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1.
Cerebellum ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33651372

RESUMO

Technologies that enable frequent, objective, and precise measurement of ataxia severity would benefit clinical trials by lowering participation barriers and improving the ability to measure disease state and change. We hypothesized that analyzing characteristics of sub-second movement profiles obtained during a reaching task would be useful for objectively quantifying motor characteristics of ataxia. Participants with ataxia (N=88), participants with parkinsonism (N=44), and healthy controls (N=34) performed a computer tablet version of the finger-to-nose test while wearing inertial sensors on their wrists. Data features designed to capture signs of ataxia were extracted from participants' decomposed wrist velocity time-series. A machine learning regression model was trained to estimate overall ataxia severity, as measured by the Brief Ataxia Rating Scale (BARS). Classification models were trained to distinguish between ataxia participants and controls and between ataxia and parkinsonism phenotypes. Movement decomposition revealed expected and novel characteristics of the ataxia phenotype. The distance, speed, duration, morphology, and temporal relationships of decomposed movements exhibited strong relationships with disease severity. The regression model estimated BARS with a root mean square error of 3.6 points, r2 = 0.69, and moderate-to-excellent reliability. Classification models distinguished between ataxia participants and controls and ataxia and parkinsonism phenotypes with areas under the receiver-operating curve of 0.96 and 0.89, respectively. Movement decomposition captures core features of ataxia and may be useful for objective, precise, and frequent assessment of ataxia in home and clinic environments.

3.
Cerebellum ; 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33159660

RESUMO

The posterior cerebellum is the most significantly compromised brain structure in individuals with metabolic syndrome (MetS) (Hum Brain Mapp 40(12):3575-3588, 2019). In light of this, we hypothesized that cognitive decline reported in patients with MetS is likely related to posterior cerebellar atrophy. In this study, we performed a post hoc analyses using T1-weighted magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) in the form of voxel-wise tract-based spatial statistics (TBSS), biometric, and psychometric data from young participants with (n = 52, aged 18-35 years) and without MetS (n = 52, aged 18-35 years). To test the predictive value of components of the Schmahmann syndrome scale (SSS), also known as the cerebellar cognitive affective syndrome scale, we used structural equation modeling to adapt available psychometric scores in our participant sample to the SSS and compare them to the composite score of all psychometric data available. Our key findings point to a statistically significant correlation between TBSS fractional anisotropy (FA) values from DTI and adapted SSS psychometric scores in individuals with MetS (r2 = .139, 95% CI = 0.009, .345). This suggests that the SSS could be applied to assess cognitive and likely neuroanatomical effects associated with MetS. We strongly suggest that future work aimed at investigating the neurocognitive effects of MetS and related comorbidities (i.e., dyslipidemia, diabetes, obesity) would benefit from implementing and further exploring the validity of the SSS in this patient population.

4.
Sci Rep ; 10(1): 18641, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122811

RESUMO

Eye movements are disrupted in many neurodegenerative diseases and are frequent and early features in conditions affecting the cerebellum. Characterizing eye movements is important for diagnosis and may be useful for tracking disease progression and response to therapies. Assessments are limited as they require an in-person evaluation by a neurology subspecialist or specialized and expensive equipment. We tested the hypothesis that important eye movement abnormalities in cerebellar disorders (i.e., ataxias) could be captured from iPhone video. Videos of the face were collected from individuals with ataxia (n = 102) and from a comparative population (Parkinson's disease or healthy participants, n = 61). Computer vision algorithms were used to track the position of the eye which was transformed into high temporal resolution spectral features. Machine learning models trained on eye movement features were able to identify abnormalities in smooth pursuit (a key eye behavior) and accurately distinguish individuals with abnormal pursuit from controls (sensitivity = 0.84, specificity = 0.77). A novel machine learning approach generated severity estimates that correlated well with the clinician scores. We demonstrate the feasibility of capturing eye movement information using an inexpensive and widely accessible technology. This may be a useful approach for disease screening and for measuring severity in clinical trials.

