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This historical review on the semantic evolution of human senses and sensors revealed that Aristotle's list of the five senses sight, hearing, touch, taste, and smell is still in use among non-scientific lay persons. It is no surprise that his classification in the work "De Anima" (On the Soul) from 350 BC confuses the sensor "touch" with the now more comprehensively defined somatosensory system and that senses are missing such as the later discovered vestibular system and the musculotendinous proprioception of the position of parts of the body in space. However, it is surprising that in the three most influential ancient cultures, Egypt, Greece, and China-which shaped the history of civilization-the concept prevailed that the heart rather than the brain processes perception, cognition, and emotions. This "cardiocentric view" can be traced back to the "Doctrine of Aristotle," the "Book of the Dead" in ancient Egypt, and the traditional Chinese medicine of correspondence documented in the book "Huang di Neijing." In Greek antiquity the philosophers Empedocles, Democritus and Aristotle were proponents of the allocation of the spirit and the soul to the heart connected to the body via the blood vessels. Opponents were the pre-Socratic mathematician Pythagoras, the philosopher Plato, and especially the Greek physician Hippocrates who regarded the brain as the most powerful organ in humans in his work "De Morbo Sacro." The Greek physician Galen of Pergamon further elaborated on the concept of the brain ("cephalocentric hypothesis") connected to the body by a network of nerves. The fundamental concepts for understanding functions and disorders of the vestibular system, the perception of self-motion, verticality and balance control were laid by a remarkable group of 19th century scientists including PurkynÓ, Mach, Breuer, Helmholtz, and Crum-Brown. It was also in the 19th century that Bell described a new sense of a reciprocal sensorimotor loop between the brain and the muscles which he called "muscular sense," later termed "kinaesthesia" by Bastian and defined in 1906 as "proprioception" by Sherrington as "the perception of joint and body movements as well as position of the body or body segments, in space." Both, the vestibular system and proprioception could be acknowledged as senses six or seven. However, we hesitate to recommend "pain"-which is variously assigned to the somatosensory system or extero-, intero-, visceroception-as a separate sensory system. Pain sensors are often not specific but have multisensory functions. Because of this inconsistent, partly contradictory classification even by experts in the current literature on senses and sensors we consider it justified to recommend a comprehensive reorganization of classification features according to the present state of knowledge with an expansion of the number of senses. Such a project has also to include the frequent task-dependent multisensory interactions for perceptual and sensorimotor achievements, and higher functions or disorders of the visual and vestibular systems as soon as cognition or emotions come into play. This requires a cooperation of sensory physiologists, neuroscientists and experienced physicians involved in the management of patients with sensory and multisensory disorders.
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PURPOSE OF REVIEW: The aim of this study was to illuminate the extent of the bilateral central vestibular network from brainstem and cerebellum to subcortical and cortical areas and its interrelation to higher cortical functions such as spatial cognition and anxiety. RECENT FINDINGS: The conventional view that the main function of the vestibular system is the perception of self-motion and body orientation in space and the sensorimotor control of gaze and posture had to be developed further by a hierarchical organisation with bottom-up and top-down interconnections. Even the vestibulo-ocular and vestibulo-spinal reflexes are modified by perceptual cortical processes, assigned to higher vestibulo-cortical functions. A first comparative fMRI meta-analysis of vestibular stimulation and fear-conditioning studies in healthy participants disclosed widely distributed clusters of concordance, including the prefrontal cortex, anterior insula, temporal and inferior parietal lobe, thalamus, brainstem and cerebellum. In contrast, the cortical vestibular core region around the posterior insula was activated during vestibular stimulation but deactivated during fear conditioning. In recent years, there has been increasing evidence from studies in animals and humans that the central vestibular system has numerous connections related to spatial sensorimotor performance, memory, and emotion. The clinical implication of the complex interaction within various networks makes it difficult to assign some higher multisensory disorders to one particular modality, for example in spatial hemineglect or room-tilt illusion. SUMMARY: Our understanding of higher cortical vestibular functions is still in its infancy. Different brain imaging techniques in animals and humans are one of the most promising methodological approaches for further structural and functional decoding of the vestibular and other intimately interconnected networks. The multisensory networking including cognition and emotion determines human behaviour in space.
