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- Aphasia Screening Test (TeRAp): construction and validation for european portuguesePublication . Fonseca, José; Miranda, Filipa; Stein, Beatriz; Maruta, CarolinaIntroduction: Aphasia is a common acquired language disorder following stroke or other brain injuries. However, it is not always easy to make a differential diagnosis with another communication disorder. Communication assessment in acute phases of the stroke, when the patient is bedridden or when there is no time for a more in-depth assessment, needs to be done with a formal screening test that has normative data. The aim of this study was to develop the Aphasia Screening Test (TeRAp) in digital format (appWeb) and present its clinimetric values. Methods: A screening test (TeRAp) was built in appWeb format that assesses the main areas of language processing and automatically provides a diagnostic hypothesis. A group of people with aphasia was evaluated and their performance was compared with three control groups, one of healthy people and two groups of people with neurological conditions, one with dysarthria and the other with mild cognitive impairment. Results: Ceiling values were obtained in all the tests. Sensitivity values of 1 and specificity values of 0.99 were obtained for the presence of aphasia. Conclusion: An online aphasia screening test was developed, with excellent sensitivity and specificity results, which can be used by any health professional.
- Cognitive aging in migraine sufferers is associated with more subjective complaints but similar age-related decline: a 5-year longitudinal studyPublication . Martins, Isabel Pavão; Maruta, Carolina; Alves, Pedro Nacimento; Loureiro, Clara; Morgado, Joana; Tavares, Joana; Gil-Gouveia, RaquelObjectives and background: The effect of headache on cognitive performance is controversial, due to conflicting results obtained from studies in clinical or population settings. We aimed to understand if migraine and other headaches modify the rates of decline on different cognitive measures, during a 5-year interval. Design and method: A cohort of community dwelling adults (> 50 years) with migraine (MH), non-migraine headaches (NMH) and controls without headache (WoH), was assessed by a comprehensive neuropsychological battery with tests of memory, language and executive functions, repeated 5 years apart. Change in performance between baseline and reevaluation was compared between groups, and controlled for age, gender, literacy and depressive symptoms. Results: A total of 275 participants (78.5% WoH, 12.7% MH, 8.7% NMH) were reevaluated (average age 70.40 + 8.34 years, 64% females). Cognitive decline or dementia occurred in 11.4%, with a similar proportion among the three groups. Although MH participants had significantly more subjective cognitive complaints (p = 0.030, 95%CI:]-3.929,-0.014[), both MH and NMH subjects showed an age-associated decline identical to controls. Furthermore, migraine features (disease and attack duration, frequency and aura) were unrelated with cognitive performance. Conclusion: Migraine and non-migraine headache are not associated with increasing risk of dementia or cognitive decline at an older age although subjects with migraine have more cognitive complaints. Longer longitudinal studies are necessary to understand if this pattern persists for more than 5 years.
- Cognitive performance along the migraine cycle: a negative exploratory studyPublication . Quadros, Maria Ana; Granadeiro, Marta; Ruiz-Tagle, Amparo; Maruta, Carolina; Gil-Gouveia, Raquel; Martins, Isabel PavãoMigraine patients frequently report cognitive difficulties in the proximity and during migraine attacks. We performed an exploratory comparison of executive functioning across the four stages of the migraine cycle. Consecutive patients with episodic migraine undertook cognitive tests for attention, processing speed, set-shifting, and inhibitory control. Performance was compared between patients in different migraine stages, controlling for attack frequency and prophylactic medication. One hundred forty-three patients (142 women, average age 36.2 ± 9.9 years) were included, 28 preictal (≤48 h before the attack), 21 ictal (during the attack), 18 postictal (≤24 h after attack), and 76 interictal. Test performance (age and literacy adjusted z-scores) was not significantly different across migraine phases, despite a tendency for a decline before the attack. This negative study shows that cognitive performance fluctuates as patients approach the attack. To control for individual variability, this comparison needs to be better characterized longitudinally with a within-patient design.
- CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementiaPublication . the Genetic FTD Initiative, GENFI; Woollacott, Ione O.C.; Swift, Imogen J.; Sogorb-Esteve, Aitana; Heller, Carolin; Knowles, Kathryn; Bouzigues, Arabella; Russell, Lucy L.; Peakman, Georgia; Greaves, Caroline V.; Convery, Rhian; Heslegrave, Amanda; Rowe, James B.; Borroni, Barbara; Galimberti, Daniela; Tiraboschi, Pietro; Masellis, Mario; Tartaglia, Maria Carmela; Finger, Elizabeth; van Swieten, John C.; Seelaar, Harro; Jiskoot, Lize; Sorbi, Sandro; Butler, Chris R.; Graff, Caroline; Gerhard, Alexander; Laforce, Robert; Sanchez-Valle, Raquel; de Mendonça, Alexandre; Moreno, Fermin; Synofzik, Matthis; Vandenberghe, Rik; Ducharme, Simon; Ber, Isabelle Le; Levin, Johannes; Otto, Markus; Pasquier, Florence; Santana, Isabel; Zetterberg, Henrik; Rohrer, Jonathan D.; Nelson, Annabel; Bocchetta, Martina; Cash, David; Thomas, David L.; Todd, Emily; Benotmane, Hanya; Nicholas, Jennifer; Samra, Kiran; Maruta, Carolina; do Couto, Frederico Simões; Almeida, Maria RosárioBackground: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.
- Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementiaPublication . Genetic FTD Initiative (GENFI); Samra, Kiran; Peakman, Georgia; MacDougall, Amy M.; Bouzigues, Arabella; Greaves, Caroline V.; Convery, Rhian S.; Swieten, John C. van; Jiskoot, Lize; Seelaar, Harro; Moreno, Fermin; Sanchez-Valle, Raquel; Laforce, Robert; Graff, Caroline; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James B.; Borroni, Barbara; Finger, Elizabeth; Synofzik, Matthis; Galimberti, Daniela; Vandenberghe, Rik; Mendonça, Alexandre de; Butler, Chris R.; Gerhard, Alexander; Ducharme, Simon; Ber, Isabelle Le; Tiraboschi, Pietro; Santana, Isabel; Pasquier, Florence; Levin, Johannes; Otto, Markus; Sorbi, Sandro; Rohrer, Jonathan D.; Russell, Lucy L.; Bocchetta, Martina; Cash, David; Thomas, David L.; Cope, Thomas; Rittman, Timothy; Benussi, Alberto; Premi, Enrico; Gasparotti, Roberto; Archetti, Silvana; Gazzina, Stefano; Cantoni, Valentina; Arighi, Andrea; Maruta, Carolina; do Couto, Frederico Simões; Alves, Patricia; Almeida, Maria RosarioINTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.
- Gender-related demographic, polysomnographic, cognitive and psychological factors in insomniaPublication . Maruta, Carolina; Reis, Cátia; Alvarenga, Tathiana; Neutel, Dulce; Rebelo-Pinto, Helena; Paiva, Teresa
- Language impairment in the genetic forms of behavioural variant frontotemporal dementiaPublication . On Behalf of the Genetic FTD Initiative (GENFI); Samra, Kiran; MacDougall, Amy M.; Bouzigues, Arabella; Bocchetta, Martina; Cash, David M.; Greaves, Caroline V.; Convery, Rhian S.; van Swieten, John C.; Seelaar, Harro; Jiskoot, Lize; Moreno, Fermin; Sanchez-Valle, Raquel; Laforce, Robert; Graff, Caroline; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James B.; Borroni, Barbara; Finger, Elizabeth; Synofzik, Matthis; Galimberti, Daniela; Vandenberghe, Rik; de Mendonça, Alexandre; Butler, Christopher R.; Gerhard, Alexander; Ducharme, Simon; Le Ber, Isabelle; Tiraboschi, Pietro; Santana, Isabel; Pasquier, Florence; Levin, Johannes; Otto, Markus; Sorbi, Sandro; Rohrer, Jonathan D.; Russell, Lucy L.; Nelson, Annabel; Thomas, David L.; Todd, Emily; Benotmane, Hanya; Nicholas, Jennifer; Shafei, Rachelle; Timberlake, Carolyn; Cope, Thomas; Rittman, Timothy; Benussi, Alberto; Premi, Enrico; Gasparotti, Roberto; Archetti, Silvana; Maruta, Carolina; do Couto, Frederico SimõesBackground: Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. Methods: Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. Results: 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. Conclusions: Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.
