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1.
Exp Brain Res ; 241(6): 1523-1531, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37097301

RESUMO

Motion sickness is a physiological condition that negatively impacts a person's comfort and will be an emerging condition in autonomous vehicles without proper countermeasures. The vestibular system plays a key role in the origin of motion sickness. Understanding the susceptibility and (mal) adaptive mechanisms of the highly integrated vestibular system is a prerequisite for the development of countermeasures. We hypothesize a differential association between motion sickness and vestibular function in healthy individuals with and without susceptibility for motion sickness. We quantified vestibular function by measuring the high-frequency vestibulo-ocular reflex (VOR) using video head impulse testing (vHIT) in 17 healthy volunteers before and after a 11 min motion sickness-inducing naturalistic stop-and-go car ride on a test track (Dekra Test Oval, Klettwitz, Germany). The cohort was classified as motion sickness susceptible (n = 11) and non-susceptible (n = 6). Six (out of 11) susceptible participants developed nausea symptoms, while a total of nine participants were free of these symptoms. The VOR gain (1) did not differ significantly between participant groups with (n = 8) and without motion sickness symptoms (n = 9), (2) did not differ significantly in the factor time before and after the car ride, and showed no interaction between symptom groups and time, as indicated by a repeated measures ANOVA (F(1,15) = 2.19, p = 0.16. Bayesian inference confirmed that there was "anecdotal evidence" for equality of gain rather than difference across groups and time (BF10 < 0.77). Our results suggest that individual differences in VOR measures or adaptation to motion sickness provocative stimuli during naturalistic stop-and-go driving cannot predict motion sickness susceptibility or the likelihood of developing motion sickness.


Assuntos
Enjoo devido ao Movimento , Reflexo Vestíbulo-Ocular , Humanos , Reflexo Vestíbulo-Ocular/fisiologia , Automóveis , Teorema de Bayes , Suscetibilidade a Doenças , Enjoo devido ao Movimento/etiologia , Teste do Impulso da Cabeça
2.
Hum Brain Mapp ; 41(6): 1416-1434, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31789477

RESUMO

We investigated the brain atrophy distribution pattern and rate of regional atrophy change in Parkinson's disease (PD) in association with the cognitive status to identify the morphological characteristics of conversion to mild cognitive impairment (MCI) and dementia (PDD). T1-weighted longitudinal 3T MRI data (up to four follow-up assessments) from neuropsychologically well-characterized advanced PD patients (n = 172, 8.9 years disease duration) and healthy elderly controls (n = 85) enrolled in the LANDSCAPE study were longitudinally analyzed using a linear mixed effect model and atlas-based volumetry and cortical thickness measures. At baseline, PD patients presented with cerebral atrophy and cortical thinning including striatum, temporoparietal regions, and primary/premotor cortex. The atrophy was already observed in "cognitively normal" PD patients (PD-N) and was considerably more pronounced in cognitively impaired PD patients. Linear mixed effect modeling revealed almost similar rates of atrophy change in PD and controls. The group comparison at baseline between those PD-N whose cognitive performance remained stable (n = 42) and those PD-N patients who converted to MCI/PDD ("converter" cPD-N, n = 26) indicated suggested cortical thinning in the anterior cingulate cortex in cPD-N patients which was correlated with cognitive performance. Our results suggest that cortical brain atrophy has been already expanded in advanced PD patients without overt cognitive deficits while atrophy progression in late disease did not differ from "normal" aging regardless of the cognitive status. It appears that cortical atrophy begins early and progresses already in the initial disease stages emphasizing the need for therapeutic interventions already at disease onset.


Assuntos
Cognição , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/psicologia , Idoso , Atlas como Assunto , Atrofia , Córtex Cerebral/diagnóstico por imagem , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Demência/patologia , Demência/psicologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Modelos Lineares , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos
3.
J Neurol Neurosurg Psychiatry ; 90(2): 157-164, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30309882

RESUMO

OBJECTIVE: To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS). METHODS: This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology. RESULTS: Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time. CONCLUSIONS: Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.


