Nonmotor symptoms in spinocerebellar ataxias (SCAs)

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

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Drooling, Swallowing Difficulties and Health Related Quality of Life in Parkinson’s Disease Patients

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18158138 ◽

2021 ◽

Vol 18 (15) ◽

pp. 8138

Author(s):

Gladis Yohana Arboleda-Montealegre ◽

Roberto Cano-de-la-Cuerda ◽

César Fernández-de-las-Peñas ◽

Carlos Sanchez-Camarero ◽

Ricardo Ortega-Santiago

Keyword(s):

Quality Of Life ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Duration ◽

Health Related Quality ◽

Nonmotor Symptoms ◽

Related Quality ◽

Health Related ◽

Swallowing Difficulties

Background: Parkinson’s disease (PD) is the most common neurodegenerative disorder associated with motor and nonmotor symptoms. Drooling, one of the nonmotor symptoms, can be present in 70–80% of patients with PD. The aim of this paper is to study the characteristics of PD patients with drooling compared to those without in terms of age, gender, disease duration, stage of the disease, swallowing difficulties, and health-related quality of life; methods: a cross-sectional study was conducted. The sample was divided into two groups: PD with drooling (n = 32) and PD without drooling (n = 30). Age, gender, disease duration and Hoehn & Yahr (H & Y) stage, Sialorrhea Clinical Scale for Parkinson’s Disease (SCS-PD), the 10-item Eating Assessment Tool (EAT-10), and the 39-item Parkinson’s Disease Questionnaire (PDQ-39) were compared between groups; Results: 62 individuals with PD, 40 men and 22 women (mean age 73 ± 8 years), were included. Overall, 32 patients reported drooling, and 30 did not exhibit it. The ANCOVA found significant differences between groups for the EAT-10 score (0.83, 95% CI = 5.62–9.03; p = 0.016) and SCS-PD score (1.48, 95% CI = 0.86–6.81; p < 0.001). Analysis of the PDQ-39 scores revealed no significant differences between groups for the PDQ-39 total score (p > 0.057) and in all subscales. The inclusion of gender, age, disease duration, and H & Y as covariates did not influence the results (all p > 0.05). Conclusions: drooling is related to swallowing difficulties assessed with EAT-10 but not with health-related quality of life assessed with PDQ-39 in PD patients with drooling compared to PD patients without it. Age, gender, duration of the disease, and the H & Y state of PD patients with and without drooling seem to be similar.

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Molecular epidemiology of spinocerebellar ataxias in Cuba: Insights into SCA2 founder effect in Holguin

Neuroscience Letters ◽

10.1016/j.neulet.2009.03.015 ◽

2009 ◽

Vol 454 (2) ◽

pp. 157-160 ◽

Cited By ~ 66

Author(s):

Luis Velázquez Pérez ◽

Gilberto Sánchez Cruz ◽

Nieves Santos Falcón ◽

Luis Enrique Almaguer Mederos ◽

Karel Escalona Batallan ◽

...

Keyword(s):

Molecular Epidemiology ◽

Founder Effect ◽

Spinocerebellar Ataxias

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Protective Effect of Memantine on Bergmann Glia and Purkinje Cells Morphology in Optogenetic Model of Neurodegeneration in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22157822 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7822

Author(s):

Anton N. Shuvaev ◽

Olga S. Belozor ◽

Oleg I. Mozhei ◽

Elena D. Khilazheva ◽

Andrey N. Shuvaev ◽

...

Keyword(s):

Excitatory Amino Acid ◽

Average Length ◽

Glutamate Transporter ◽

Bergmann Glia ◽

Spinocerebellar Ataxias ◽

Excitatory Amino Acid Transporter ◽

Glial Glutamate Transporter ◽

Gfap Immunoreactivity ◽

Cerebellar Ataxias ◽

Receptor Blockers

Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer’s disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter—excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 μm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 μm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 μm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias.

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Fatigue in Patients With Multiple System Atrophy

Neurology ◽

10.1212/wnl.0000000000012968 ◽

2021 ◽

Vol 98 (1) ◽

pp. e73-e82

Author(s):

Lingyu Zhang ◽

Bei Cao ◽

Yanbing Hou ◽

Xiaojing Gu ◽

Qian-Qian Wei ◽

...

Keyword(s):

Multiple System Atrophy ◽

Regression Model ◽

Rating Scale ◽

Early Stage ◽

Progression Rate ◽

Nonmotor Symptoms ◽

Binary Logistic Regression Model ◽

Neurofilament Light Chain ◽

Neurofilament Light

Background and ObjectivesNonmotor symptoms are common in patients with multiple system atrophy (MSA), but there is limited knowledge regarding fatigue in MSA. This study aimed to investigate the frequency and evolution of fatigue and the factors related to fatigue and its progression in patients with MSA at an early stage.MethodsPatients with probable MSA were comprehensively evaluated at both baseline and the 1-year follow-up, including their motor and nonmotor symptoms. Fatigue and anxiety were assessed using the Fatigue Severity Scale (FSS) and Hamilton Anxiety Rating Scale (HARS), respectively. Orthostatic hypotension (OH) was defined as a decrease in the systolic or diastolic blood pressure by at least 30 and 15 mm Hg, respectively. The binary logistic regression model and linear regression model were used to analyze the factors related to fatigue and its progression, respectively.ResultsThis study enrolled 146 patients with MSA. The frequency of fatigue was 60.3%, 55.1%, and 64.9% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. The frequency of fatigue and the FSS score in patients with MSA increased from baseline to the 1-year follow-up (p < 0.05). Young age (odds ratio [OR] 0.939, 95% confidence interval [CI] 0.894–0.987), OH (OR 2.806, 95% CI 1.253–6.286), and high HARS score (OR 1.014, 95% CI 1.035–1.177) were associated with fatigue in MSA. OH was associated with fatigue in MSA-P (OR 3.391, 95% CI 1.066–10.788), while high HARS score was associated with fatigue in MSA-C (OR 1.159, 95% CI 1.043–1.287). In addition, only low FSS scores at baseline were associated with the annual progression rate of FSS scores in MSA, MSA-P, and MSA-C (p < 0.05). Neurofilament light chain, α-synuclein, glial fibrillary acidic protein, brain-derived neurotrophic factor, and triggering receptor expressed on myeloid cell-2 were not significantly associated with fatigue and its progression in MSA.DiscussionFatigue was prevalent in early-stage MSA, and it increased and remained persistent over time. This study demonstrated that OH and anxiety were associated with fatigue in patients with MSA.

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