Saccade velocity is controlled by polyglutamine size in spinocerebellar ataxia 2

Velázquez‐Pérez, Luis; Seifried, Carola; Santos-Falcón, N; Abele, Michael; Ziemann, Ulf; Almaguer, Luis Enrique; Martínez-Góngora, E; Sánchez-Cruz, Gilberto; Canales, Nalia; Pérez-González, Ruth; Velázquez-Manresa, Mercedes; Viebahn, Bettina; Stuckrad-Barre, Sebastian von; Fetter, M.; Klockgether, Thomas; Auburger, Georg

doi:10.1002/ana.20220

Cited by 91 publications

(70 citation statements)

References 18 publications

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“…In this context, the crucial role of the pontine brainstem in the neurodegenerative process in this disease is compatible with the prominent horizontal saccade slowing that SCA2 patients exhibit even before the ataxia onset,32, 33 since the horizontal saccade velocity has their main generators at pontine levels, specifically in the paramedian pontine reticular formation 34. Indeed, this notion is supported by our data showing strong correlations between pontine brainstem volumes and saccade slowing in manifest SCA2 as well as preclinical subjects.…”

Section: Discussionsupporting

confidence: 79%

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Reetz

Rodríguez‐Labrada²,

Dogan

et al. 2018

Ann Clin Transl Neurol

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ObjectiveSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease mainly affecting the cerebellum and brainstem. In this Cuban‐German research collaboration, we aimed to characterize atrophy patterns and associations with clinical measures in preclinical and manifest SCA2.MethodsIn this study, 16 nonmanifest SCA2 mutation carriers, 26 manifest patients with SCA2, and 18 healthy control subjects underwent magnetic resonance imaging, as well as genetic and clinical characterization including assessment of ataxia (Scale for the Assessment and Rating of Ataxia) and saccade velocity in Cuba were enrolled. Semiautomated quantitative volumetry of the cerebellum and brainstem, subdivided into the medulla oblongata, the pontine brainstem, and mesencephalon was performed. Additionally, the anteroposterior diameter of the pontine brainstem was measured.ResultsAnalysis of volumetric data revealed degeneration of the cerebellum and brainstem, in particular of pontine volumes and the anteroposterior diameter of the pons, in both manifest SCA2 patients and individuals at risk for SCA2 compared to controls. Comparing patients with nonataxic preclinical SCA2 mutation carriers, we found more pronounced reductions of the pontine brainstem and cerebellum in manifest SCA2. Volumetric data further showed associations with CAG repeat length and predicted age of onset in preclinical SCA2 individuals, and by trend with ataxia signs in patients. Although saccade velocity was associated with reduction in the pontine brainstem in preclinical and manifest SCA2, reduced ability to suppress interfering stimuli measured by the Stroop task was related to cerebellar volume loss in patients.InterpretationPreclinical SCA2 mutation carriers exhibit brain abnormalities, which could be targeted as surrogate parameters for disease progression and in future preventive trials.

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Section: Discussionsupporting

confidence: 79%

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Reetz

Rodríguez‐Labrada²,

Dogan

et al. 2018

Ann Clin Transl Neurol

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“…Software written inhouse was used for manually setting markers of saccade onsets and offsets. SPV (in 1/s) was determined by automatic identification of the maximum value between a pair of markers of saccade onset and offset using a thirdorder polynomial fit of the raw signal (Velazquez-Perez et al, 2004). Conditional SPV averages were calculated for left-and rightward saccades and a grand mean was finally calculated for each individual, session, and time point.…”

Section: Saccadic Peak Velocity Measurementsmentioning

confidence: 99%

Deleterious Effects of a Low Amount of Ethanol on LTP-Like Plasticity in Human Cortex

Lücke

Heidegger

Röhner

et al. 2014

Neuropsychopharmacol

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Ingesting ethanol (EtOH) at low doses during social drinking is a common human behavior for its facilitating effects on social interactions. However, low-dose EtOH may have also detrimental effects that so far are underexplored. Here we sought to test the effects of lowdose EtOH on long-term potentiation (LTP)-like plasticity in human motor cortex. Previous cellular experiments showed that low-dose EtOH potentiates extrasynaptic GABAAR and reduces NMDAR-mediated currents, processes that would limit the expression of LTP. Paired associative transcranial magnetic stimulation (PAS LTP ) was employed in nine healthy subjects for induction of LTP-like plasticity, indexed by a long-term increase in motor-evoked potential input-output curves. Synaptic a1-GABAAR function was measured by saccadic peak velocity (SPV). Very low doses of EtOH (resulting in blood concentrations of o5 mM) suppressed LTP-like plasticity but did not affect SPV when compared with a placebo condition. In contrast, 1 mg of alprazolam, a classical benzodiazepine, or 10 mg of zolpidem, a non-benzodiazepine hypnotic, decreased SPV but did not significantly affect LTP-like plasticity when compared with placebo. This double dissociation of low-dose EtOH vs alprazolam/zolpidem effects is best explained by the putatively high affinity of EtOH but not alprazolam/zolpidem to extrasynaptic GABAARs and to NMDARs. Findings suggest that enhancement of extrasynaptic GABAARmediated tonic inhibition and/or reduction of NMDAR-mediated neurotransmission by EtOH blocks LTP-like plasticity in human cortex at very low doses that are easily reached during social drinking. Therefore, low-dose EtOH may jeopardize LTP-dependent processes, such as learning and memory formation.

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“…A preliminary follow-up evaluation of saccadic slowing after one year in 30 SCA2 patients revealed no significant changes of MSV (Seifried et al, 2004). Nevertheless, other follow-up study during a larger period time it is being conducted in a large Cuban SCA2 cohort.…”

Section: Spinocerebellar Ataxia Type 2 (Sca2)mentioning

confidence: 92%

Eye Movement Abnormalities in Spinocerebellar Ataxias

Rodríguez‐Labrada¹,

Velázquez‐Pérez²

2012

Spinocerebellar Ataxia

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Saccade velocity is controlled by polyglutamine size in spinocerebellar ataxia 2

Cited by 91 publications

References 18 publications

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Deleterious Effects of a Low Amount of Ethanol on LTP-Like Plasticity in Human Cortex

Eye Movement Abnormalities in Spinocerebellar Ataxias

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