Papers by cristina Januario
Frontiers in Psychology, Mar 22, 2019
Introduction: Impairments in executive functions are common in neurogenetic disorders such as Hun... more Introduction: Impairments in executive functions are common in neurogenetic disorders such as Huntington's disease (HD) and are thought to significantly influence the patient's functional status. Reliable tools with higher ecological validity that can assess and predict the impact of executive dysfunction in daily-life performance are needed. This study aimed to develop and validate a novel non-immersive virtual reality task ("EcoKitchen") created with the purpose of capturing cognitive and functional changes shown by HD carriers without clinical manifestations of the disease (Premanifest HD), in a more realistic setting. Materials and Methods: We designed a virtual reality task with three blocks of increasing executive load. The performance of three groups (Controls, CTRL; Premanifest HD individuals, HP; Early Manifest HD patients, HD) was compared in four main components of the study protocol: the EcoKitchen; a subjective (selfreport) measure-"The Adults and Older Adults Functional Assessment Inventory (IAFAI)"; the "Behavioural Assessment of Dysexecutive Syndrome battery (BADS)"; and a conventional neuropsychological test battery. We also examined statistical associations between EcoKitchen and the other executive, functional and clinical measures used. Results: The HD group showed deficits in all the assessment methods used. In contrast, the HP group was only found to be impaired in the EcoKitchen task, particularly in the most cognitively demanding blocks, where they showed a higher number of errors compared to the CTRL group. Statistically significant correlations were identified between the EcoKitchen, measures of the other assessment tools, and HD clinical features. Discussion: The EcoKitchen task, developed as an ecological executive function assessment tool, was found to be sensitive to early deficits in this domain. Critically, in premanifest HD individuals, it identifies dysfunction prior to symptom onset. Further it adds a potential tool for diagnosis and management of the patients' real-life problems.
Journal of Neurology, Neurosurgery, and Psychiatry, Aug 29, 2012
Background Neuropsychiatric symptoms are common in Huntington's disease (HD), often preceding... more Background Neuropsychiatric symptoms are common in Huntington's disease (HD), often preceding motor symptoms onset. Apathy, believed to result from prefrontal-subcortical circuit dysfunction, is a frequent symptom with significant negative impact on patient's daily function. Aims Estimate the prevalence and clinical correlates of apathy in a population of HD patients at different stages of disease severity. Methods Evaluation of consecutive patients with genetically confirmed HD, followed at our department. Demographic, clinical and treatment data were collected. Marin's Apathy Evaluation Scale used for apathy assessment, Hamilton Depression Scale used for depression assessment and Montreal Cognitive Assessment (MOCA) used to evaluate cognitive impairment. Motor abnormalities quantified using UHDRS motor score. Statistical analysis with comparisons, correlations and regression analysis performed using SPSS software. p-values <0.05 considered statistically significant. Results 30 patients included, 56.7% female, with mean age of 51.1±17.8 years and mean disease duration of 5.5±5.7 years. Number of CAG repeats varied from 38 to 49 (median: 43). Mean UHDRS motor score was 27.6±19.6. Apathy diagnosed in 40%, depression in 16.7% and cognitive impairment in 63.3% of patients. Patients with apathy had significantly higher UHDRS motor scores (p=0.001) and lower MOCA scores (p<0.001). Apathy Evaluation Scale score significantly correlated with UHDRS motor score (r=0.54, p=0.001) and MOCA score (r=−0.65, p<0.001). Linear regression analysis revealed significant inverse correlation between apathy and MOCA scores (β=−0.62, p=0.023). Conclusions We identified a high prevalence of apathy in our patients and a strong correlation between apathy and cognitive dysfunction. Our results also suggest apathy and depression are independent entities with apathy being more prevalent in HD patients. Given the negative consequences of apathy, it must be considered an important target in HD treatment.
