New insights into atypical Alzheimer's disease in the era of biomarkers

Most patients with Alzheimer's disease present with amnestic problems; however, a substantial proportion, over-represented in young-onset cases, have atypical phenotypes including predominant visual, language, executive, behavioural, or motor dysfunction. In the past, these individuals often received a late diagnosis; however, availability of CSF and PET biomarkers of Alzheimer's disease pathologies and incorporation of atypical forms of Alzheimer's disease into new diagnostic criteria increasingly allows them to be more confidently diagnosed early in their illness. This early diagnosis in turn allows patients to be offered tailored information, appropriate care and support, and individualised treatment plans. These advances will provide improved access to clinical trials, which often exclude atypical phenotypes. Research into atypical Alzheimer's disease has revealed previously unrecognised neuropathological heterogeneity across the Alzheimer's disease spectrum. Neuroimaging, genetic, biomarker, and basic science studies are providing key insights into the factors that might drive selective vulnerability of differing brain networks, with potential mechanistic implications for understanding typical late-onset Alzheimer's disease

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Peer reviewedPostprin

Primary progressive aphasia : neuropsychological analysis and evolution

Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2015Frontotemporal lobar degeneration (FTLD) is the second leading cause of early-onset ( 2) revealed some clusters composed mostly by nonfluent or by semantic PPA cases. However, we could not evidence any group chiefly composed of logopenic PPA cases. Hence, findings obtained with the application of unsupervised data mining approaches do not clearly support a logopenic PPA. However further, supervised learning studies may indicate distinct results. Behaviour changes may occur early in PPA but the frequency of these symptoms across the three variants is still controversial. In the third study, 94 consecutive PPA patients (26 nonfluent, 36 semantic, 32 logopenic) underwent language and neuropsychological assessments. The presence of behavioural changes was ascertained by semi-structured informant-based interviews using the Blessed Dementia Rating Scale. Eighty-two percent of the cases endorsed at least one behaviour change. Nonfluent patients presented significantly more behaviour changes and scored more often (46.2%) the item “hobbies relinquished” when compared to logopenic patients. These differences in behaviour symptoms probably reflect distinct underlying neurodegenerative diseases. PPA is a neurodegenerative disorder with no effective pharmacological treatment. Cognition-based interventions are adequate alternatives, but their benefit has not been thoroughly explored. The aim of this last investigation was to study the effect of speech and language therapy (SLT) on naming ability in PPA. An open parallel prospective longitudinal study involving two centers was designed to compare patients with PPA submitted to SLT (1 h/week for 11 months, on average) with patients receiving no therapy. Twenty patients were enrolled and undertook baseline language and neuropsychological assessments; among them, 10 received SLT and 10 constituted an age- and education-matched historical control group. The primary outcome measure was the change in group mean performance on the Snodgrass and Vanderwart Naming Test between baseline and follow-up assessments. Intervention and control groups did not significantly differ on demographic and clinical variables at baseline. A mixed repeated measures ANOVA revealed a significant main effect of therapy (F(1,18) = 10.763; p = 0.005) on the performance on the Snodgrass and Vanderwart Naming Test. Although limited by a non-randomized open study design with a historical control group, the present study suggests that SLT may have a benefit in PPA, and it should prompt a randomized, controlled, rater-blind clinical trial. Conclusion: Despite the recent harmonization efforts, the delineation of certain PPA variants is still controversial. The present results show that neuropsychology is a key instrument not only for the clear definition of PPA subtypes but also for the study of the abnormal mechanisms and features underlying the main forms of PPA. Moreover, a neuropsychological approach to disease management seems to be feasible. Specifically, SLT emerges as an alternative and adequate approach to tackle the increasing language deficits experienced in all PPA phenotypes for some time. The emergence of promising disease-modifying therapies in the context of FTLD, in association with these cognitive-based interventions, will certainly be the future of PPA disease management

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L + R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau. After confirmation of an additional hTau species (~60 kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which coincided with the emergence of FTD relevant behavioural traits. In line with the non-cognitive symptomatology of FTD, PLB2Tau mice demonstrated early emerging (~6 months) phenotypes of heightened anxiety in the elevated plus maze, depressive/apathetic behaviour in a sucrose preference test and generally reduced exploratory activity in the absence of motor impairments. Investigations of cognitive performance indicated prominent dysfunctions in semantic memory, as assessed by social transmission of food preference, and in behavioural flexibility during spatial reversal learning in a home cage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12 months of age in the corner learning but not in the water maze task. Electroencephalographic (EEG) investigations indicated a vigilance-stage specific loss of alpha power during wakefulness at both parietal and prefrontal recording sites, and site-specific EEG changes during non-rapid eye movement sleep (prefrontal) and rapid eye movement sleep (parietal). Further investigation of hippocampal electrophysiology conducted in slice preparations indicated a modest reduction in efficacy of synaptic transmission in the absence of altered synaptic plasticity. Together, our data demonstrate that the transgenic PLB2Tau mouse model presents with a striking behavioural and physiological face validity relevant for FTD, driven by the low level expression of mutant FTD hTau.</p