Assuntos
Esclerose Lateral Amiotrófica/sangue , Esclerose Lateral Amiotrófica/diagnóstico , Proteínas de Neurofilamentos/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
4.
Mov Disord ; 34(10): 1566-1570, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31433875

RESUMO

BACKGROUND: The pathophysiology of the hypothalamic involvement in Parkinson's disease (PD) is not well understood. The objective of this study was the quantification of hypothalamic volumes in vivo in PD. METHODS: High-resolution T1 -weighted magnetic resonance imaging (MRI) data from 232 individuals with PD and 130 healthy non-PD individuals were used for quantification of the hypothalamic volumes. RESULTS: The hypothalamus in PD was not atrophied, as indicated by volumetric analyses in the prospectively collected subcohort (30 PD, V = 921 ± 78 mm3 vs 30 non-PD, V = 917 ± 67 mm3 ; P = 0.850) and validated in a large cohort (202 PD, V = 925 ± 88 mm3 vs 100 non-PD, V = 932 ± 114 mm3 ; P = 0.602). CONCLUSIONS: Hypothalamic involvement in PD as shown by a large body of histopathological evidence does not appear to be detectable by MRI-based volumetric quantification. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Atrofia/patologia , Hipotálamo/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Transtornos Parkinsonianos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Hipotálamo/metabolismo , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
5.
Int J Neuropsychopharmacol ; 21(7): 705-715, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29554302

RESUMO

Background: Low dopamine D2/3 receptor availability in the nucleus accumbens shell is associated with highly impulsive behavior in rats as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the nucleus accumbens is equally linked to intolerance for delayed rewards, a related form of impulsivity. Methods: We investigated the relationship between D2/3 receptor availability in the nucleus accumbens and impulsivity in a delay-discounting task where animals must choose between immediate, small-magnitude rewards and delayed, larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high and low impulsivity using in vivo [18F]fallypride positron emission tomography and ex vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. Results: Delay-discounting task impulsivity was inversely related to D2/3 receptor availability in the nucleus accumbens core but not the dorsal striatum, with higher D2/3 binding in the nucleus accumbens shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high- vs low-impulsive rats. Conclusions: We conclude that delay-discounting task impulsivity is associated with low D2/3 receptor binding in the nucleus accumbens core. Thus, two related forms of waiting impulsivity-premature responding and delay intolerance in a delay-of-reward task-implicate an involvement of D2/3 receptor availability in the nucleus accumbens shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction, and other psychiatric disorders.


Assuntos
Comportamento Animal/fisiologia , Córtex Cerebral/fisiologia , Conectoma/métodos , Corpo Estriado/fisiologia , Desvalorização pelo Atraso/fisiologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Recompensa , Animais , Autorradiografia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Ratos
6.
J Neurol Neurosurg Psychiatry ; 89(4): 374-381, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29101254

RESUMO

OBJECTIVE: Neuropathological studies in amyotrophic lateral sclerosis (ALS) have shown a dissemination in a regional sequence in four anatomically defined patterns. The aim of this retrospective study was to see whether longitudinal diffusion tensor imaging (DTI) data support the pathological findings. METHODS: The application of DTI analysis to fibre structures that are prone to be involved at each neuropathological pattern of ALS was performed in a monocentre sample of 67 patients with ALS and 31 controls that obtained at least one follow-up scan after a median of 6 months. RESULTS: At the group level, longitudinal ALS data showed significant differences for the stage-related tract systems. At the individual level, 27% of the longitudinally scanned patients with ALS showed an increase in ALS stage, while the remaining were stable or were at the highest ALS stage. Longitudinal fractional anisotropy changes in the respective tract systems correlated significantly with the slope of the revised ALS functional rating scale. INTERPRETATION: The DTI-based protocol was able to image the disease patterns of ALS in vivo cross-sectionally and longitudinally, in support of DTI as a technical marker to image ALS stages.