Background Impairments in functional cognition (cognitive skills underlying the performance of ev... more Background Impairments in functional cognition (cognitive skills underlying the performance of everyday activities) are frequent in Huntington and Parkinson Disease (HD and PD) and are thought to significantly influence the quality of life of patients. Assessment tools that can fully apprehend this domain are scarce. Aims This study aims to use novel subjective and objective assessment tools to capture the early cognitive and functional changes of HD and PD patients. Methods The performance of three groups (Controls, Early Manifest HD patients and Early Onset PD patients) was compared in two measures: ‘The Adults and Older Adults Functional Assessment Inventory – IAFAI’, a self-report assessment tool, and EcoKitchen, a non-immersive virtual reality task. Incapacity percentages (IAFAI) and Time and Error variables (EcoKitchen) were computed for each participant. Results In IAFAI, the two clinical groups reported higher percentages of incapacity in performing activities of daily living compared to controls. PD patients reported higher percentages of incapacity than HD patients. In EcoKitchen, HD patients showed an increased performance time and higher number of errors compared to controls. PD patients were also slower than controls, but no differences were found in the error variables. HD and PD patients differed in the most cognitively demanding trial of EcoKitchen – HD patients had a higher number of errors. Conclusion The two novel tools used to assess the functional cognition of HD and PD patients were able to detect early impairments in this domain. Moreover, they signalled inconsistencies between the subjective and objective information collected from patients. PD patients reported more functional incapacities than HD patients in IAFAI, but HD patients exhibited more impairments than PD patients in EcoKitchen. Sensitive and ecologically valid assessment methods will allow a more accurate identification and management of the patients’ real-life problems.
Neurology, Apr 6, 2015
OBJECTIVE: To compare the retinal nerve fiber layer thickness (RNFL) between patients with idiopa... more OBJECTIVE: To compare the retinal nerve fiber layer thickness (RNFL) between patients with idiopathic Parkinson disease (iPD), LRRK2-associated Parkinson Disease (LRRK2-PD) and controls, using optical coherence tomography (OCT) with a novel protocol for macular evaluation. BACKGROUND: Mutations in the LRRK2 gene are responsible for 10[percnt] of familial and autosomal dominant Parkinson disease (PD), with a phenotype indistinguishable from iPD. Vision is one of the affected non-motor systems in PD, probably due to a dopaminergic deficit in the retina. RNFL measure with OCT provides an indirect measure of these changes. Papillary and macular thinning in PD have been previously reported. There are no studies concerning retinal structure in LRRK2-PD patients. DESIGN/METHODS: Three independent samples of iPD (n=11), LRRK2-PD (n=17) and healthy subjects (n=14) were recruited for the study. The diagnosis of PD was based on the criteria from the United Kingdom Parkinson Disease Society Brain Bank. All participants underwent a full ophthalmologic and neurologic examination and HD-OCT with RNFL macular area analysis. From the volumetric scans, parameters were used to train a support vector machine (SVM), an automatic classification system. RESULTS: Twenty-three eyes of LRRK2-PD patients (age 55.9±10.4, 57.1[percnt] male), 18 iPD eyes (age: 73±8.9, 33.1[percnt] male), and 14 control eyes (age: 59±8.8, 50[percnt] male) were imaged. Macular RNFL was significantly different (p<0.05) between iPD and LRRK2-PD patients in temporal inferior (26.9±4.8 vs. 24.1±4.2) and superior nasal (45.3±6.8 vs. 50.4±6.3) perifovea areas. Patients with iPD showed significantly thicker perifovea temporal RNFL and thinner perifovea superior RNFL compared to controls (p<0.02). The optimized age-matched SVM had 77.8[percnt] specificity (S) for identifying iPD vs. controls, 55.6[percnt] S for iPD vs. LRRK2-PD and 83.3[percnt] S for LRRK2-PD vs. controls. CONCLUSIONS: Neurodegeneration in PD may be detected by RNFL macular thinning in OCT images, and this technique may further differentiate between PD genetic phenotypes. Disclosure: Dr. Duque has nothing to disclose. Dr. Januario has nothing to disclose. Dr. Lemos has nothing to disclose. Dr. Fonseca has nothing to disclose. Dr. Correia has nothing to disclose. Dr. Ribeiro has nothing to disclose. Dr. Bernardes has nothing to disclose. Dr. Freire has nothing to disclose.
