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1.
Neurobiol Dis ; 130: 104516, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31229688

RESUMO

Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

2.
Neurology ; 93(2): e125-e134, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31171647

RESUMO

OBJECTIVE: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease. METHODS: We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials. RESULTS: Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. CONCLUSION: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.

3.
J Alzheimers Dis ; 70(3): 937-952, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31227651

RESUMO

Soluble amyloid-ß (Aß) oligomers (AßOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer's disease (AD). Since AßOs are a key therapeutic target, we attempted to identify natural agents that reduce AßO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AßOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AßO-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast, tyrosol administration did not affect Aß accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AßO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo. We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31105016

RESUMO

INTRODUCTION: Spinocerebellar ataxia (SCA) type 34, a form of autosomal dominantly inherited ataxia, has recently been associated with mutations in the ELOVL4 gene. However, a genetic study of the prevalence of SCA34 in an ataxia cohort has never been reported. METHODS: We performed a mutation screening of ELOVL4 in a cohort of 153 undiagnosed index ataxia patients, selected after excluding for common SCA types, in a series of 506 Japanese index ataxia patients. RESULTS: Heterozygous mutation c.698C > T (p.T233M) was detected in an index patient with multisystem neurodegeneration including ataxia and erythrokeratodermia skin lesions, an archetypal skin phenotype in SCA34. The patient's father also presented with ataxia but not skin lesions. Although this mutation has been recently reported in a single English-Canadian patient, the present study confirms its cosegregation with the ataxia phenotype in the Japanese kindred. Brain magnetic resonance imaging (MRI) of the patient and his father revealed marked pontine and cerebellar atrophy as well as the hot cross bun sign, that is common in cerebellar type of multiple system atrophy and was also described in SCA34 patients harboring two other mutations: p.L168F and p.W246G. CONCLUSION: This represents the first genetic study of the prevalence of SCA34 in an ataxia cohort and demonstrates its low prevalence (0.2%) in ataxia patients. The broad SCA34 clinical spectrum suggests variable multisystem neurodegeneration. Clinicians should be aware of this rare disease entity, particularly if erythrokeratodermia or the hot cross bun sign in MRI are present in undiagnosed degenerative ataxia patients.

5.
Prion ; 12(5-6): 315-319, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30394185

RESUMO

Although colocalization of amyloid ß (Aß) with prion protein (PrP) in the kuru plaque has previously been observed in the brain of prion diseases patients, the participating Aß species has not been identified. Here, we present an immunohistochemical assessment of the brain and spinal cord of a 69-year-old Japanese female patient with Gerstmann-Sträussler-Scheinker disease with a P105L mutation on the PRNP gene (GSS-P105L). Immunohistochemical assessment of serial brain sections was performed using anti-PrP and -Aß antibodies in the hippocampus, frontal and occipital lobes. She died 69 years after a 21-year clinical course. Immunohistochemistorical examination revealed that ~50% of the kuru plaques in the cerebrum were colocalized with Aß, and Aß42 was predominantly observed to be colocalized with PrP-plaques. The Aß deposition patterns were unique, and distinct from diffuse plaques observed in the normal aging brain or Alzheimer's disease brain. The spinal cord exhibited degeneration in the lateral corticospinal tract, posterior horn, and fasciculus gracilis. We have demonstrated for the first time that Aß42, rather than Aß40, is the main Aß component associated with PrP-plaques, and also the degeneration of the fasciculus gracilis in the spinal cord in GSS-P105L, which could be associated with specific clinical features of GSS-P105L.