5.
Cogn Behav Neurol ; 33(3): 226-229, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889955

RESUMO

Coronavirus 2019 (COVID-19) has profoundly impacted the well-being of society and the practice of medicine across health care systems worldwide. As with many other subspecialties, the clinical paradigm in behavioral neurology and neuropsychiatry (BN-NP) was transformed abruptly, transitioning to real-time telemedicine for the assessment and management of the vast majorities of patient populations served by our subspecialty. In this commentary, we outline themes from the BN-NP perspective that reflect the emerging lessons we learned using telemedicine during the COVID-19 pandemic. Positive developments include the ability to extend consultations and management to patients in our high-demand field, maintenance of continuity of care, enhanced ecological validity, greater access to a variety of well-reimbursed telemedicine options (telephone and video) that help bridge the digital divide, and educational and research opportunities. Challenges include the need to adapt the mental state examination to the telemedicine environment, the ability to perform detailed motor neurologic examinations in patients where motor features are important diagnostic considerations, appreciating nonverbal cues, managing acute safety and behavioral concerns in less controlled environments, and navigating intervention-based (neuromodulation) clinics requiring in-person contact. We hope that our reflections help to catalyze discussions that should take place within the Society for Behavioral and Cognitive Neurology, the American Neuropsychiatric Association, and allied organizations regarding how to optimize real-time telemedicine practices for our subspecialty now and into the future.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Doenças do Sistema Nervoso/diagnóstico , Exame Neurológico , Pandemias , Pneumonia Viral , Telemedicina/organização & administração , Humanos , Massachusetts , Neurologia , Neuropsiquiatria
6.
Cerebellum ; 19(6): 833-868, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32632709

RESUMO

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions.

7.
Brain Behav Immun ; 89: 601-603, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32681865

RESUMO

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 (COVID-19). Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient's prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.


Assuntos
Encéfalo/diagnóstico por imagem , Infecções por Coronavirus/complicações , Síndrome de Creutzfeldt-Jakob/complicações , Pneumonia Viral/complicações , Idoso , Betacoronavirus , Encéfalo/fisiopatologia , Infecções por Coronavirus/imunologia , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/imunologia , Síndrome de Creutzfeldt-Jakob/fisiopatologia , Progressão da Doença , Eletroencefalografia , Fluordesoxiglucose F18 , Humanos , Imagem por Ressonância Magnética , Masculino , Pandemias , Pneumonia Viral/imunologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos
8.
Front Neurol ; 11: 516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574247

RESUMO

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.

9.
Cerebellum ; 19(4): 562-568, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32405955

RESUMO

The current worldwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that causes coronavirus disease 2019 (COVID-19) has brought some medical systems to the brink of collapse. This crisis is also negatively impacting the care of patients with non-COVID-19 conditions, including those with cerebellar ataxia (CA). Older patients with CA and those with immune-mediated ataxias on immunosuppressive medication are potentially at high risk of developing serious complications of the infection, although it is also possible that immunosuppressive agents may provide a defense against cytokine storm. This has implications for even greater attention to preventing contracting the disease through physical distancing and/or isolation. The CA patient population is also at higher risk because of the neurological complexities of their underlying disorder and the comorbid medical illnesses that often accompany the genetic ataxias. As the disruption of social patterns and healthcare delivery in response to the crisis continues, interruption of rehabilitation, speech and language therapy, and face-to-face consultations threatens to have a negative impact on the course and well-being of CA patients. Mental and physical health is also potentially at greater risk because the prevailing uncertainty and anxiety may be superimposed upon cerebellum-specific neuropsychological challenges. We identify and review some of the short- and long-term consequences of this global pandemic for the community of ataxia patients and their families and for the clinical and academic neurologists/ataxiologists caring for these patients. This includes the recognition that telemedicine has emerged as a principle means of caregiver-patient contact and that neurological manifestations of COVID-19 including those specific to cerebellar neurobiology are increasingly recognized and will require close surveillance and monitoring. This COVID-19 Cerebellum Task Force consensus provides some guidance on how we may approach this uncertain time and consider preparing for the new realities we face in CA patient care once this acute crisis has passed.


