Impaired Efficiency and Resilience of Structural Network in Spinocerebellar Ataxia Type 3

Background: Recent studies have shown that the patients with spinocerebellar ataxia type 3 (SCA3) may not only have disease involvement in the cerebellum and brainstem but also in the cerebral regions. However, the relations between the widespread degenerated brain regions remains incompletely explored.Methods: In the present study, we investigate the topological properties of the brain networks of SCA3 patients (n = 40) constructed based on the correlation of three-dimensional fractal dimension values. Random and targeted attacks were applied to measure the network resilience of normal and SCA3 groups.Results: The SCA3 networks had significantly smaller clustering coefficients (P < 0.05) and global efficiency (P < 0.05) but larger characteristic path length (P < 0.05) than the normal controls networks, implying loss of small-world features. Furthermore, the SCA3 patients were associated with reduced nodal betweenness (P < 0.001) in the left supplementary motor area, bilateral paracentral lobules, and right thalamus, indicating that the motor control circuit might be compromised.Conclusions: The SCA3 networks were more vulnerable to targeted attacks than the normal controls networks because of the effects of pathological topological organization. The SCA3 revealed a more sparsity and disrupted structural network with decreased values in the largest component size, mean degree, mean density, clustering coefficient, and global efficiency and increased value in characteristic path length. The cortico-cerebral circuits in SCA3 were disrupted and segregated into occipital-parietal (visual-spatial cognition) and frontal-pre-frontal (motor control) clusters. The cerebellum of SCA3 were segregated from cerebellum-temporal-frontal circuits and clustered into a frontal-temporal cluster (cognitive control). Therefore, the disrupted structural network presented in this study might reflect the clinical characteristics of SCA3

Medical and Paramedical Care of Patients With Cerebellar Ataxia During the COVID-19 Outbreak: Seven Practical Recommendations of the COVID 19 Cerebellum Task Force

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the cause of the current pandemic coronavirus disease 2019 (COVID-19), primarily targets the respiratory system. Some patients also experience neurological signs and symptoms ranging from anosmia, ageusia, headache, nausea, and vomiting to confusion, encephalitis, and stroke. Approximately 36% of those with severe COVID-19 experience neurological complications. The virus may enter the central nervous system through the olfactory nerve in the nasal cavity and damage neurons in the brainstem nuclei involved in the regulation of respiration. Patients with cerebellar ataxia (CA) are particularly vulnerable to severe outcome if they contract COVID-19 because of the complexity of their disease, the presence of comorbidities, and their use of immunosuppressive therapies. Most CA patients burdened by progressive neurologic deficits have substantially impaired mobility and other essential functions, for which they rely heavily on ambulatory services, including rehabilitation and psychosocial care. Cessation of these interventions because of isolation restrictions places the CA patient population at risk of further deterioration. This international panel of ataxia experts provides recommendations for neurologists caring for patients with CA, emphasizing a pro-active approach designed to maintain their autonomy and well-being: continue long-term medications, promote rehabilitation efforts, utilize the technology of virtual visits for regular contact with healthcare providers, and pay attention to emotional and psychosocial health. Neurologists should play an active role in decision-making in those CA cases requiring escalation to intensive care and resuscitation. Multi-disciplinary collaboration between care teams is always important, and never more so than in the context of the current pandemic

Gabapentin for complex regional pain syndrome in Machado-Joseph disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Chronic pain is a common problem for patients with Machado-Joseph disease. Most of the chronic pain in Machado-Joseph disease has been reported to be of musculoskeletal origin, but now there seems to be different chronic pain in patients with Machado-Joseph disease.</p> <p>Case presentation</p> <p>A 29-year-old man (Han Chinese, Hoklo) with Machado-Joseph disease experienced severe chronic pain in both feet, cutaneous thermal change, thermal hypersensitivity, focal edema, and sweating and had a history of bone fracture. These symptoms were compatible with a diagnosis of complex regional pain syndrome. After common analgesics failed to relieve his pain, gabapentin was added and titrated to 2000 mg/day (500 mg every six hours) in less than two weeks. This relieved 40% of his pain and led to significant clinical improvement.</p> <p>Conclusions</p> <p>The pathophysiology of complex regional pain syndrome includes peripheral and central sensitizations, the latter of which might be associated with the neurodegeneration in Machado-Joseph disease. In this report, we suggest that gabapentin could inhibit central sensitization as an adjunct for complex regional pain syndrome in patients with Machado-Joseph disease.</p

The Mutational Spectrum in a Cohort of Charcot-Marie-Tooth Disease Type 2 among the Han Chinese in Taiwan

BACKGROUND: Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese. METHODOLOGY AND PRINCIPAL FINDINGS: Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159_Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%). CONCLUSIONS AND SIGNIFICANCE: This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Sleep disruption in spinocerebellar ataxia type 3: A genetic and polysomnographic study

Background: Sleep structure disruption and rapid eye movement (REM) sleep behavior disorders (RBD) have been previously reported in patients with neurodegenerative diseases. However, similar studies have rarely been quantitatively conducted in type 3 spinocerebellar ataxia (SCA3). Methods: Fifteen patients with SCA3 and 16 healthy controls were recruited and evaluated by clinical history, International Cooperative Ataxia Rating Scale (ICARS), Epworth sleepiness scale (ESS), and polysomnography. Results: Patients with SCA3 had reductions in sleep efficiency and percentage of REM sleep, which were negatively correlated with the severity of ataxia as evaluated by ICARS. REM sleep reduction occurred regardless of the presence of RBD, and severe reduction of REM sleep may significantly disturb the assessment of RBD. Conclusion: Poor sleep efficiency and REM sleep aberrations are the characteristics of sleep structure disruption in SCA3 as the disease progresses. The incidence of respiratory disturbance during sleep or excessive daytime sleepiness was not significantly higher in SCA3 patients than controls

