[Abstract unavailable

Background SMPD1 (acid‐sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. Methods SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid‐sphingomyelinase activity was measured by a mass spectrometry‐based assay in the New York cohort. α‐Synuclein levels were measured in vitro following CRISPR/Cas9‐mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)‐M17 cells. Lysosomal localization of acid‐sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid‐sphingomyelinase structure was performed. Results SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6‐8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid‐sphingomyelinase activity was associated with a 3.5‐ to 5.8‐year earlier onset of PD in the lowest quartile versus the highest quartile of acid‐sphingomyelinase activity (P = 0.01‐0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α‐synuclein levels in HeLa and BE(2)‐M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid‐sphingomyelinase to the lysosome. Conclusions Our results support an association between SMPD1 variants, acid‐sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid‐sphingomyelinase activity may lead to α‐synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society

PURPOSE OF REVIEW: This article reviews the symptoms, laboratory and neuroimaging diagnostic tests, genetics, and management of cerebellar ataxia. RECENT FINDINGS: Recent advances in genetics have led to the identification of novel genetic causes for ataxia and a more comprehensive understanding of the biological pathways critical for normal cerebellar function. When these molecular pathways become dysfunctional, patients develop cerebellar ataxia. In addition, several ongoing clinical trials for Friedreich ataxia and spinocerebellar ataxia will likely result in novel symptomatic and disease-modifying therapies for ataxia. Antisense oligonucleotides for spinocerebellar ataxias associated with CAG repeat expansions might be a promising therapeutic strategy. SUMMARY: Cerebellar ataxias include heterogeneous disorders affecting cerebellar function, leading to ataxic symptoms. Step-by-step diagnostic workups with genetic investigations are likely to reveal the underlying causes of ataxia. Some disease-specific therapies for ataxia exist, such as vitamin E for ataxia with vitamin E deficiency and thiamine for Wernicke encephalopathy, highlighting the importance of recognizing these forms of ataxia. Finally, genetic diagnosis for patients with ataxia will accelerate clinical trials for disease-modifying therapy and will have prognostic value and implications for family planning for these patients.

For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).

Neuronal oscillations at beta frequencies (20-50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson's disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy.

Background: Tremor is the most common movement disorder; however, the pathophysiology of tremor remains elusive. While several neuropathological alterations in tremor disorders have been observed in post-mortem studies of human brains, a full understanding of the relationship between brain circuitry alterations and tremor requires testing in animal models. Additionally, tremor animal models are critical for our understanding of tremor pathophysiology, and/or to serve as a platform for therapy development. Methods: A PubMed search was conducted in May 2018 to identify published papers for review. Results: The methodology used in most studies on animal models of tremor lacks standardized measurement of tremor frequency and amplitude; instead, these studies are based on the visual inspection of phenotypes, which may fail to delineate tremor from other movement disorders such as ataxia. Of the animal models with extensive tremor characterization, harmaline-induced rodent tremor models provide an important framework showing that rhythmic and synchronous neuronal activities within the olivocerebellar circuit can drive action tremor. In addition, dopamine-depleted monkey and mouse models may develop rest tremor, highlighting the role of dopamine in rest tremor generation. Finally, other animal models of tremor have involvement of the cerebellar circuitry, leading to altered Purkinje cell physiology. Discussion: Both the cerebellum and the basal ganglia are likely to play a role in tremor generation. While the cerebellar circuitry can generate rhythmic movements, the nigrostriatal system is likely to modulate the tremor circuit. Tremor disorders are heterogeneous in nature. Therefore, each animal model may represent a subset of tremor disorders, which collectively can advance our understanding of tremor.

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Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine (Q) encoding CAG repeats in the gene Ataxin-1 (ATXN1). Although motor and balance deficits are the core symptoms of SCA1, cognitive decline is also commonly observed in patients. While mutant ATXN1 is expressed throughout the brain, pathological findings reveal severe atrophy of cerebellar cortex in SCA1 patients. The cerebellum has recently been implicated in diverse cognitive functions, yet to what extent cerebellar neurodegeneration contributes to cognitive alterations in SCA1 remains poorly understood. Much of our understanding of the mechanisms underlying pathogenesis of motor symptoms in SCA1 comes from mouse models. Reasoning that mouse models could similarly offer important insights into the mechanisms of cognitive alterations in SCA1 we tested cognition in several mouse lines using Barnes maze and fear conditioning. We confirmed cognitive deficits in Atxn1154Q/2Q knock-in mice with brain wide expression of mutant ATXN1 and in ATXN1 null mice. We found that shorter polyQ length and haploinsufficiency of ATXN1 do not cause significant cognitive deficits. Finally, ATXN1[82Q] transgenic mice—with cerebellum limited expression of mutant ATXN1—demonstrated milder impairment in most aspects of cognition compared to Atxn1154Q/2Q mice, supporting the concept that cognitive deficits in SCA1 arise from a combination of cerebellar and extra-cerebellar dysfunctions.