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Vestíbulo do Labirinto , Animais , Humanos , Ansiedade , Transtornos de Ansiedade , Tronco Encefálico , Córtex Cerebral , CogniçãoRESUMO
Background: This study aims to investigate the presence of spatial cognitive impairments in patients with acute unilateral peripheral vestibulopathy (vestibular neuritis, AUPV) during both the acute phase and the recovery phase. Methods: A total of 72 AUPV patients (37 with right-sided AUPV and 35 with left-sided AUPV; aged 34-80 years, median 60.5; 39 males, 54.2%) and 35 healthy controls (HCs; aged 43-75 years, median 59; 20 males, 57.1%) participated in the study. Patients underwent comprehensive neurotological assessments, including video-oculography, video head impulse and caloric tests, ocular and cervical vestibular-evoked myogenic potentials, and pure-tone audiometry. Additionally, the Visual Object and Space Perception (VOSP) battery was used to evaluate visuospatial perception, while the Block design test and Corsi block-tapping test assessed visuospatial memory within the first 2 days (acute phase) and 4 weeks after symptom onset (recovery phase). Results: Although AUPV patients were able to successfully perform visuospatial perception tasks within normal parameters, they demonstrated statistically worse performance on the visuospatial memory tests compared to HCs during the acute phase. When comparing right versus left AUPV groups, significant decreased scores in visuospatial perception and memory were observed in the right AUPV group relative to the left AUPV group. In the recovery phase, patients showed substantial improvements even in these previously diminished visuospatial cognitive performances. Conclusion: AUPV patients showed different spatial cognition responses, like spatial memory, depending on the affected ear, improving with vestibular compensation over time. We advocate both objective and subjective visuospatial assessments and the development of tests to detect potential cognitive deficits after unilateral vestibular impairments.
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In a retrospective study, the data of direction-dependent deviations in dynamic subjective visual vertical (SVV) testing were analysed in 1811 dizzy patients (174 benign paroxysmal positional vertigo, 99 unilateral vestibulopathy, 67 bilateral vestibulopathy, 151 Menière's disease, 375 vestibular migraine, 82 cerebellar disorder, 522 functional dizziness, 341 unclear diagnosis) and in 59 healthy controls. Major findings were (i) a significant gender difference with higher directional deviations in females over the entire range of age, (ii) a significant increase of directional deviations with increasing age for both genders and in all disease subgroups as well as in healthy controls, and (iii) a lack of significant difference of directional deviations between all tested diseases. Thus, the data allow no recommendation for performing additional angular deviation analysis in dynamic SVV testing as part of routine clinical management of dizzy patients. However, as shown in earlier longitudinal studies, it still appears reasonable that dynamic SVV in acute rather than chronic vestibular disorders may provide a useful instrument for the monitoring of acute unilateral vestibular tonus imbalances in the course of the disease.
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BACKGROUND: There is increasing evidence for close interrelations between vestibular and emotional brain networks. A study in patients with bilateral peripheral vestibulopathy (BVP) showed relatively low vertigo-related anxiety (VRA), despite high physical impairment. The current working hypothesis proposes the integrity of the peripheral vestibular system as a prerequisite for development of VRA. Here we contribute by evaluating VRA and vestibular-related handicap in central vestibular disorders. METHODS: Of 6396 patients presenting in a tertiary vertigo centre, 306 were identified with four clear central vestibular disorders: pure cerebellar ocular motor disorder (COD; 61), cerebellar ataxia (CA; 63), atypical parkinsonian syndromes (APS; 28), vestibular migraine (VM; 154). Their results of the Vertigo Handicap Questionnaire (VHQ), with its subscales for anxiety and handicapped activity, were compared to those of 65 BVP patients. Postural instability was measured on a force-plate. Multivariate linear regression was used to adjust for patient demographics. RESULTS: Patients with chronic central vestibular disorders (COD, CA, APS) had relatively low VRA levels comparable to those in BVP, independent of increased handicapped activity or postural instability. Only VM patients showed significantly higher VRA, although their activity impairment and postural instability were lowest. No significant differences within chronic central vestibular disorders were found for VRA and subjective activity impairment. CONCLUSIONS: Subjective and objective vestibular-related impairment are not necessarily correlated with vestibular-related anxiety in central vestibular disorders. Our findings rather support the hypothesis that, in addition to an intact peripheral, an intact central vestibular system could also serve as a prerequisite to develop specific VRA.