Journal of Neurology, Jul 18, 2023
Background Progressive cognitive decline is an inevitable feature of Huntington's disease (HD) bu... more Background Progressive cognitive decline is an inevitable feature of Huntington's disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. Methods We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another. Results The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories. Conclusion The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia.
European Journal of Neurology
Background and purposeClinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomar... more Background and purposeClinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.MethodsTo evaluate total tau (t‐tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and neurofilament light‐chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD‐1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t‐tau and phosphorylated tau (p‐tau181). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t‐tau levels.ResultsPlasma t‐tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non‐Ataxia Signs was associated with t‐tau in ataxic patients (p = 0.004). Pre‐ataxic carriers showed higher cerebrospinal fluid t‐tau and p‐tau181 concentrations compared to ata...
Journal of Neurology, 2021
The original version of this article unfortunately contained a mistake. Affiliation 4 was incorre... more The original version of this article unfortunately contained a mistake. Affiliation 4 was incorrect. The corrected affiliation is given below.
Proceedings of the National Academy of Sciences, 2021
Significance The association between molecular and functional brain plasticities in health and di... more Significance The association between molecular and functional brain plasticities in health and disease remains an outstanding research challenge. Functional up-regulation of postsynaptic D2 receptors has been documented in PD while its significance at the neural activity level has never been identified. Here we provide a link between synaptic plasticity at the molecular level and reorganization of brain activity patterns. We combined molecular imaging of dopamine D 2 receptors and fMRI to identify molecular mechanisms underlying functional reorganization in PD. The identification of a relationship between neural activation changes with compensatory molecular phenotypes at the synaptic level paves the way for future work to understand the limits of brain reorganization of functional networks in neurological disorders.
Investigative Ophthalmology & Visual Science, 2008
Movement Disorders, 2021
ABSTRACTBackgroundLifestyle could influence the course of hereditary ataxias, but representative ... more ABSTRACTBackgroundLifestyle could influence the course of hereditary ataxias, but representative data are missing.ObjectiveThe objective of this study was to characterize lifestyle in spinocerebellar ataxia type 3 (SCA3) and investigate possible associations with disease parameters.MethodsIn a prospective cohort study, data on smoking, alcohol consumption, physical activity, physiotherapy, and body mass index (BMI) were collected from 243 patients with SCA3 and 119 controls and tested for associations with age of onset, disease severity, and progression.ResultsCompared with controls, patients with SCA3 were less active and consumed less alcohol. Less physical activity and alcohol abstinence were associated with more severe disease, but not with progression rates or age of onset. Smoking, BMI, or physiotherapy did not correlate with disease parameters.ConclusionDifferences in lifestyle factors of patients with SCA3 and controls as well as associations of lifestyle factors with diseas...
Science Translational Medicine, 2020
PolyQ ATXN3 is a pharmacodynamic marker for SCA3, and a SNP associated with the expanded allele m... more PolyQ ATXN3 is a pharmacodynamic marker for SCA3, and a SNP associated with the expanded allele may serve to specifically target mutant ATXN3 .
Translational Neurodegeneration, 2020
Background The identification of circulating biomarkers that closely correlate with Parkinson’s D... more Background The identification of circulating biomarkers that closely correlate with Parkinson’s Disease (PD) has failed several times in the past. Nevertheless, in this pilot study, a translational approach was conducted, allowing the evaluation of the plasma levels of two mitochondrial-related proteins, whose combination leads to a robust model with potential diagnostic value to discriminate the PD patients from matched controls. Methods The proposed translational approach was initiated by the analysis of secretomes from cells cultured under control or well-defined oxidative stress conditions, followed by the identification of proteins related to PD pathologic mechanisms that were altered between the two states. This pipeline was further translated into the analysis of undepleted plasma samples from 28 control and 31 PD patients. Results From the secretome analysis, several mitochondria-related proteins were found to be differentially released between control and stress conditions ...