6.
Psychogeriatrics ; 18(4): 307-312, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30133939

RESUMO

BACKGROUND: The behavioural variant of frontotemporal dementia (bvFTD) is the most common phenotype of frontotemporal lobar degeneration (FTLD). FTLD is divided into three main pathological subtypes: tau-positive FTLD (FTLD-tau), FTLD-TAR DNA-binding protein (TDP), and FTLD-Fused in sarcoma (FUS). At present, it is difficult to predict the underlying pathological subtypes of sporadic bvFTD before a patient's death. METHODS: We retrospectively investigated the clinical features of 34 Japanese patients with sporadic bvFTD, with or without motor neuron disease (MND), who had been pathologically diagnosed with FTLD. We examined whether, and how, the clinical features differed among Pick's disease, FTLD-TDP, and FTLD-FUS patients. RESULTS: Six of the 34 patients developed MND during the course of bvFTD. These six bvFTD-MND patients were all pathologically diagnosed with FTLD-TDP. The other 28 patients were composed of 12 FTLD-tau patients including 11 Pick's disease patients, 8 FTLD-TDP patients, and 8 FTLD-FUS patients. A comparison of the clinical features of the three pathological subtypes of the 33 patients demonstrated that the age at onset was significantly younger in FTLD-FUS patients than in Pick's disease or FTLD-TDP patients. Furthermore, while hyperorality and dietary changes in the early stage of the disease were present in approximately 40% of Pick's disease and FTLD-FUS patients, they were absent in FTLD-TDP patients. CONCLUSION: The comorbidity of MND, a younger age at onset, and hyperorality and dietary changes in the early stage may be useful clinical features for predicting underlying pathological subtypes of sporadic bvFTD. The results of our study should be confirmed by prospective studies employing a larger number of cases.

7.
Intern Med ; 57(23): 3451-3458, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29984771

RESUMO

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an autoimmune disorder involving the brainstem and spinal cord and is sometimes associated with thymoma. We encountered a 75-year-old woman with typical PERM features, glycine receptor antibody, and thymoma. Her neurologic symptoms improved after thymectomy, but she unexpectedly developed anasarca with massive pleural effusions and hypoalbuminemia and finally succumbed to death. The autopsy showed edema and mononuclear infiltration in the pleura but no neuropathological findings typical of PERM. Effective treatment of PERM can reverse the neuropathological signs of encephalomyelitis. The autoimmune nature of anasarca is possible but not proven.

8.
Handb Clin Neurol ; 153: 207-218, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29887137

RESUMO

Iatrogenic transmission of Creutzfeldt-Jakob disease (CJD) has occurred through particular medical procedures. Among them, dura mater grafts and pituitary-derived growth hormone obtained from human cadavers undiagnosed as CJD are the most frequent sources of infection. Recent advances in our knowledge about dura mater graft- and human pituitary-derived growth hormone-associated CJD patients have revealed that the combination of the infected CJD strain and the PRNP genotype of the patient determines their clinical, neuropathologic, and biochemical features. In this chapter, we summarize the clinical, neuropathologic, biochemical, and diagnostic features of dura mater graft- and human pituitary-derived growth hormone-associated CJD patients for the appropriate diagnosis of iatrogenic CJD.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doença Iatrogênica , Proteínas Priônicas/genética , Encéfalo/metabolismo , Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/fisiopatologia , Síndrome de Creutzfeldt-Jakob/transmissão , Genótipo , Hormônio do Crescimento Humano/metabolismo , Humanos , Proteínas Priônicas/metabolismo
9.
Proc Natl Acad Sci U S A ; 115(28): 7428-7433, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29941578

RESUMO

In performing skillful movement, humans use predictions from internal models formed by repetition learning. However, the computational organization of internal models in the brain remains unknown. Here, we demonstrate that a computational architecture employing a tandem configuration of forward and inverse internal models enables efficient motor learning in the cerebellum. The model predicted learning adaptations observed in hand-reaching experiments in humans wearing a prism lens and explained the kinetic components of these behavioral adaptations. The tandem system also predicted a form of subliminal motor learning that was experimentally validated after training intentional misses of hand targets. Patients with cerebellar degeneration disease showed behavioral impairments consistent with tandemly arranged internal models. These findings validate computational tandemization of internal models in motor control and its potential uses in more complex forms of learning and cognition.