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Vestibulopatia Bilateral , Transtornos dos Movimentos , Doenças Vestibulares , Humanos , Doenças Vestibulares/complicações , Doenças Vestibulares/psicologia , Vertigem/psicologia , Ansiedade/etiologia , Ansiedade/psicologia , Encéfalo , Transtornos de Ansiedade , Tontura/psicologiaRESUMO
BACKGROUND: Naturalistic head accelerations can be used to elicit vestibular evoked potentials (VestEPs). These potentials allow for analysis of cortical vestibular processing and its multi-sensory integration with a high temporal resolution. METHODS: We report the results of two experiments in which we compared the differential VestEPs elicited by randomized translations, rotations, and tilts in healthy subjects on a motion platform. RESULTS: An event-related potential (ERP) analysis revealed that established VestEPs were verifiable in all three acceleration domains (translations, rotations, tilts). A further analysis of the VestEPs showed a significant correlation between rotation axes (yaw, pitch, roll) and the amplitude of the evoked potentials. We found increased amplitudes for rotations in the roll compared to the pitch and yaw plane. A distributed source localization analysis showed that the activity in the cingulate sulcus visual (CSv) area best explained direction-dependent amplitude modulations of the VestEPs, but that the same cortical network (posterior insular cortex, CSv) is involved in processing vestibular information, regardless of the motion direction. CONCLUSION: The results provide evidence for an anisotropic, direction-dependent processing of vestibular input by cortical structures. The data also suggest that area CSv plays an integral role in ego-motion perception and interpretation of spatial features such as acceleration direction and intensity.
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Percepção de Movimento , Vestíbulo do Labirinto , Humanos , Vestíbulo do Labirinto/fisiologia , AceleraçãoAssuntos
Cacau , Chocolate , Doença de Parkinson , Humanos , Cafeína/uso terapêutico , Doença de Parkinson/terapiaRESUMO
OBJECTIVE: Thalamic dysfunction in lesions or neurodegeneration may alter verticality perception and lead to postural imbalance and falls. The aim of the current study was to delineate the structural and functional connectivity network architecture of the vestibular representations in the thalamus by multimodal magnetic resonance imaging. METHODS: Seventy-four patients with acute unilateral isolated thalamic infarcts were studied prospectively with emphasis on the perception of verticality (tilts of the subjective visual vertical [SVV]). We used multivariate lesion-symptom mapping based on support-vector regression to determine the thalamic nuclei associated with ipsiversive and contraversive tilts of the SVV. The lesion maps were used to evaluate the white matter disconnection and whole brain functional connectivity in healthy subjects. RESULTS: Contraversive SVV tilts were associated with lesions of the ventral posterior lateral/medial, ventral lateral, medial pulvinar, and medial central/parafascicular nuclei. Clusters associated with ipsiversive tilts were located inferiorly (ventral posterior inferior nucleus) and laterally (ventral lateral, ventral posterior lateral, and reticular nucleus) to these areas. Distinct ascending vestibular brainstem pathways terminated in the subnuclei for ipsi- or contraversive verticality processing. The functional connectivity analysis showed specific patterns of cortical connections with the somatomotor network for lesions with contraversive tilts, and with the core multisensory vestibular representations (areas Ri, OP2-3, Ig, 3av, 2v) for lesions with ipsiversive tilts. INTERPRETATION: The functional specialization may allow both a stable representation of verticality for sensorimotor integration and flexible adaption to sudden changes in the environment. A targeted modulation of this circuitry could be a novel therapeutic strategy for higher level balance disorders of thalamocortical origin. ANN NEUROL 2023;94:133-145.
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Encéfalo , Percepção Espacial , Humanos , Tronco Encefálico , Mapeamento Encefálico , Tálamo/diagnóstico por imagemRESUMO
BACKGROUND: A bidirectional functional link between vestibular and fear-related disorders has been previously suggested. OBJECTIVE: To test a potential overlap of vestibular and fear systems with regard to their brain imaging representation maps. METHODS: By use of voxel-based mapping permutation of subject images, we conducted a meta-analysis of earlier functional magnetic resonance imaging (fMRI) studies applying vestibular stimulation and fear conditioning in healthy volunteers. RESULTS: Common clusters of concordance of vestibular stimulation and fear conditioning were found in the bilateral anterior insula cortex, ventrolateral prefrontal cortex and the right temporal pole, bilaterally in the adjacent ventrolateral prefrontal cortex, cingulate gyrus, secondary somatosensory cortex, superior temporal and intraparietal lobe, supplementary motor area and premotor cortex, as well as subcortical areas, such as the bilateral thalamus, mesencephalic brainstem including the collicular complex, pons, cerebellar vermis and bilateral cerebellar hemispheres. Peak areas of high concordance for activations during vestibular stimulation but deactivations during fear conditioning were centered on the posterior insula and S2. CONCLUSIONS: The structural overlap of both networks allows the following functional interpretations: first, the amygdala, superior colliculi, and antero-medial thalamus might represent a release of preprogramed sensorimotor patterns of approach or avoidance. Second, the activation (vestibular system) and deactivation (fear system) of the bilateral posterior insula is compatible with the view that downregulation of the fear network by acute vestibular disorders or unfamiliar vestibular stimulation makes unpleasant perceived body accelerations less distressing. This also fits the clinical observation that patients with bilateral vestibular loss suffer from less vertigo-related anxiety.