Assuntos
Esclerose Lateral Amiotrófica/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Via Perfurante/diagnóstico por imagem , Ponte/diagnóstico por imagem , Tratos Piramidais/diagnóstico por imagem , Núcleo Rubro/diagnóstico por imagem , Idoso , Esclerose Lateral Amiotrófica/patologia , Anisotropia , Estudos de Casos e Controles , Córtex Cerebral/patologia , Corpo Estriado/patologia , Imagem de Tensor de Difusão , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Via Perfurante/patologia , Ponte/patologia , Tratos Piramidais/patologia , Núcleo Rubro/patologia , Estudos Retrospectivos
7.
J Neurol Neurosurg Psychiatry ; 88(12): 1033-1041, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28596251

RESUMO

OBJECTIVE: Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers. METHODS: High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI). RESULTS: We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (-21.8%, p<0.0001) and symptomatic ALS mutation carriers (-13.4%, p<0.001). The atrophy in patients with sporadic ALS was observed in both the anterior (-27.6% p<0.0001) and the posterior parts of the hypothalamus (-17.7%, p<0.0001). Notably, this atrophy was also observed in presymptomatic ALS mutation carriers (-15.5%, p<0.001) and was unrelated to whole brain volume atrophy or disease stage as assessed using DTI or functional status. Hypothalamic volume was correlated with body mass index (BMI) in patients with sporadic ALS (p=0.0434, ρ=+0.1579), and this correlation was much stronger in patients with familial ALS (fALS) (p=0.0060, ρ=+0.6053). Anterior hypothalamic volume was correlated with age at onset, but not with survival after MRI. CONCLUSIONS: Hypothalamus is atrophied in ALS, even in premorbid stages, and correlates with BMI, especially in fALS. Decreased anterior hypothalamic volume is associated with earlier onset of disease.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Hipotálamo/patologia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Atrofia , Índice de Massa Corporal , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Coortes , Imagem de Tensor de Difusão , Feminino , Humanos , Hipotálamo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Mov Disord ; 32(7): 1006-1015, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28544256

RESUMO

BACKGROUND: The topography of functional network changes in progressive supranuclear palsy can be mapped by intrinsic functional connectivity MRI. The objective of this study was to study functional connectivity and its clinical and behavioral correlates in dedicated networks comprising the cognition-related default mode and the motor and midbrain functional networks in patients with PSP. METHODS: Whole-brain-based "resting-state" functional MRI and high-resolution T1-weighted magnetic resonance imaging data together with neuropsychological and video-oculographic data from 34 PSP patients (22 with Richardson subtype and 12 with parkinsonian subtype) and 35 matched healthy controls were subjected to network-based functional connectivity and voxel-based morphometry analysis. RESULTS: After correction for global patterns of brain atrophy, the group comparison between PSP patients and controls revealed significantly decreased functional connectivity (P < 0.05, corrected) in the prefrontal cortex, which was significantly correlated with cognitive performance (P = 0.006). Of note, midbrain network connectivity in PSP patients showed increased connectivity with the thalamus, on the one hand, whereas, on the other hand, lower functional connectivity within the midbrain was significantly correlated with vertical gaze impairment, as quantified by video-oculography (P = 0.004). PSP Richardson subtype showed significantly increased functional motor network connectivity with the medial prefrontal gyrus. CONCLUSIONS: PSP-associated neurodegeneration was attributed to both decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (ie, dementia severity and gaze palsy), whereas the pattern of increased functional connectivity may be a potential adaptive mechanism. © 2017 International Parkinson and Movement Disorder Society.


Assuntos
Transtornos Cognitivos/fisiopatologia , Conectoma/métodos , Mesencéfalo , Córtex Pré-Frontal , Paralisia Supranuclear Progressiva , Tálamo , Idoso , Idoso de 80 Anos ou mais , Atrofia/patologia , Transtornos Cognitivos/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/patologia , Mesencéfalo/fisiopatologia , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/patologia , Tálamo/fisiopatologia
9.
Neurodegener Dis ; 17(4-5): 117-126, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28268209