Assuntos
Cerebelo/patologia , Aprendizagem/fisiologia , Modelos Neurológicos , Atividade Motora/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mãos/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
10.
PLoS One ; 13(5): e0197466, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29772021

RESUMO

Although the development of effective therapeutic drugs and radical treatment options for dementia and Alzheimer's disease (AD) remains urgent, progress in recent clinical trials of AD drugs has been less than adequate. In order to advance the progress of clinical trials, it is necessary to establish more efficient methods of recruitment. In Japan, there are registration systems stratified by mild cognitive impairment and preclinical and clinical stages of early and advanced stage dementia, but there is no registration system for healthy individuals yet. Therefore, in the present study, we developed a large-scale, internet-based health registry to investigate factors associated with cognitive function among registered participants. A total of 1038 participants completed the initial questionnaire and word list memory test. Among these participants, 353 individuals completed a second questionnaire and memory test. Stepwise multiple regression analysis was performed using IBM SPSS version 23.0 for Windows at a statistical significance level of p<0.05. We found that mood, motivation, and a decreased ability to perform activities of daily living were significantly associated with cognitive function. The results of the present study suggest that maintaining social involvement is important to prevent decreases in physical activity, daily function, mood, and motivation.


Assuntos
Disfunção Cognitiva/fisiopatologia , Memória/fisiologia , Idoso , Doença de Alzheimer/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários
11.
J Neurol Sci ; 387: 187-195, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29571861

RESUMO

Cerebellar ataxias (CAs) are heterogeneous conditions often require differential diagnosis. This study aimed to establish a diagnostic decision tree for differentiating CAs based on pontine MRI findings. Two-hundred and two consecutive ataxia patients were clinically classified into 4 groups: (1) spinocerebellar ataxia (SCA) with brainstem involvement (SCA-BSI), (2) Pure cerebellar SCA, (3) cerebellar dominant multiple system atrophy (MSA-c), and (4) Other CA. Signal intensity in pons was graded into 3 types: hot cross bun sign (HCBS), pontine midline linear T2-hyperintensity (PMH), or normal. The distance ratio of pontine base to tegmentum, named "BT-ratio", was measured. The presence of HCBS indicated either MSA-c with a specificity of 97.7%, or SCA2. When PMH was observed, a BT-ratio above 3.54 strongly indicated SCA-BSI, namely Machado-Joseph disease, SCA1, or dentatorubral-pallidoluysian atrophy, whereas a BT-ratio below 3.54 indicated MSA-c or SCA2. When the signal intensity was normal, a BT-ratio above 3.52 indicated SCA-BSI, whereas a BT-ratio below 3.52 suggested Pure cerebellar SCA or Other CA with pure cerebellar type. The decision tree was confirmed useful in a different 30 CA patients. We propose that differential diagnosis of CAs can be supported by combining pontine MRI signal intensity changes and BT-ratio.

12.
MMWR Morb Mortal Wkly Rep ; 67(9): 274-278, 2018 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-29518068

RESUMO

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder that, according to the most well accepted hypothesis (1), is caused by replicating, transmissible, abnormal forms of a host-encoded prion protein (prions). Most CJD cases occur spontaneously (sporadic CJD) or are inherited (genetic CJD). Iatrogenic CJD can occur after exposure to prion-contaminated instruments or products in medical/surgical settings. Cadaveric dura mater graft-associated CJD (dCJD) accounts for a common form of iatrogenic CJD. This report summarizes the epidemiologic features of 154 cases of dCJD identified in Japan during 1975-2017; these cases account for >60% of dCJD cases reported worldwide (1,2). The unusually high prevalence of dCJD in Japan was first reported in 1997 (3). In 2008, a single brand of graft (Lyodura [B. Braun Melsungen AG, Melsungen, Germany]), frequently used as a patch in neurosurgical procedures, was identified as the probable vehicle of transmission (4). No international recall of the implicated Lyodura occurred, the product had a relatively long shelf life, and the grafts were used frequently in Japanese patients with non-life-threatening conditions (4,5). Since 2008, additional cases have been ascertained, reflecting the identification of previously missed cases and the occurrence of new cases with longer latency periods (interval from exposure to symptom onset) for dCJD (up to 30 years), underscoring the importance of maintaining surveillance for dCJD.