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Medo , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Mapeamento Encefálico , Córtex Cerebral , Lobo Temporal , EncéfaloRESUMO
BACKGROUND AND PURPOSE: Acute ischemic stroke due to basilar artery occlusion (BAO) causes the most severe strokes and has a poor prognosis. Data regarding efficacy of endovascular thrombectomy in BAO are sparse. Therefore, in this study, we performed an analysis of the therapy of patients with BAO in routine clinical practice. METHODS: Patients enrolled between June 2015 and December 2019 in the German Stroke Registry-Endovascular Treatment (GSR-ET) were analyzed. Primary outcomes were successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b-3), substantial neurological improvement (≥8-point National Institute of Health Stroke Scale [NIHSS] score reduction from admission to discharge or NIHSS score at discharge ≤1), and good functional outcome at 3 months (modified Rankin Scale [mRS] score of 0-2). RESULTS: Out of 6635 GSR-ET patients, 640 (9.6%) patients (age 72.2 ± 13.3, 43.3% female) experienced BAO (median [interquartile range] NIHSS score 17 [8, 27]). Successful reperfusion was achieved in 88.4%. Substantial neurological improvement at discharge was reached by 45.5%. At 3-month follow-up, good clinical outcome was observed in 31.1% of patients and the mortality rate was 39.2%. Analysis of mTICI3 versus mTICI2b groups showed considerable better outcome in those with mTICI3 (38.9% vs. 24.4%; p = 0.005). The strongest predictors of good functional outcome were intravenous thrombolysis (IVT) treatment (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.76-5.23) and successful reperfusion (OR 4.92, 95% CI 1.15-21.11), while the effect of time between symptom onset and reperfusion seemed to be small. CONCLUSIONS: Acute reperfusion strategies in BAO are common in daily practice and can achieve good rates of successful reperfusion, neurological improvement and good functional outcome. Our data suggest that, in addition to IVT treatment, successful and, in particular, complete reperfusion (mTICI3) strongly predicts good outcome, while time from symptom onset seemed to have a lower impact.
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Arteriopatias Oclusivas , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Artéria Basilar , AVC Isquêmico/cirurgia , AVC Isquêmico/etiologia , Resultado do Tratamento , Estudos Retrospectivos , Acidente Vascular Cerebral/cirurgia , Acidente Vascular Cerebral/diagnóstico , Trombectomia , Arteriopatias Oclusivas/cirurgia , Arteriopatias Oclusivas/etiologia , Sistema de Registros , Procedimentos Endovasculares/efeitos adversosRESUMO
BACKGROUND: Although of high individual and socioeconomic relevance, a reliable prediction model for the prognosis of juvenile stroke (18-55 years) is missing. Therefore, the study presented in this protocol aims to prospectively validate the discriminatory power of a prediction score for the 3 months functional outcome after juvenile stroke or transient ischemic attack (TIA) that has been derived from an independent retrospective study using standard clinical workup data. METHODS: PREDICT-Juvenile-Stroke is a multi-centre (n = 4) prospective observational cohort study collecting standard clinical workup data and data on treatment success at 3 months after acute ischemic stroke or TIA that aims to validate a new prediction score for juvenile stroke. The prediction score has been developed upon single center retrospective analysis of 340 juvenile stroke patients. The score determines the patient's individual probability for treatment success defined by a modified Rankin Scale (mRS) 0-2 or return to pre-stroke baseline mRS 3 months after stroke or TIA. This probability will be compared to the observed clinical outcome at 3 months using the area under the receiver operating characteristic curve. The primary endpoint is to validate the clinical potential of the new prediction score for a favourable outcome 3 months after juvenile stroke or TIA. Secondary outcomes are to determine to what extent predictive factors in juvenile stroke or TIA patients differ from those in older patients and to determine the predictive accuracy of the juvenile stroke prediction score on other clinical and paraclinical endpoints. A minimum of 430 juvenile patients (< 55 years) with acute ischemic stroke or TIA, and the same number of older patients will be enrolled for the prospective validation study. DISCUSSION: The juvenile stroke prediction score has the potential to enable personalisation of counselling, provision of appropriate information regarding the prognosis and identification of patients who benefit from specific treatments. TRIAL REGISTRATION: The study has been registered at https://drks.de on March 31, 2022 ( DRKS00024407 ).