Assuntos
Ataxia Cerebelar , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Betacoronavirus , Ataxia Cerebelar/epidemiologia , Ataxia Cerebelar/virologia , Comorbidade , Infecções por Coronavirus/epidemiologia , Humanos , Pneumonia Viral/epidemiologia , Fatores de Risco
10.
J Neurol Sci ; 415: 116878, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454319

RESUMO

BACKGROUND: Dysphagia is a common symptom and may be a cause of death in patients with spinocerebellar ataxias (SCAs). However, little is known about at which disease stage dysphagia becomes clinically relevant. Therefore, our study aims to investigate the prevalence of dysphagia in different disease stages of SCA 1, 2, 3 and 6. METHODS: We studied 237 genetically confirmed patients with SCA 1, 2, 3, 6 from the Clinical Research Consortium for SCAs and investigated the prevalence of self-reported dysphagia and the association between dysphagia and other clinical characteristics. We further stratified ataxia severity and studied the prevalence of dysphagia at each disease stage. RESULTS: Dysphagia was present in 59.9% of SCA patients. Patients with dysphagia had a longer disease duration and more severe ataxia than patients without dysphagia (patients with dysphagia vs. without dysphagia, disease duration (years): 14.51 ± 8.91 vs. 11.22 ± 7.82, p = .001, scale for the assessment and rating of ataxia [SARA]: 17.90 ± 7.74 vs. 13.04 ± 7.51, p = .000). Dysphagia was most common in SCA1, followed by SCA3, SCA 6, and SCA 2. Dysphagia in SCA1 and 3 was associated robustly with ataxia severity, whereas this association was less obvious in SCA2 and 6, demonstrating genotype-specific clinical variation. CONCLUSION: Dysphagia is a common clinical symptom in SCAs, especially in the severe disease stage. Understanding dysphagia in SCA patients can improve the care of these patients and advance knowledge on the roles of the cerebellum and brainstem control in swallowing.

11.
Neurology ; 94(7): e705-e717, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-31964693

RESUMO

OBJECTIVE: A cross-sectional study was performed to evaluate whether quantitative oculomotor measures correlate with disease severity in late-onset GM2 gangliosidosis (LOGG) and assess cognition and sleep as potential early nonmotor features. METHODS: Ten patients with LOGG underwent quantitative oculomotor recordings, including measurements of the angular vestibulo-ocular reflex (VOR), with results compared to age- and sex-matched controls. Disease severity was assessed by ataxia rating scales. Cognitive/neuropsychiatric features were assessed by the cerebellar cognitive affective syndrome (CCAS) scale, Cerebellar Neuropsychiatric Rating Scale, and sleep quality evaluated using subjective sleep scales. RESULTS: Oculomotor abnormalities were found in all participants, including 3/10 with clinically normal eye movements. Abnormalities involved impaired saccadic accuracy (5/10), abnormal vertical (8/10) and horizontal (4/10) pursuit, reduced optokinetic nystagmus (OKN) responses (7/10), low VOR gain (10/10), and impaired VOR cancellation (2/10). Compared to controls, the LOGG group showed significant differences in saccade, VOR, OKN, and visually enhanced VOR gains. Severity of saccadic dysmetria, OKN, and VOR fixation-suppression impairments correlated with ataxia scales (p < 0.05). Nine out of ten patients with LOGG had evidence of the CCAS (5/10 definite, 2/10 probable, 2/10 possible). Excessive daytime sleepiness was present in 4/10 and 8/10 had poor subjective sleep quality. CONCLUSIONS: Cerebellar oculomotor abnormalities were present in all patients with LOGG, including those with normal clinical oculomotor examinations. Saccade accuracy (dorsal cerebellar vermis localization), fixation suppression, and OKN gain (cerebellar flocculus/paraflocculus localization) correlated with disease severity, suggesting that quantitative oculomotor measurements could be used to track disease progression. We found evidence of the CCAS, suggesting that cerebellar dysfunction may explain the cognitive disorder in LOGG. Sleep impairments were prevalent and require further study.


Assuntos
Movimentos Oculares , Gangliosidoses GM2/diagnóstico , Adulto , Encéfalo/diagnóstico por imagem , Cognição , Estudos de Coortes , Estudos Transversais , Feminino , Gangliosidoses GM2/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/etiologia , Transtornos da Motilidade Ocular/fisiopatologia , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Sono , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/fisiopatologia
12.
Cerebellum ; 19(1): 16-29, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31321675