Allele-specific All-or-None PCR Product Diagnostic Strategy for Charcot-Marie-Tooth 1A and Hereditary Neuropathy with Liability to Pressure Palsies

We designed allele-specific primers to amplify genomic DNA of patients with Charcot-Marie-Tooth 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). Methods: Genomic DNA analysis was performed on 40 unrelated CMT1A duplication patients, 25 unrelated HNPP deletion patients, and 50 unaffected control individuals. The CMT1A and HNPP patients had previously been identified with microsatellite mapping. Results: Amplification products came to 3.6 kb in length from the normal proximal CMT1A repeated segment on chromosome 17p11.2 (proximal CMT1A-REP), 3.57 kb from the normal distal CMT1A repeated segment on chromosome 17p11.2 (distal CMT1A-REP), 3.6 kb from HNPP patients, and 3.58 kb from CMT1A patients. We could identify the mutations by means of agarose gel electrophoresis after polymerase chain reaction (PCR) amplification without restriction enzyme digestion from 33 of the 40 CMT1A and 19 of the 25 HNPP samples. Conclusion: Stringently specific primers were used to overcome the problem of nonspecific amplification and provide a rapid, all-or-none PCR product and efficient screening test for CMT1A and HNPP

Acute simultaneous multiple lacunar infarcts as the initial presentation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult-onset, dominantly inherited small-vessel disease of the brain caused by NOTCH3 mutations and characterized by recurrent subcortical infarctions, dementia, migraine with aura, and mood disturbance. We report a patient with unusual presentation of CADASIL with acute simultaneous multiple subcortical lacunar infarcts as the first manifestation. A 69-year-old man developed confusion, drowsiness, right hemiparesis, and slurred speech following orthopedic surgeries. Brain magnetic resonance imaging revealed diffuse leukoencephalopathy and multiple acute subcortical lacunar infarcts. Brain magnetic resonance angiography, echocardiography and 24-hour electrocardiography were unremarkable. The symptoms improved quickly after treatment with fluid hydration and antiplatelet agent, and his consciousness and mentality totally recovered within 3 days. The NOTCH3 genetic testing showed a heterozygous missense mutation, c.1630C>T (p. Arg544Cys). The experience in this case suggests that brain imaging is important in managing postoperative confusion, and any patient with diffuse leukoencephalopathy of unknown etiology may need to be tested for NOTCH3 mutations. Surgery is an important factor of encephalopathy and acute infarction in individuals with NOTCH3 mutations. Comprehensive presurgical evaluations and proactive perioperative precautions to avoid dehydration and anemia are necessary for patients with CADASIL who are about to receive anesthesia and surgery

Intra- and Inter-Modular Connectivity Alterations in the Brain Structural Network of Spinocerebellar Ataxia Type 3

In addition to cerebellar degeneration symptoms, patients with spinocerebellar ataxia type 3 (SCA3) exhibit extensive involvements with damage in the prefrontal cortex. A network model has been proposed for investigating the structural organization and functional mechanisms of clinical brain disorders. For neural degenerative diseases, a cortical feature-based structural connectivity network can locate cortical atrophied regions and indicate how their connectivity and functions may change. The brain network of SCA3 has been minimally explored. In this study, we investigated this network by enrolling 48 patients with SCA3 and 48 healthy subjects. A novel three-dimensional fractal dimension-based network was proposed to detect differences in network parameters between the groups. Copula correlations and modular analysis were then employed to categorize and construct the structural networks. Patients with SCA3 exhibited significant lateralized atrophy in the left supratentorial regions and significantly lower modularity values. Their cerebellar regions were dissociated from higher-level brain networks, and demonstrated decreased intra-modular connectivity in all lobes, but increased inter-modular connectivity in the frontal and parietal lobes. Our results suggest that the brain networks of patients with SCA3 may be reorganized in these regions, with the introduction of certain compensatory mechanisms in the cerebral cortex to minimize their cognitive impairment syndrome

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

This cross-sectional study investigated the correlation between the CAG repeat length and the degeneration of cerebellum in spinocerebellar ataxia type 3 (SCA3) patients based on neuroimaging approaches. Forty SCA3 patients were recruited and classified into two subgroups according to their CAG repeat lengths (≥74 and <74). We measured each patient's Scale for the Assessment and Rating of Ataxia (SARA) score, N-acetylaspartate (NAA)/creatine (Cr) ratios based on magnetic resonance spectroscopy (MRS), and 3-dimensional fractal dimension (3D-FD) values derived from magnetic resonance imaging (MRI) results. Furthermore, the 3D-FD values were used to construct structural covariance networks based on graph theoretical analysis. The results revealed that SCA3 patients with a longer CAG repeat length demonstrated earlier disease onset. However, the CAG repeat length did not significantly correlate with their SARA scores, cerebellar NAA/Cr ratios or cerebellar 3D-FD values. Network dissociation between cerebellar regions and parietal-occipital regions was found in SCA3 patients with CAG ≥ 74, but not in those with CAG < 74. In conclusion, the CAG repeat length is uncorrelated with the change of SARA score, cerebellar function and cerebellar structure in SCA3. Nevertheless, a longer CAG repeat length may indicate early structural covariance network dissociation