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Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Adulto Jovem , Idoso , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/epidemiologia , Ataque Isquêmico Transitório/complicações , AVC Isquêmico/complicações , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/complicações , Prognóstico , Valor Preditivo dos Testes , Estudos Observacionais como AssuntoRESUMO
Knowledge of the physiological endolymphatic space (ELS) is necessary to estimate endolymphatic hydrops (ELH) in patients with vestibulocochlear syndromes. Therefore, the current study investigated age-dependent changes in the ELS of participants with normal vestibulocochlear testing. Sixty-four ears of 32 participants with normal vestibulocochlear testing aged between 21 and 75 years (45.8 ± 17.2 years, 20 females, 30 right-handed, two left-handed) were examined by intravenous delayed gadolinium-enhanced magnetic resonance imaging of the inner ear (iMRI). Clinical diagnostics included neuro-otological assessment, video-oculography during caloric stimulation, and head-impulse test. iMRI data analysis provided semi-quantitative visual grading and automatic algorithmic quantitative segmentation of ELS volume (3D, mm3) using a deep learning-based segmentation of the inner ear's total fluid space (TFS) and volumetric local thresholding, as described earlier. As a result, following a 4-point ordinal scale, a mild ELH (grade 1) was found in 21/64 (32.8%) ears uni- or bilaterally in either cochlear, vestibulum, or both. Age and ELS were found to be positively correlated for the inner ear (r(64) = 0.33, p < 0.01), and vestibulum (r(64) = 0.25, p < 0.05). For the cochlea, the values correlated positively without reaching significance (r(64) = 0.21). In conclusion, age-dependent increases of the ELS should be considered when evaluating potential ELH in single subjects and statistical group comparisons.
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Orelha Interna , Hidropisia Endolinfática , Feminino , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Imageamento Tridimensional , Imageamento por Ressonância Magnética/métodos , SíndromeRESUMO
OBJECTIVE: Approximately 20% of strokes are embolic strokes of undetermined source (ESUS). Undetected atrial fibrillation (AF) remains an important cause. Yet, oral anticoagulation in unselected ESUS patients failed in secondary stroke prevention. Guidance on effective AF detection is lacking. Here, we introduce a novel, non-invasive AF risk assessment after ESUS. METHODS: Catch-Up ESUS is an investigator-initiated, observational cohort study conducted between 2018 and 2019 at the Munich University Hospital. Besides clinical characteristics, patients received ≥72 h digital electrocardiogram recordings to generate the rhythm irregularity burden. Uni- and multivariable regression models predicted the primary endpoint of incident AF, ascertained by standardized follow-up including implantable cardiac monitors. Predictors included the novel rhythm irregularity burden constructed from digital electrocardiogram recordings. We independently validated our model in ESUS patients from the University Hospital Tübingen, Germany. RESULTS: A total of 297 ESUS patients were followed for 15.6 ± 7.6 months. Incident AF (46 patients, 15.4%) occurred after a median of 105 days (25th to 75th percentile 31-33 days). Secondary outcomes were recurrent stroke in 7.7% and death in 6.1%. Multivariable-adjusted analyses identified the rhythm irregularity burden as the strongest AF-predictor (hazard ratio 3.12, 95% confidence interval 1.62-5.80, p < 0001) while accounting for the known risk factors age, CHA2 DS2 -VASc-Score, and NT-proBNP. Independent validation confirmed the rhythm irregularity burden as the most significant AF-predictor (hazard ratio 2.20, 95% confidence interval 1.45-3.33, p < 0001). INTERPRETATION: The novel, non-invasive, electrocardiogram-based rhythm irregularity burden may help adjudicating AF risk after ESUS, and subsequently guide AF-detection after ESUS. Clinical trials need to clarify if high-AF risk patients benefit from tailored secondary stroke prevention. ANN NEUROL 2023;93:479-488.