Assuntos
Colágeno , Síndrome de Creutzfeldt-Jakob/epidemiologia , Síndrome de Creutzfeldt-Jakob/transmissão , Dura-Máter/transplante , Transplante de Tecidos/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
13.
Neurology ; 90(10): 464-471, 2018 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-29440566

RESUMO

OBJECTIVE: To systematically review evidence regarding ataxia treatment. METHODS: A comprehensive systematic review was performed according to American Academy of Neurology methodology. CONCLUSIONS: 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).

14.
Biochem Biophys Res Commun ; 496(4): 1055-1061, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29382530

RESUMO

Valine-to-isoleucine substitution at codon 180 of the prion protein gene is only observed in patients with Creutzfeldt-Jakob disease and accounts for approximately half of all cases of genetic prion disease in Japan. In the present study, we investigated the biochemical characteristics of valine-to-isoleucine substitution at codon 180 in the prion protein gene, using samples obtained from the autopsied brains of seven patients with genetic Creutzfeldt-Jakob disease exhibiting this mutation (diagnoses confirmed via neuropathological examination). Among these patients, we observed an absence of diglycosylated and monoglycosylated forms of PrPres at codon 181. Our findings further indicated that the abnormal prion proteins were composed of at least three components, although smaller carboxyl-terminal fragments were predominant. Western blot analyses revealed large amounts of PrPres in the cerebral neocortices, where neuropathological examination revealed marked spongiosis. Relatively smaller amounts of PrPres were detected in the hippocampus, where milder spongiosis was observed, than in the cerebral neocortex. These findings indicate that abnormal prion proteins in the neocortex are associated with severe toxicity, resulting in severe spongiosis. Our findings further indicate that the valine-to-isoleucine substitution is not a polymorphism, but rather an authentic pathogenic mutation associated with specific biochemical characteristics that differ from those observed in sporadic Creutzfeldt-Jakob disease.


Assuntos
Substituição de Aminoácidos/genética , Códon/genética , Síndrome de Creutzfeldt-Jakob/genética , Isoleucina/genética , Proteínas Priônicas/química , Proteínas Priônicas/genética , Valina/genética , Idoso de 80 Anos ou mais , Códon/química , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Neocórtex/química , Valina/química
15.
J Neurol Sci ; 384: 30-35, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29249373

RESUMO

Cortical cerebellar atrophy (CCA) and multiple system atrophy with predominant cerebellar ataxia (MSA-C) are the two major forms of adult-onset sporadic ataxia. Contrary to MSA-C, there are neither diagnostic criteria nor neuroimaging features pathognomonic for CCA. Therefore, it is assumed that the category of CCA in the Japanese national registry include heterogeneous cerebellar ataxic disorders. To refine this category in more detail, we here used a clinical-based term, "idiopathic cerebellar ataxia (IDCA)", and proposed its diagnostic criteria. We collected 346 consecutive patients with the core features of the criteria (sporadic, insidious-onset and slowly progressive cerebellar ataxia in adults, and cerebellar atrophy on brain imaging). Of these, 212 (61.3%) were diagnosed with probable or possible MSA, and 30, who did not meet the diagnostic criteria for MSA at examination, were also excluded because of MRI findings suggestive of MSA. Twenty two were proven to have hereditary spinocerebellar ataxias by genetic testing, and 19 had secondary ataxias. Finally, the remaining 63 (18.2%) were diagnosed with IDCA. The mean (standard deviation) age at onset was 57.2 (10.8) years. Of these, 25 (39.7%) showed pure cerebellar ataxia, and the remaining 38 (60.3%) had some of extracerebellar features including abnormal tendon reflexes (46.0%), positive Babinski sign (9.5%), sensory disturbance (12.7%), cognitive impairment (9.5%), and involuntary movements (7.9%). Our results show that IDCA refined by the diagnostic criteria still includes clinically and genetically heterogeneous ataxic disorders. More extensive genetic analyses will be of significance for further clarification of this group.