- Locations of objects are better remembered than their identities in naturalistic scenes: an eye-tracking experiment in mild cognitive impairmentPublication . Coco, Moreno I.; Maruta, Carolina; Martins, Isabel Pavão; Sala, Sergio DellaObjective: Retaining the identity or location of decontextualized objects in visual short-term working memory (VWM) is impaired by healthy and pathological ageing, but research remains inconclusive on whether these two features are equally impacted by it. Moreover, it is unclear whether similar impairments would manifest in naturalistic visual contexts. Method: 30 people with mild cognitive impairment (MCI) and 32 age-matched control participants (CPs) were eye-tracked within a change detection paradigm. They viewed 120 naturalistic scenes, and after a retention interval (1 s) asked whether a critical object in the scene had (or not) changed on either: identity (became a different object), location (same object but changed location), or both (changed in location and identity). Results: MCIs performed worse than CP but there was no interaction with the type of change. Changes in both were easiest while changes in identity alone were hardest. The latency to first fixation and first-pass duration to the critical object during successful recognition was not different between MCIs and CPs. Objects that changed in both features took longer to be fixated for the first time but required a shorter first pass compared to changes in identity alone which displayed the opposite pattern. Conclusions: Locations of objects are better remembered than their identities; memory for changes is best when involving both features. These mechanisms are spared by pathological ageing as indicated by the similarity between groups besides trivial differences in overall performance. These findings demonstrate that VWM mechanisms in the context of naturalistic scene information are preserved in people with MCI.
- May subjective language complaints predict future language decline in community-dwelling subjects?Publication . Maruta, Carolina; Martins, Isabel PavãoSubjective cognitive complaints are rather prevalent in the elderly population and are associated with an increased risk of cognitive impairment and dementia. However, the predictive role of specific types of cognitive complaints has been less systematically assessed. The aim of the present study is to examine the predictive value of language complaints for cognitive and language decline in a cohort of community-dwelling healthy older adults, followed longitudinally over a 5-year period. A total of 402 subjects were enrolled in a prospective longitudinal study on aging and cognition. Participants answered a cognitive complaints questionnaire including two questions directed to language and were classified at baseline as having “Language Complaints” (LC) or “No Language Complaints” (NLC). They also performed a neuropsychological assessment tackling attention/processing speed, memory, executive functioning, and language at baseline. From these, 275 (68.4%) participated in a follow-up evaluation 4.9 (±0.6) years later. At re-evaluation, subjects had a mean age of 70.4 (±8.3) years, 7.5 (±4.4) years of education, and 63.3% were female. Multivariate linear regression analysis was used to investigate whether language complaints at baseline predicted poorer language performance at follow-up or increased the risk of cognitive decline, with correction for sex, depressive symptoms, living status, baseline performance, and composite memory and executive performance. Results indicated that LC subjects had significantly worse performances than NLC subjects on semantic fluency 5 years later, but with a similar rate of decline overtime that was not associated with a follow-up outcome of cognitive decline/dementia. Language difficulties may represent a specific type of age-related cognitive complaints. Longer follow-ups are necessary to understand if they are associated with an increased risk of language or cognitive decline.
- Temporal order of clinical and biomarker changes in familial frontotemporal dementiaPublication . Frontotemporal Dementia Prevention Initiative (FPI) Investigators; ALLFTD Investigators; GENFI investigators; Staffaroni, Adam M.; Quintana, Melanie; Wendelberger, Barbara; Heuer, Hilary W.; Russell, Lucy L.; Cobigo, Yann; Wolf, Amy; Goh, Sheng Yang Matt; Petrucelli, Leonard; Gendron, Tania F.; Heller, Carolin; Clark, Annie L.; Taylor, Jack Carson; Wise, Amy; Ong, Elise; Forsberg, Leah; Brushaber, Danielle; Rojas, Julio C.; VandeVrede, Lawren; Ljubenkov, Peter; Kramer, Joel; Casaletto, Kaitlin B.; Appleby, Brian; Bordelon, Yvette; Botha, Hugo; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Fields, Julie A.; Foroud, Tatiana; Gavrilova, Ralitza; Geschwind, Daniel; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathon; Graff-Radford, Neill; Grossman, Murray; Hall, Matthew G.H.; Hsiung, Ging Yuek; Huey, Edward D.; Irwin, David; Jones, David T.; Kantarci, Kejal; Kaufer, Daniel; Knopman, David; Kremers, Walter; Lago, Argentina Lario; Lapid, Maria I.; Maruta, Carolina; Simões do Couto, Frederico; Almeida, Maria RosarioUnlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.