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Fibrilação Atrial , AVC Embólico , Embolia Intracraniana , Acidente Vascular Cerebral , Humanos , Fibrilação Atrial/complicações , AVC Embólico/complicações , Medição de Risco , Fatores de Risco , Embolia Intracraniana/etiologiaRESUMO
Combining magnetic resonance imaging (MRI) sequences that permit the determination of vestibular nerve angulation (NA = change of nerve caliber or direction), structural nerve integrity via diffusion tensor imaging (DTI), and exclusion of endolymphatic hydrops (ELH) via delayed gadolinium-enhanced MRI of the inner ear (iMRI) could increase the diagnostic accuracy in patients with vestibular paroxysmia (VP). Thirty-six participants were examined, 18 with VP (52.6 ± 18.1 years) and 18 age-matched with normal vestibulocochlear testing (NP 50.3 ± 16.5 years). This study investigated whether (i) NA, (ii) DTI changes, or (iii) ELH occur in VP, and (iv) to what extent said parameters relate. Methods included vestibulocochlear testing and MRI data analyses for neurovascular compression (NVC) and NA verification, DTI and ELS quantification. As a result, (i) NA increased NVC specificity. (ii) DTI structural integrity was reduced on the side affected by VP (p < 0.05). (iii) 61.1% VP showed mild ELH and higher asymmetry indices than NP (p > 0.05). (iv) "Disease duration" and "total number of attacks" correlated with the decreased structural integrity of the affected nerve in DTI (p < 0.001). NVC distance within the nerve's root-entry zone correlated with nerve function (Roh = 0.72, p < 0.001), nerve integrity loss (Roh = - 0.638, p < 0.001), and ELS volume (Roh = - 0.604, p < 0.001) in VP. In conclusion, this study is the first to link eighth cranial nerve function, microstructure, and ELS changes in VP to clinical features and increased vulnerability of NVC in the root-entry zone. Combined MRI with NVC or NA verification, DTI and ELS quantification increased the diagnostic accuracy at group-level but did not suffice to diagnose VP on a single-subject level due to individual variability and lack of diagnostic specificity.
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Hidropisia Endolinfática , Vestíbulo do Labirinto , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Imagem de Tensor de Difusão , Nervo Vestibular , Hidropisia Endolinfática/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodosRESUMO
INTRODUCTION: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. METHODS: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. RESULTS: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. DISCUSSION: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/patologia , Disfunção Cognitiva/genética , Exame NeurológicoRESUMO
OBJECTIVE: The aim of the study was to deepen our insights into central compensatory processes of brain networks in patients with cerebellar ataxia (CA) before and with treatment with acetyl-DL-leucine (AL) by means of resting-state [18F]-FDG-PET brain imaging. METHODS: Retrospective analyses of [18F]-FDG-PET data in 22 patients with CA (with vestibular and ocular motor disturbances) of different etiologies who were scanned before (PET A) and on AL treatment (PET B). Group subtraction analyses, e.g., for responders and non-responders, comparisons with healthy controls and correlation analyses of regional cerebral glucose metabolism (rCGM) with symptom duration, ataxia (SARA) and quality of life (QoL) scores were calculated. RESULTS: Prior to treatment rCGM was consistently downregulated at the cerebellar level and increased in multisensory cortical areas, e.g., somatosensory, primary and secondary visual (including V5, precuneus), secondary vestibular (temporal gyrus, anterior insula), and premotor/supplementary motor areas. With AL (PET B vs. A) cerebellar hypometabolism was deepened and sensorimotor hypermetabolism increased only in responders with clinical benefit, but not for the non-responders and the whole CA group. A positive correlation of ataxia improvement with rCGM was found in visual and vestibular cortices, a negative correlation in cerebellar and brainstem areas. QoL showed a positive correlation with rCGM in the cerebellum and symptom duration in premotor and somatosensory areas. CONCLUSIONS: Central compensatory processes in CA mainly involve multisensory visual, vestibular, and somatosensory networks as well as premotor/primary motor areas at the cortical level. The enhanced divergence of cortical sensorimotor up- and cerebellar downregulation with AL in responders could reflect amplification of inhibitory cerebellar mechanisms.