RESUMO

A patient diagnosed with developmental delay, intellectual disability, and autistic and obsessive-compulsive symptoms was found to have a posterior fossa arachnoid cyst (PFAC) compressing the cerebellum. The patient was referred to our Ataxia Unit for consideration of surgical drainage of the cyst to improve his clinical constellation. This scenario led to an in-depth analysis including a literature review, functional resting-state MRI analysis of our patient compared to a group of controls, and genetic testing. While it is reasonable to consider that there may be a causal relationship between PFAC and neurodevelopmental or psychiatric symptoms in some patients, there is also a nontrivial prevalence of PFAC in the asymptomatic population and a significant possibility that many PFAC are incidental findings in the context of primary cognitive or psychiatric symptoms. Our functional MRI analysis is the first to examine brain function, and to report cerebellar dysfunction, in a patient presenting with cognitive/psychiatric symptoms found to have a structural abnormality compressing the cerebellum. These neuroimaging findings are inherently limited due to their correlational nature but provide unprecedented evidence suggesting that cerebellar compression may be associated with cerebellar dysfunction. Exome gene sequencing revealed additional etiological possibilities, highlighting the complexity of this field of cerebellar clinical and scientific practice. Our findings and discussion may guide future investigations addressing an important knowledge gap-namely, is there a link between cerebellar compression (including arachnoid cysts and possibly other forms of cerebellar compression such as Chiari malformation), cerebellar dysfunction (including fMRI abnormalities reported here), and neuropsychiatric symptoms?


Assuntos
Cistos Aracnóideos/diagnóstico por imagem , Doenças Cerebelares/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Transtornos Mentais/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Adulto , Cistos Aracnóideos/complicações , Cistos Aracnóideos/cirurgia , Doenças Cerebelares/complicações , Doenças Cerebelares/cirurgia , Cerebelo/cirurgia , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Transtornos Mentais/complicações , Transtornos Mentais/cirurgia , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/cirurgia
13.
Cerebellum ; 19(1): 102-125, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31522332

RESUMO

Sporadically advocated over the last two centuries, a cerebellar role in cognition and affect has been rigorously established in the past few decades. In the clinical domain, such progress is epitomized by the "cerebellar cognitive affective syndrome" ("CCAS") or "Schmahmann syndrome." Introduced in the late 1990s, CCAS reflects a constellation of cerebellar-induced sequelae, comprising deficits in executive function, visuospatial cognition, emotion-affect, and language, over and above speech. The CCAS thus offers excellent grounds to investigate the functional topography of the cerebellum, and, ultimately, illustrate the precise mechanisms by which the cerebellum modulates cognition and affect. The primary objective of this task force paper is thus to stimulate further research in this area. After providing an up-to-date overview of the fundamental findings on cerebellar neurocognition, the paper substantiates the concept of CCAS with recent evidence from different scientific angles, promotes awareness of the CCAS as a clinical entity, and examines our current insight into the therapeutic options available. The paper finally identifies topics of divergence and outstanding questions for further research.


Assuntos
Comitês Consultivos , Doenças Cerebelares/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Transtornos do Humor/diagnóstico por imagem , Doenças Cerebelares/epidemiologia , Doenças Cerebelares/psicologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Humanos , Transtornos do Humor/epidemiologia , Transtornos do Humor/psicologia , Síndrome
14.
Childs Nerv Syst ; 36(6): 1205-1214, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31240391

RESUMO

BACKGROUND: Cerebellar mutism (CM), pseudobulbar palsy, posterior fossa syndrome (PFS), and cerebellar cognitive affective syndrome (CCAS) are terms that have been used, sometimes interchangeably, to refer to the complex neurological constellation that occurs following surgical removal of cerebellar and fourth ventricular tumors, mostly in children, but also sometimes in adults. METHODS: This paper reviews the origins of what is now regarded as pediatric post-operative cerebellar mutism, the cerebellar cognitive affective syndrome, and the neurological manifestations of injury to or disruption of brainstem and cerebellar structures. It examines the specific components of each of these phenomena in the context of the evolving understanding of the role of the cerebellum in nervous system function. RESULTS: Children undergoing surgical management of tumors in the posterior cranial fossa are at risk of experiencing cranial neuropathies, corticospinal damage, cerebellar ataxia and related motor disorders, neuropsychiatric and cognitive changes, and in some patients, mutism. These clinical presentations are differentiated from each other and examined in the context of the relevant anatomical structures and distributed neural circuits. The term posterior fossa syndrome is not sufficiently helpful in distinguishing the different elements of the clinical phenomena from each other, and because of this lack of precision and specificity, there is consensus among investigators in the international Posterior Fossa Society that the designation be retired. CONCLUSIONS: Using contemporary brain imaging methods and guided by careful clinical observation and meticulous definition of clinical phenomenology, it is now feasible to perform detailed structure function correlation analyses to achieve two critical goals in the care of children with tumors in the posterior cranial fossa. The first goal is to identify and understand the neural circuits responsible for the different manifestations-arousal, cranial neuropathies, long tract signs, cerebellar motor syndrome, cerebellar vestibular syndrome, cerebellar cognitive affective syndrome including emotional dyscontrol, and mutism. The second goal is to transform this knowledge into practical clinical intervention, preventing the complications inherent in the necessary surgery whenever possible, and develop new approaches to treatment with methods including brain modulation targeting interconnected nodes of the damaged neural circuits.