Assuntos
Ataxia Cerebelar/diagnóstico , Idoso , Encéfalo/diagnóstico por imagem , Ataxia Cerebelar/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Japão , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/fisiopatologia , Estudos Retrospectivos
16.
Brain Imaging Behav ; 12(2): 309-323, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28290071

RESUMO

Left hemispatial neglect (neglect) is an impaired state of spatial attention. We aimed to reconstruct structural connectivity in the spatial attention network and to identify disconnection patterns underlying neglect. We enrolled 59 right-handed patients who had their first-ever infarction in the right hemisphere and classified them into neglect group (34 patients with neglect) and control group (25 patients without neglect). The neglect group was further subcategorized into 6 subgroups based on infarcted vascular territories. Diffusion tensor imaging data were obtained from all patients. Fractional anisotropy maps were compared between neglect group/subgroups and the control group by using non-parametric voxel-based analysis, generating a lesion path mask. Probabilistic tractography analysis using the lesion path mask reconstructed the following structural connectivity in the spatial attention network, which is specifically damaged in neglect patients: (1) superior longitudinal fasciculus (SLF) I connecting the superior parietal lobule/intraparietal sulcus with the superior frontal gyrus/frontal eye field (SFG/FEF) (dorsal attention network); (2) SLF III/the arcuate fasciculus (AF) and the extreme capsule/inferior fronto-occipital fasciculus (IFOF) connecting the right inferior parietal lobule/temporoparietal junction/superior temporal gyrus (IPL/TPJ/STG) with the middle frontal gyrus/inferior frontal gyrus (ventral attention network); (3) the thalamic radiations to the spatial attention-related cortices; and (4) SLF II and IFOF interconnecting dorsal and ventral attention networks. Individual analysis indicated that isolated damage in SLF I, SLF II, SLF III/AF or the thalamic radiations to IPL/TPJ/STG due to posterior cerebral artery infarction, or simultaneous damage in four thalamic radiations due to anterior choroidal artery infarction, underlies different phenotypes of neglect.

17.
J Neurol Sci ; 382: 108-115, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29111001

RESUMO

OBJECTIVE: To survey AOAN member countries regarding their organizational structure, postgraduate neurology training program, and resources for neurological care provision. METHODOLOGY: A cross-sectional survey using a 36-item questionnaire was conducted among country representatives to AOAN from August 2015 to August 2016. RESULTS: A total of 18/20 AOAN member countries participated in the survey. All the countries have organized association with regular meetings, election of officers and neurology training program. In 9/18 countries, professionals other than neurologists were eligible for affiliation. In 11/18 countries, prior Internal medicine training (or equivalent postgraduate housemanship) is prerequisite to neurology program. Recertification examination is not a practice, but submission of CME is required in 7/18 countries to maintain membership. 12/18 countries publish peer-reviewed journals with at least 1 issue per year. Subspecialty training is offered in 14/18 countries. The ratio of neurologist to population ranges from 1:14,000 to as low as 1:32 million with 9/18 having <1 neurologist per 100,000 population. 6/18 countries have at least 1 specialized center solely for neurological diseases. In government-funded hospitals, the lag time to be seen by a neurologist and/or obtain neuroimaging scan ranges from 1day to 3months. All except one country have several medical- and lay- advocacy or support groups for different neurological conditions. IMPLICATIONS: The data generated can be used for benchmarking to improve neurological care, training, collaborative work and research in the field of neurosciences among the AOAN member countries. The paper presented several strategies used by the different organizations to increase their number of neurologists and improve the quality of training. Sharing of best practices, academic networking, exchange programs and use of telemedicine have been suggested.