La maladie d’Alzheimer comme syndrome de déconnexion et son impact sur le système du langage

La forme typique de la maladie d’Alzheimer (MA) se caractérise par des troubles progressifs de la mémoire épisodique. Néanmoins, les patients atteints par cette maladie présentent également des symptômes langagiers. Parmi les problèmes langagiers que les patients MA présentent, l’anomie, c’est-à-dire une difficulté à trouver les mots justes, serait le plus prédominant. Ainsi, il s’agit d’un marqueur cognitif intéressant pour la détection de la maladie ainsi que son diagnostic différentiel avec d’autres maladies présentant certains symptômes similaires, telle que la variante sémantique de l’aphasie primaire progressive (vs-APP). Malgré tout, le profil anomique des patients MA reste incomplètement caractérisé sur le plan de la dénomination de certains types d’entités. Par ailleurs, les bases cognitives et cérébrales de l’anomie demeurent sujet de débat dans la MA. En addition à des dommages structurels ou des altérations fonctionnelles dans des régions cérébrales spécifiques, plusieurs auteurs ont récemment suggéré qu’une déconnexion au sein de réseaux cérébraux pourrait sous-tendre les difficultés cognitives présentées chez les patients MA, incluant les symptômes langagiers. Toutefois, aucune étude n’a validé le fait que la MA était un syndrome de déconnexion à l’aide de la technique des réseaux de covariance structurelle de la matière grise. De surcroît, très peu d’études ont investigué l’impact de la MA sur le réseau cérébral langagier, ce qui pourrait nous apporter un éclairage sur les symptômes langagiers des patients tels que l’anomie. Le premier volet de la thèse visait à mieux caractériser le profil anomique des patients MA, à le comparer à celui des patients vs-APP et finalement, à clarifier ses bases cognitives et cérébrales (article #1). Les résultats suggéraient d’abord une atteinte diffuse en dénomination pour tous les types d’items (entités non uniques, personnes célèbres, lieux célèbres et logos célèbres) chez les patients MA en comparaison aux sujets contrôles. L’atteinte était néanmoins prédominante pour la dénomination de personnes célèbres, suggérant un profil prosopoanomique dans la MA. Les connaissances sémantiques générales pour ces mêmes entités étaient préservées chez les patients MA, bien qu’une légère altération ait été observée pour les connaissances sémantiques spécifiques. Les résultats comportementaux des patients MA se distinguaient clairement des résultats obtenus chez les patients vs-APP, qui présentaient une anomie plus sévère et un trouble sémantique net. Le profil d’anomie tel qu’évalué en dénomination de personnes célèbres chez les patients MA corrélait avec l’atrophie de la matière grise dans la jonction temporo-pariétale gauche (une région associée avec l’accès lexical), et ne corrélait pas avec l’atrophie de la matière grise dans le LTA gauche (une région associée à la sémantique). Ainsi, ces résultats soulignent l’apport important du trouble d’accès lexical dans l’anomie chez les patients MA, mais suggère tout de même un trouble de nature mixte en raison des lacunes sémantiques observées chez ces patients pour les connaissances spécifiques. Le deuxième volet de la thèse visait à démontrer que la MA est un syndrome de déconnexion (article #2), et que cette déconnexion touchait également le réseau cérébral responsable du langage (article #3). D’abord, les résultats ont permis de démontrer des changements de la connectivité structurelle dans les réseaux clés associés à la MA. En effet, une diminution de la connectivité structurelle a été observée dans les sous-composantes du réseau du mode par défaut, apportant ainsi un appui à l’hypothèse de la MA comme syndrome de déconnexion. Ensuite, il a été possible de confirmer que les atteintes de connectivité sont également présentes à l’extérieur du réseau du mode par défaut, soit dans le réseau cérébral langagier. Des diminutions de connectivité fonctionnelle ont principalement été relevées dans le gyrus temporal postérieur moyen gauche et le lobe temporal antérieur gauche, en relation avec d’autres régions du réseau langagier. En lien avec l’anomie chez les patients MA, les altérations de la connectivité fonctionnelle sont compatibles avec la nature mixte de l’anomie chez les patients MA. Mis ensemble, ces résultats mettent en relief l’importance des marqueurs cognitifs liés à l’anomie et des marqueurs de connectivité cérébrale dans la caractérisation de la MA et son diagnostic différentiel avec d’autres maladies neurodégénératives telles que la vs-APP. Étant donné l’impact au quotidien des troubles langagiers sur