15.
Cereb Cortex ; 30(4): 2401-2417, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-31701117

RESUMO

Anatomical connections link the cerebellar cortex with multiple sensory, motor, association, and paralimbic cerebral areas. The majority of fibers that exit cerebellar cortex synapse in dentate nuclei (DN) before reaching extracerebellar structures such as cerebral cortex, but the functional neuroanatomy of human DN remains largely unmapped. Neuroimaging research has redefined broad categories of functional division in the human brain showing that primary processing, attentional (task positive) processing, and default-mode (task negative) processing are three central poles of neural macroscale functional organization. This broad spectrum of human neural processing categories is represented not only in the cerebral cortex, but also in the thalamus, striatum, and cerebellar cortex. Whether functional organization in DN obeys a similar set of macroscale divisions, and whether DN are yet another compartment of representation of a broad spectrum of human neural processing categories, remains unknown. Here, we show for the first time that human DN are optimally divided into three functional territories as indexed by high spatio-temporal resolution resting-state MRI in 77 healthy humans, and that these three distinct territories contribute uniquely to default-mode, salience-motor, and visual cerebral cortical networks. Our findings provide a systems neuroscience substrate for cerebellar output to influence multiple broad categories of neural control.

16.
Mov Disord ; 35(2): 354-358, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31769069

RESUMO

BACKGROUND: Objective assessments of movement impairment are needed to support clinical trials and facilitate diagnosis. The objective of the current study was to determine if a rapid web-based computer mouse test (Hevelius) could detect and accurately measure ataxia and parkinsonism. METHODS: Ninety-five ataxia, 46 parkinsonism, and 29 control participants and 229,017 online participants completed Hevelius. We trained machine-learning models on age-normalized Hevelius features to (1) measure severity and disease progression and (2) distinguish phenotypes from controls and from each other. RESULTS: Regression model estimates correlated strongly with clinical scores (from r = 0.66 for UPDRS dominant arm total to r = 0.83 for the Brief Ataxia Rating Scale). A disease change model identified ataxia progression with high sensitivity. Classification models distinguished ataxia or parkinsonism from healthy controls with high sensitivity (≥0.91) and specificity (≥0.90). CONCLUSIONS: Hevelius produces a granular and accurate motor assessment in a few minutes of mouse use and may be useful as an outcome measure and screening tool. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

20.
Cell ; 178(5): 1159-1175.e17, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31442405

RESUMO

Expansion of CAG trinucleotide repeats in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordination and cognition. While ATXN1 is associated with increased Alzheimer's disease (AD) risk, CAG repeat number in AD patients is not changed. Here, we investigated the consequences of ataxin-1 loss of function and discovered that knockout of Atxn1 reduced CIC-ETV4/5-mediated inhibition of Bace1 transcription, leading to increased BACE1 levels and enhanced amyloidogenic cleavage of APP, selectively in AD-vulnerable brain regions. Elevated BACE1 expression exacerbated Aß deposition and gliosis in AD mouse models and impaired hippocampal neurogenesis and olfactory axonal targeting. In SCA1 mice, polyglutamine-expanded mutant ataxin-1 led to the increase of BACE1 post-transcriptionally, both in cerebrum and cerebellum, and caused axonal-targeting deficit and neurodegeneration in the hippocampal CA2 region. These findings suggest that loss of ataxin-1 elevates BACE1 expression and Aß pathology, rendering it a potential contributor to AD risk and pathogenesis.


Assuntos
Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Ataxina-1/metabolismo , Encéfalo/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ataxina-1/deficiência , Ataxina-1/genética , Encéfalo/patologia , Região CA2 Hipocampal/metabolismo , Região CA2 Hipocampal/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Frequência do Gene , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neurogênese , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Genética , Repetições de Trinucleotídeos/genética , Regulação para Cima
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