Journal of Neurology, 2020
Background Cognitive impairment is an essential feature of Huntington’s disease (HD) and dementia... more Background Cognitive impairment is an essential feature of Huntington’s disease (HD) and dementia is a predictable outcome in all patients. However, validated instruments to assess global cognitive performance in the field of HD are lacking. Objectives We aimed to explore the utility of the Parkinson’s disease-Cognitive Rating Scale (PD-CRS) for the screening of global cognition in HD. Methods A multicenter cohort of 132 HD patients at different disease stages and 33 matched healthy controls were classified as having preserved cognition, mild cognitive impairment (HD-MCI) or dementia (HD-Dem) according to the Clinical Dementia Rating and Functional Independence Score. The PD-CRS and the Mini-Mental State Examination were administered. Receiver operating characteristic curve analysis was used to determine optimal cutoffs to differentiate patients according to their cognitive status. Results A PD-CRS cutoff score ≤ 81/82 was optimal to detect HD-MCI (sensitivity = 93%; specificity = 80%; area under the curve (AUC) = 0.940), and ≤ 63/64 was optimal to detect HD-Dem (sensitivity = 90%; specificity = 87%; AUC = 0.933). MMSE scores failed to show robust psychometric properties in this context. Discussion The PD-CRS is a valid and reliable instrument to assess global cognition in HD in routine clinical care and clinical trials.
PLOS ONE, 2019
A top priority in biomarker development for Alzheimer's disease (AD) and Parkinson's disease (PD)... more A top priority in biomarker development for Alzheimer's disease (AD) and Parkinson's disease (PD) is the focus on early diagnosis, where the use of the retina is a promising avenue of research. We computed fundus images from optical coherence tomography (OCT) data and analysed the structural arrangement of the retinal tissue using texture metrics. We built clinical class classification models to distinguish between healthy controls (HC), AD, and PD, using machine learning (support vector machines). Median sensitivity is 88.7%, 79.5% and 77.8%, for HC, AD, and PD eyes, respectively. When the same subject has the same classification for both eyes, 94.4% (median) of the classifications are correct. A significant amount of information discriminating between multiple neurodegenerative states is conveyed by OCT imaging of the human retina, even when differences in thickness are not yet present. This technique may allow for simultaneously diagnosing Alzheimer's and Parkinson's diseases.
Brain research, Oct 1, 2016
Saccadic behaviour ranges from reflexive (e.g., prosaccade) to goal oriented voluntary movements ... more Saccadic behaviour ranges from reflexive (e.g., prosaccade) to goal oriented voluntary movements (e.g., antisaccade). Behavioural asymmetries between vertical and horizontal saccades have been described both in normal individuals (greater delay of vertical prosaccades) and in disease states such as Parkinson's disease (PD) (prosaccades are short and antisaccades are delayed, especially in the vertical plane, possibly due to a frontostriatal deficit). Importantly, the cortical mechanisms for the generation of vertical saccades are largely unknown, both in health and disease, when compared with their horizontal counterpart. Moreover, studies exploring saccadic neural correlates and putative compensatory mechanisms at a functional level in PD are scarce. We investigated horizontal and vertical prosaccades and antisaccades in an eye tracking paradigm in 19 PD patients off medication and 22 healthy controls, followed by a block-design functional Magnetic Resonance Imaging (fMRI) stud...
Journal of the neurological sciences, Jan 15, 2017
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder showing predominant brainste... more Progressive supranuclear palsy (PSP) is a neurodegenerative disorder showing predominant brainstem involvement, characterized by marked slowing of rapid eye movements (saccades), particularly along the vertical plane. While the contribution of the brainstem damage for the saccadic disturbance in PSP has been extensively studied, much less is known about its cortical and subcortical pathomechanisms. We measured reflexive (prosaccades) and voluntary (antisaccades) saccades in the vertical and horizontal plane in PSP patients (n=8) and controls (n=10) in an eye tracking study, followed by the measurement of blood oxygenation-level dependent (BOLD) activation (PSP, n=6; controls, n=10) during similar saccade paradigms. Behaviorally, PSP patients evidenced slower and lower amplitude prosaccades (horizontal and vertical) and lower amplitude antisaccades (vertical) than controls. Functionally, patients showed decreased frontostriatal BOLD activation during prosaccades (horizontal and verti...