les patients MA et leurs proches, nous croyons qu’une meilleure caractérisation des bases cognitives et cérébrales de leurs déficits contribuera au développement d’interventions auprès de ceux-ci.The typical form of Alzheimer’s disease (AD) is characterized by progressive episodic memory impairments. Nonetheless, patients affected by this disease also present with language symptoms. Among common language deficits in AD, anomia, i.e. a difficulty to recall names, is recognized as the most predominant. Therefore, it represents an interesting cognitive marker for the detection of the disease as well as its differential diagnosis with other neurodegenerative diseases characterized by overlapping symptoms, such as the semantic variant of primary progressive aphasia (sv-PPA). Still, the anomic profile of AD patients remains incompletely characterized in terms of the naming of certain types of entities. Also, the cognitive and cerebral bases of anomia are still a matter of debate in AD. In addition to structural damage or functional alteration in specific brain regions, many authors have recently suggested that a disconnection across brain networks could sustain cognitive difficulties experienced by AD patients, including language impairments. However, most studies demonstrating that AD is a disconnection syndrome have used functional connectivity techniques, and no study using the gray matter structural covariance networks technique has been conducted to support this hypothesis. In addition, very few studies have investigated the impact of AD on the language brain network, which could significantly extend our understanding of language symptoms such as anomia. The first section of this thesis aimed to better characterize the anomic profile of AD patients, to compare it with the profile of sv-PPA patients and finally, to clarify its cognitive and cerebral bases (article #1). The results first suggested a diffuse naming impairment affecting every type of items (non-unique entities, famous persons, famous places and famous logos) in AD patients in comparison to control subjects. Famous persons naming was nonetheless predominantly impaired in AD patients in comparison to other types of entities, suggesting a prosopoanomia. General semantic knowledge for these same entities was preserved in AD, although a slight but significant impairment was observed in terms of specific semantic knowledge. Behavioral results in AD patients clearly distinguished them from sv-PPA patients, in which naming, general and specific semantic knowledge were cleary impaired. Famous persons naming in AD patients correlated with gray matter atrophy in the left temporo-parietal junction (a region functionally associated with lexical access), but not with the left anterior temporal lobe (a region functionally associated with semantics). Overall, these results underline the contribution of a lexical access deficit in anomia in AD patients, but nonetheless argue in favor of a mixed cognitive basis of anomia given that a slight semantic impairment for specific knowledge was also present. The second section of this thesis aimed at demonstrating that AD is a disconnection syndrome (article #2), and that this disconnection also affects the brain network responsible for language (article #3). Results showed significant changes in the structural connectivity of the key networks in AD. In fact, a reduced structural connectivity was observed in the subcomponents of the default-mode network, giving support to the theory of AD as a disconnection syndrome. Furthermore, our results confirmed that structural connectivity alterations were also present outside of the default-mode network, also affecting the language network. Reduced functional connectivity was mainly observed in the left posterior middle temporal gyrus as well as in the left anterior temporal lobe, in relation to other regions of the language network. These results have implications for our understanding of language symptoms in AD patients, since they are also compatible with a mixed basis (lexical access and semantic impairments) of anomia in AD. Taken together, these results highlight the importance of anomia as a cognitive marker and structural/functional connectivity as a neuroimaging marker in the characterisation of AD as well as its differential diagnosis with other neurodegenerative diseases such as sv-PPA. Given the negative impact of language difficulties in the daily life of AD patients as well as their caregivers, we believe that a better characterisation of the cognitive and cerebral bases of their language deficits will contribute to the development of interventions