Assuntos
Neurologia/educação , Neurologia/organização & administração , Ásia , Estudos Transversais , Assistência à Saúde , Educação de Pós-Graduação em Medicina , Humanos , Oceania , Sociedades Médicas , Inquéritos e Questionários
18.
J Neurol Sci ; 382: 87-90, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-29111027

RESUMO

Spinocerebellar ataxia type 8 (SCA8), an autosomal dominant neurodegenerative disorder showing slowly progressive cerebellar ataxia, is caused by a tri-nucleotide CTG repeat expansion (CTGexp) in the SCA8 gene. As the CTGexp is not fully penetrant, the significance of screening CTGexp in ataxia subjects remains obscure. We tested SCA8 CTGexp in a cohort of 797 ataxia subjects, and if present, its sequence configuration was analyzed. CTGexp was found in 16 alleles from 14 individuals, 2 of which was homozygous for CTGexp. Nucleotide sequencing disclosed 3 types of CTGexp sequence configurations: uninterrupted CTGexp, tri-nucleotide CTA interruption and CCG interruption. The 2 individuals with homozygous expansions were both sporadic cases with clinical features compatible with SCA8, supporting gene dosage effect. Seven out of 14 CTGexp-positive subjects were also carriers of other SCA expansions [Machado-Joseph disease (n=1), SCA6 (n=3) and SCA31 (n=3)], whereas 7 others were not complicated with such major SCAs. Ages of onset in subjects with pure CTGexp tended to be earlier than those with interrupted CTGexp among the 7 subjects not complicated by major SCAs, suggesting that pure CTGexp have stronger pathogenic effect than interrupted CTGexps. The present study underscores importance of disclosing sequence configuration when testing SCA8.


Assuntos
RNA Longo não Codificante/genética , Degenerações Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Idade de Início , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Humanos , Japão , Pessoa de Meia-Idade , Prevalência , Degenerações Espinocerebelares/epidemiologia
19.
Biomark Res ; 5: 28, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29018524

RESUMO

BACKGROUND: Because soluble (or secreted) amyloid precursor protein-ß (sAPPß) and -α (sAPPα) possibly reflect pathological features of Alzheimer's disease (AD), they are potential biomarker candidates for dementia disorders, including AD and mild cognitive impairment (MCI) due to AD (MCI-AD). However, controversial results have been reported regarding their alterations in the cerebrospinal fluid (CSF) of AD and MCI-AD patients. In this study, we re-assessed the utility of sAPPα and sAPPß in CSF as diagnostic biomarkers of dementia disorders. METHODS: We used a modified and sensitive detection method to analyze sAPPs levels in CSF in four groups of patients: AD (N = 33), MCI-AD (N = 17), non-AD dementia (N = 27), and disease controls (N = 19). Phosphorylated tau (p-tau), total tau, and Aß42 were also analyzed using standard methods. RESULTS: A strong correlation was observed between sAPPα and sAPPß, consistent with previous reports. Both sAPPα and sAPPß were highly correlated with p-tau and total tau, suggesting that sAPPs possibly reflect neuropathological changes in the brain. Levels of sAPPα were significantly higher in MCI-AD cases compared with non-AD and disease control cases, and those of sAPPß were also significantly higher in MCI-AD and AD cases relative to other cases. A logistic regression analysis indicated that sAPPα and sAPPß have good discriminative power for the diagnosis of MCI-AD. CONCLUSIONS: Our findings collectively suggest that both sAPPs are pathologically relevant and potentially useful biomarkers for early and accurate diagnosis of dementia disorders. We also suggest that careful measurement is important in assessing the diagnostic utility of CSF sAPPs.

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