of the midbrain network for covert attentional orienting
    While the pathogenesis of cervical dystonia remains unknown, recent animal and clinical experimental studies have indicated its probable mechanisms. Abnormal temporal discrimination is a mediational endophenotype of cervical dystonia and informs new concepts of disease pathogenesis. Our hypothesis is that both abnormal temporal discrimination and cervical dystonia are due to a disorder of the midbrain network for covert attentional orienting caused by reduced gamma-aminobutyric acid (GABA) inhibition, resulting, in turn, from as yet undetermined, genetic mutations. Such disinhibition is (a) subclinically manifested by abnormal temporal discrimination due to prolonged duration firing of the visual sensory neurons in the superficial laminae of the superior colliculus and (b) clinically manifested by cervical dystonia due to disinhibited burst activity of the cephalomotor neurons of the intermediate and deep laminae of the superior colliculus. Abnormal temporal discrimination in unaffected first-degree relatives of patients with cervical dystonia represents a subclinical manifestation of defective GABA activity both within the superior colliculus and from the substantia nigra pars reticulata. A number of experiments are required to prove or disprove this hypothesis.
      387Scopus© Citations 35