RESUMO

BACKGROUND: One common feature of neurodegenerative parkinsonism including Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) is altered eye movement control. Characteristic regional structural atrophy patterns in MRI can be observed in PD, MSA, and PSP. OBJECTIVE: To investigate the association between eye movement disturbances and regional brain atrophy in patients with PD, MSA, and PSP. METHODS: High-resolution 3-dimensional T1-weighted MRI images and video-oculographic recordings (EyeLink®) were obtained from 39 PD, 32 PSP, and 18 MSA patients and 24 matched healthy control subjects. Automatic regional volumetric assessment was performed using atlas-based volumetry (ABV). RESULTS: The prevalence of saccadic intrusions as a measure of inhibitory control was significantly increased in PD patients compared to controls (p < 0.001) and negatively correlated with whole brain volume, cerebral brain volume, and occipital lobe volume (p = 0.0057, p = 0.0049, and p = 0.0059, respectively; all p values are false discovery rate corrected). In MSA, smooth pursuit was disturbed by characteristic "catch-up" saccades (p < 0.001) and it was significantly correlated with cerebellar volume (p = 0.004) and pontine volume (p < 0.001). The hallmark of PSP was pathologically slowed vertical peak eye velocities (p < 0.001); the lower the peak eye velocity, the more marked midbrain atrophy (p = 0.007). CONCLUSIONS: Foci of regional atrophy correlated with disease-specific eye movement alterations in all investigated parkinsonian syndromes. Oculomotor impairment in PD, predominantly the result of executive dysfunction, was linked to cerebral atrophy. Impairment in the corresponding oculomotor pathways was associated with atrophy of pontocerebellar oculomotor structures in MSA and midbrain atrophy in PSP.


Assuntos
Encéfalo/patologia , Atrofia de Múltiplos Sistemas/complicações , Transtornos da Motilidade Ocular/etiologia , Transtornos da Motilidade Ocular/patologia , Doença de Parkinson/complicações , Paralisia Supranuclear Progressiva/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia/diagnóstico por imagem , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Eletroculografia , Movimentos Oculares , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/diagnóstico por imagem
11.
Neurology ; 101(6): 264-269, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-36997323

RESUMO

OBJECTIVES: Up to 50% of patients with amyotrophic lateral sclerosis (ALS) present with cognitive problems and behavioral dysfunctions including recognition of human faces presenting different emotions. We investigated whether impaired processing of emotional faces is associated with abnormal scan paths during visual exploration. METHODS: Cognitively unimpaired patients with ALS (n = 45) and matched healthy controls (n = 37) underwent neuropsychological assessment and video-based eye tracking. Eye movements were recorded while participants visually explored faces expressing different emotions (neutral, disgusted, happy, fearful, and sad) and houses mimicking faces. RESULTS: Compared with controls, patients with ALS fixated significantly longer to regions which are not relevant for emotional information when faces expressed fear (p = 0.007) and disgust (p = 0.006), whereas the eyes received less attention in faces expressing disgust (p = 0.041). Fixation duration in any area of interest was not significantly associated with the cognitive state or clinical symptoms of disease severity. DISCUSSION: In cognitively unimpaired patients with ALS, altered gaze patterns while visually exploring faces expressing different emotions might derive from impaired top-down attentional control with possible involvement of subliminal frontotemporal areas. This may account for indistinctness in emotion recognition reported in previous studies because nonsalient features retrieve more attention compared with salient areas. Current findings may indicate distinct emotion processing dysfunction of ALS pathology, which may be different from, for example, executive dysfunction.


Assuntos
Esclerose Lateral Amiotrófica , Humanos , Emoções , Reconhecimento Psicológico , Olho , Movimentos Oculares , Expressão Facial
12.
Neurobiol Aging ; 109: 31-42, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34649002

RESUMO

Recently, it was shown that patients with Parkinson's disease (PD) who exhibit an "Alzheimer's disease (AD)-like" pattern of brain atrophy are at greater risk for future cognitive decline. This study aimed to investigate whether this association is domain-specific and whether atrophy associated with brain aging also relates to cognitive impairment in PD. SPARE-AD, an MRI index capturing AD-like atrophy, and atrophy-based estimates of brain age were computed from longitudinal structural imaging data of 178 PD patients and 84 healthy subjects from the LANDSCAPE cohort. All patients underwent an extensive neuropsychological test battery. Patients diagnosed with mild cognitive impairment or dementia were found to have higher SPARE-AD scores as compared to patients with normal cognition and healthy controls. All patient groups showed increased brain age. SPARE-AD predicted impairment in memory, language and executive functions, whereas advanced brain age was associated with deficits in attention and working memory. Data suggest that SPARE-AD and brain age are differentially related to domain-specific cognitive decline in PD. The underlying pathomechanisms remain to be determined.