Social Signal Decoding in Frontotemporal Lobar Degeneration

Frontotemporal lobar degeneration (FTLD) is associated with progressive social cognitive impairment. Currently a comprehensive pathophysiological model allowing disease effects to be understood and anticipated at the level of the whole brain is lacking. In this thesis I explored candidate cognitive operations underpinning complex behaviours in patients with the canonical syndromes of FTLD; behavioural variant frontotemporal dementia (bvFTD) and semantic dementia (SD). I correlated behavioural deficits with brain network disintegration using the structural magnetic resonance imaging (MRI) technique, voxel based morphometry (VBM). I created synthetic scenes to manipulate congruity across semantic and emotional domains (Chapter 3) and showed deficits across both patient groups. The deficits have grey matter correlates in prefronto-parieto-temporo-insular network and a temporo-insulo-striatal network. I used music as a non-verbal syntactic probe to investigate reward anticipation and valuation (Chapter 4) and demonstrated dissociable deficits across dementias. Performance was associated with grey matter in a distributed network including anterior temporal cortex and orbitofrontal cortex (OFC), previously implicated in computing diverse rewards. I created a novel neuropsychological test of humorous intent (Chapter 5) to model incongruity processing. bvFTD demonstrates a particular difficulty decoding novel humorous situations while SD produces a more general deficit of humour detection. Humour detection accuracy was associated with temporoparietal junction (TPJ) and anterior superior temporal cortical volume which are hubs for processing incongruity and semantic associations. To assess the relevance of these findings (Chapter 5) to daily life behaviour I explored humour preferences across dementias (Chapter 6). Altered sense of humour is particularly salient in bvFTD and SD, but also frequent in AD and may predate more typical symptoms. In conclusion, impairment in incongruity processing and reward allocation was shown across paradigms. The neuroanatomical networks underpinning these processes overlapped with areas known to be targeted by FTLD. These processes have implications for our understanding of the social dysfunction that defines bvFTD

A multimodal approach to the study of self and others’ awareness in prodromal to mild Alzheimer’s disease

Patients in the early stage of Alzheimer’s disease (AD) can manifest disorders of cognitive awareness such as a lack of/limited self-awareness of their own cognitive deficits (anosognosia) or as a reduction in the ability to be aware of others, i.e., social cognition; more specifically in the ability to recognise emotions or attribute mental states to others (also known as Theory of Mind, ToM). The present thesis intended to explain the behavioural, brain neuroanatomical, structural connectivity and resting-state functional relationship between the presence of multi-domain alterations of self-awareness/anosognosia and others awareness/social cognition to understand the cognitive and neural substrates that shape conscious awareness in early AD. Behavioural findings evidenced an association between the presence of anosognosia and reduced ToM. Individually, memory anosognosia was associated with memory proxies and total anosognosia with visuospatial abilities, while social cognition was associated with language, memory, attention and most importantly, executive functions. Neuroanatomical structural findings of non-memory and total anosognosia showed reduced grey matter volume in the anterior cingulate cortex (ACC), fusiform, lingual and precentral gyri. Conversely, ToM showed reduced grey matter volume also in the ACC, but reduction extended to encompass temporoparietal junction, orbitofrontal, superior temporal and cerebellar cortices. The ACC showed a statistical shared neural overlap between self-other awareness. At the functional level, both anosognosia and social cognition were associated with reduced internetwork connectivity between the default mode network (DMN) and the executive frontoparietal network (FPN), as well as higher connectivity between the DMN and the salience network, in which the insula seems to have an essential role. Subcortical contributions to large-scale network connectivity were also found. We propose that medial frontal executive mechanisms, such as those subserved by the ACC, might support awareness in the presence of an inherently damaged DMN in early-AD. Functional adaptive reorganisation of network dynamics might increase the strain to salient system hubs (ACC) by redirecting network traffic of executive resources to cope with the progressive decline of conscious awareness

Do informal caregivers of people with dementia mirror the cognitive deficits of their demented patients?:A pilot study

Recent research suggests that informal caregivers of people with dementia (ICs) experience more cognitive deficits than noncaregivers. The reason for this is not yet clear. Objective: to test the hypothesis that ICs ‘mirror' the cognitive deficits of the demented people they care for. Participants and methods: 105 adult ICs were asked to complete three neuropsychological tests: letter fluency, category fluency, and the logical memory test from the WMS-III. The ICs were grouped according to the diagnosis of their demented patients. One-sample ttests were conducted to investigate if the standardized mean scores (t-scores) of the ICs were different from normative data. A Bonferroni correction was used to correct for multiple comparisons. Results: 82 ICs cared for people with Alzheimer's dementia and 23 ICs cared for people with vascular dementia. Mean letter fluency score of the ICs of people with Alzheimer's dementia was significantly lower than the normative mean letter fluency score, p = .002. The other tests yielded no significant results. Conclusion: our data shows that ICs of Alzheimer patients have cognitive deficits on the letter fluency test. This test primarily measures executive functioning and it has been found to be sensitive to mild cognitive impairment in recent research. Our data tentatively suggests that ICs who care for Alzheimer patients also show signs of cognitive impairment but that it is too early to tell if this is cause for concern or not