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Ataxia Cerebelar , Humanos , Ataxia Cerebelar/diagnóstico por imagem , Fluordesoxiglucose F18 , Qualidade de Vida , Estudos Retrospectivos , AtaxiaRESUMO
This cohort study aims to evaluate the predictive validity of multimodal clinical assessment and quantitative measures of in- and off-laboratory mobility for fall-risk estimation in patients with cerebellar ataxia (CA).Occurrence, severity, and consequences of falling were prospectively assessed for 6 months in 93 patients with hereditary (N = 36) and sporadic or secondary (N = 57) forms of CA and 63 healthy controls. Participants completed a multimodal clinical and functional fall risk assessment, in-laboratory gait examination, and a 2-week inertial sensor-based daily mobility monitoring. Multivariate logistic regression analyses were performed to evaluate the predictive capacity of all clinical and in- and off-laboratory mobility measures with respect to fall (1) status (non-faller vs. faller), (2) frequency (occasional vs. frequent falls), and (3) severity (benign vs. injurious fall) of patients. 64% of patients experienced one or recurrent falls and 65% of these severe fall-related injuries during prospective assessment. Mobility impairments in patients corresponded to a mild-to-moderate ataxic gait disorder. Patients' fall status and frequency could be reliably predicted (78% and 81% accuracy, respectively), primarily based on their retrospective fall status. Clinical scoring of ataxic symptoms and in- and off-laboratory gait and mobility measures improved classification and provided unique information for the prediction of fall severity (84% accuracy).These results encourage a stepwise approach for fall risk assessment in patients with CA: fall history-taking readily and reliably informs the clinician about patients' general fall risk. Clinical scoring and instrument-based mobility measures provide further in-depth information on the risk of recurrent and injurious falling.
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Ataxia Cerebelar , Humanos , Estudos de Coortes , Estudos Prospectivos , Estudos Retrospectivos , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/complicações , Medição de Risco/métodos , Marcha , Fatores de RiscoRESUMO
Parkinson´s disease (PD) pathology progresses throughout the nervous system. Whereas motor symptoms are always present, there is a high variability in the prevalence of non-motor symptoms. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed-alpha-synuclein (ASYN) on the endogenous ASYN. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology in vivo and in vitro and compared the effect of endocytosed-ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type and ASYN-KO mice. Our results show that, in vivo, pathology progression did not occur in the absence of endogenous ASYN. Remarkably, the damage caused by endocytosed-ASYN, rotenone or paraquat was independent from endogenous ASYN and related to the alteration of the host´s mitochondrial membrane potential. Dopaminergic neurons were very sensitive to these noxae compared to other neuronal subtypes. These results suggest that ASYN-mitochondrial interactions play a major role in initiating the pathological process in the host neuron and endogenous ASYN is essential for the transsynaptical transmission of the pathology. Our results also suggest that protecting mitochondrial function is a valid primary therapeutic target.
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Doença de Parkinson , alfa-Sinucleína , Camundongos , Animais , Rotenona/uso terapêutico , Paraquat , Doença de Parkinson/patologia , Neurônios Dopaminérgicos/patologiaRESUMO
Visually-induced self-motion perception (vection) relies on interaction of the visual and vestibular systems. Neuroimaging studies have identified a lateralization of the thalamo-cortical multisensory vestibular network, with left-handers exhibiting a dominance of the left hemisphere and right-handers exhibiting a dominance of the right hemisphere. Using electroencephalography (EEG), we compare the early processing of a vection-consistent visual motion stimulus against a vection-inconsistent stimulus, to investigate the temporal activation of the vection network by visual motion stimulation and the lateralization of these processes in left- versus right-handers. In both groups, vection-consistent stimulation evoked attenuated central event-related potentials (ERPs) in an early (160-220 ms) and a late (260-300 ms) time window. Differences in estimated source activity were found across visual, sensorimotor, and multisensory vestibular cortex in the early window, and were observed primarily in the posterior cingulate, retrosplenial cortex, and precuneus in the late window. Group comparisons revealed a larger ERP condition difference (i.e. vection-consistent stimulation minus vection-inconsistent stimulation) in left-handers, which was accompanied by group differences in the cingulate sulcus visual (CSv) area. Together, these results suggest that handedness may influence ERP responses and activity in area CSv during vection-consistent and vection-inconsistent visual motion stimulation.