Assuntos
Envelhecimento/patologia , Envelhecimento/psicologia , Encéfalo/patologia , Cognição , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Doença de Parkinson/patologia , Doença de Parkinson/psicologia , Idoso , Doença de Alzheimer/patologia , Atrofia , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico
13.
Orphanet J Rare Dis ; 15(1): 349, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334373

RESUMO

BACKGROUND: Neurological forms of Gaucher disease, the inherited disorder of ß-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood-brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of 'type 3' Gaucher disease. METHODS: We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. RESULTS: We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. CONCLUSIONS: This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.


Assuntos
Doença de Gaucher , Biomarcadores , Movimentos Oculares , Doença de Gaucher/diagnóstico , Doença de Gaucher/genética , Glucosilceramidase/genética , Humanos , Fenótipo
14.
Neuroimage Clin ; 24: 101979, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31421506

RESUMO

BACKGROUND: There is an ongoing debate about the concept of restricted phenotypes of amyotrophic lateral sclerosis (ALS), including progressive bulbar palsy (PBP). OBJECTIVE: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from PBP patients using a hypothesis-guided tract-of-interest-based approach (compared with 'classical' ALS patients and controls) to identify in vivo microstructural changes according to the neuropathologically defined ALS-related corticoefferent tract pathology. METHODS: DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 23 PBP and 23 ALS patients vs 23 matched controls. RESULTS: The analysis of white matter integrity demonstrated regional FA reductions along the CST and also in frontal and prefrontal brain areas both in PBP patients and ALS patients with additional regional FA reduction in the pons of the PBP group. In the tract-specific analysis according to the neuropathological ALS-staging pattern, PBP and ALS patients showed identical significant alterations of ALS-related tract systems when compared with controls. CONCLUSIONS: The DTI study including the tract-of-interest-based analysis showed the same microstructural corticoefferent involvement patterns in PBP patients as in ALS, which supports the hypothesis that PBP is a phenotypical variant of ALS.


Assuntos
Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Paralisia Bulbar Progressiva/diagnóstico por imagem , Paralisia Bulbar Progressiva/patologia , Imagem de Tensor de Difusão/métodos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
J Eye Mov Res ; 12(6)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-33828758

RESUMO

The attempt to quietly fixate at a small visual object is continuously interrupted by a variety of fixational eye movements comprising, among others, a continuum of saccadic intrusions (SI) which range in size from microsaccades with amplitudes ≤0.25° to larger refixation saccades of up to about 2°. The size and frequency of SI varies considerably among individuals and is known to increase in neurodegenerative diseases such as progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). However, studies of ALS disagree whether also the frequency of SI increases. We undertook an analysis of SI in 119 ALS patients and 47 age-matched healthy controls whose eye movements during fixation and tests of executive functions (e.g antisaccades) had been recorded by video-oculography according to standardised procedures. SI were categorised according to their spatio-temporal patterns as stair case, back-and-forth and square wave jerks (a subcategory of back-and-forth). The SI of patients and controls were qualitatively similar (same direction preferences, similar differences between patterns), but were enlarged in ALS. Notably however, no increase of SI frequency could be demonstrated. Yet, there were clear correlations with parameters such as eye blink rate or errors in a delayed saccade task that suggest an impairment of inhibitory mechanisms, in keeping with the notion of a frontal dysfunction in ALS. However, it remains unclear how the impairment of inhibitory mechanisms in ALS could selectively increase the amplitude of intrusions without changing their frequency of occurrence.