European neurology, Jan 18, 2016
The diagnosis of Parkinson's disease (PD) can sometimes be a challenge in the early stages of... more The diagnosis of Parkinson's disease (PD) can sometimes be a challenge in the early stages of the disease. Both transcranial sonography (TCS) and DaTSCAN are recommended as auxiliary examinations for the differential diagnosis of PD; however, only few data exist regarding their diagnostic accuracy in the early stage of PD and essential tremor (ET). We evaluated patients with clinically suspected diagnosis of PD at early stages (Hoehn and Yahr ≤2) or ET. All patients underwent DaTSCAN and TCS with a maximum interval of 6 months. Final diagnosis was established after 1-year follow-up. From the 63 patients recruited, 3 were excluded due to transcranial insonability and 2 for uncertain clinical diagnosis. The final clinical diagnosis was ET in 44.8% and PD in 55.2%. Compared to clinical diagnosis of PD, TCS had a sensitivity of 87.5% and specificity of 96.2%; DaTSCAN sensitivity was 84.4% and specificity was 96.2%. Both diagnostic tests demonstrated a substantial level of agreement ...
Journal of Neurology, Neurosurgery & Psychiatry, 2014
Results The occipital cortex was significantly thinner in pre-HD and early HD participants. These... more Results The occipital cortex was significantly thinner in pre-HD and early HD participants. These between-group differences were heterogeneous across regions, with the lateral occipital region showing the most pronounced effects. Significant associations were found between reduced occipital cortical thickness and poorer performance on a number of cognitive tasks involving a visual component. No association was found with finger tapping. Conclusions Regionally-specific thinning of the occipital cortex was evident more than a decade before estimated HD symptom onset. Associations were found with cognitive tasks, but not finger tapping, suggesting that occipital thickness plays an important role in cognitive tasks with a visual component. This has implications for the interpretation of impaired cognitive performances in HD, which is typically attributed to frontal and executive circuits, rather than to visual regions.
Journal of Neurology, Neurosurgery & Psychiatry, 2014
Background Cognitive and oculomotor performance have been extensively studied in Huntington Disea... more Background Cognitive and oculomotor performance have been extensively studied in Huntington Disease (HD), but evidence for significant deficits in premanifest gene carriers is still controversial. Moreover, their role as markers of disease status and progression is not yet convincingly established. Aims This study aims to understand the evolution of neuropsychological and saccadic performance in premanifest HD (preHD) over a course of 3 years. The results of the baseline assessment and preliminary longitudinal data regarding the one-year follow-up visit of the preHD group are shown here. Methods 15 preHD participants and 22 controls completed the baseline assessment. 10 preHD participants have completed the second visit so far. A comprehensive neuropsychological test battery was used to evaluate the overall cognitive functioning of the participants. An experimental paradigm was designed to assess oculomotor function. Participants completed four different horizontal saccadic tasks with an increasing executive/memory load: prosaccade, antisaccade, 1-or-2 back memory prosaccade and antisaccade. Success rate (percentage of error free trials), latency, directional and timing errors were calculated. Results No significant differences were found between preHD and controls in any of the neuropsychological tests, suggesting a similar overt cognitive baseline at visit #1. The cognitive results of the preHD group at visits #1 and #2 showed that their performance improved in some of the tests used. Concerning saccadic parameters, the preHD group exhibited at baseline a significantly faster response time compared to controls, specifically in memory antisaccades. At visit #2, preHD participants showed a lower success rate and an increased latency, particularly in tasks involving inhibitory processes. Conclusions These data suggest that oculomotor performance of the preHD group may rely on more automatic responses when an executive/memory load is added to the task, deteriorates in time, and also that temporal saccade properties can mark the presence of early neurodegeneration in HD. Furthermore, despite an already evident decline in the saccadic performance of preHD individuals after one year, this is not paralleled by overt cognitive deficits as measured by conventional neuropsychological tests.
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Papers by cristina Januario