16.
Ther Adv Neurol Disord ; 12: 1756286419843447, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205489

RESUMO

BACKGROUND: The nonmotor symptom spectrum of Parkinson's disease (PD) includes progressive cognitive decline mainly in late stages of the disease. The aim of this study was to map the patterns of altered structural connectivity of patients with PD with different cognitive profiles ranging from cognitively unimpaired to PD-associated dementia. METHODS: Diffusion tensor imaging and neuropsychological data from the observational multicentre LANDSCAPE study were analyzed. A total of 134 patients with PD with normal cognitive function (56 PD-N), mild cognitive impairment (67 PD-MCI), and dementia (11 PD-D) as well as 72 healthy controls were subjected to whole-brain-based fractional anisotropy mapping and covariance analysis with cognitive performance measures. RESULTS: Structural data indicated subtle changes in the corpus callosum and thalamic radiation in PD-N, whereas severe white matter impairment was observed in both PD-MCI and PD-D patients including anterior and inferior fronto-occipital, uncinate, insular cortices, superior longitudinal fasciculi, corona radiata, and the body of the corpus callosum. These regional alterations were demonstrated for PD-MCI and were more pronounced in PD-D. The pattern of involved regions was significantly correlated with the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score. CONCLUSIONS: The findings in PD-N suggest impaired cross-hemispherical white matter connectivity that can apparently be compensated for. More pronounced involvement of the corpus callosum as demonstrated for PD-MCI together with affection of fronto-parieto-temporal structural connectivity seems to lead to gradual disruption of cognition-related cortico-cortical networks and to be associated with the onset of overt cognitive deficits. The increase of regional white matter damage appears to be associated with the development of PD-associated dementia.

17.
Transl Neurodegener ; 8: 27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485326

RESUMO

BACKGROUND: In vivo diffusion tensor imaging (DTI) of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis (ALS). METHODS: Ten mice with TDP-43 G298S overexpression under control of the Thy1.2 promoter and 10 wild type (wt) underwent longitudinal DTI scans at 11.7 T, including one baseline and one follow-up scan with an interval of about 5 months. Whole brain-based spatial statistics (WBSS) of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43 G298S mice compared to wt at the cohort level. Results were supplemented by tractwise fractional anisotropy statistics (TFAS) and histological evaluation of motor cortex for signs of neuronal loss. RESULTS: Alterations at the cohort level in TDP-43 G298S mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract. Neuronal loss in layer V of motor cortex was detected in TDP-43 G298S at the later (but not at the earlier) timepoint compared to wt. CONCLUSION: DTI mapping of TDP-43 G298S mice demonstrated progression in motor areas M1/M2. WBSS and TFAS are useful techniques to localize TDP-43 G298S associated alterations over time in this ALS mouse model, as a biological marker.

18.
Neurobiol Aging ; 74: 235.e5-235.e8, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30342765

RESUMO

Intermediate-length ATXN2 CAG repeats are a risk factor for amyotrophic lateral sclerosis (ALS). Here we report on a female patient with heterozygous repeat expansion mutation in the CACNA1A gene presenting with a pure ALS syndrome while her father, who also carries that CACNA1A mutation, suffers from a classical spinocerebellar ataxia type 6. Hypothesizing that CACNA1A CAG repeat expansions could be a monogenic cause for familial ALS (fALS), we analyzed the CAG repeat lengths in CACNA1A in a large cohort of genetically unexplained patients with fALS. Our results indicate that CAG repeat expansion mutations in CACNA1A are not a frequent monogenic cause of fALS but could phenotypically present as ALS in rare instances.


Assuntos
Esclerose Lateral Amiotrófica/genética , Canais de Cálcio/genética , Expansão das Repetições de Trinucleotídeos/genética , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Ataxias Espinocerebelares/genética , Sequenciamento do Exoma
20.
Front Neurol ; 9: 319, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867729

RESUMO

The investigation of the human oculomotor system by eye movement recordings provides an approach to behavior and its alterations in disease. The neurodegenerative process underlying parkinsonian syndromes, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA) changes structural and functional brain organization, and thus affects eye movement control in a characteristic manner. Video-oculography has been established as a non-invasive recording device for eye movements, and systematic investigations of eye movement control in a clinical framework have emerged as a functional diagnostic tool in neurodegenerative parkinsonism. Disease-specific brain atrophy in parkinsonian syndromes has been reported for decades, these findings were refined by studies utilizing diffusion tensor imaging (DTI) and task-based/task-free functional MRI-both MRI techniques revealed disease-specific patterns of altered structural and functional brain organization. Here, characteristic disturbances of eye movement control in parkinsonian syndromes and their correlations with the structural and functional brain network alterations are reviewed. On this basis, we discuss the growing field of graph-based network analysis of the structural and functional connectome as a promising candidate for explaining abnormal phenotypes of eye movement control at the network level, both in health and in disease.

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